A Phase II/III Trial of Neoadjuvant FOLFOX With Selective Use of Combined Modality Chemoradiation Versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection With Total Mesorectal Excision (PROSPECT)
Phase: PHASE2
Conditions: Colorectal Cancer
Sponsor: Alliance for Clinical Trials in Oncology

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Alliance for Clinical Trials in Oncology (‘Alliance’) 
 
N1048 (PROSPECT**): A Phase II/III Trial of Neoadjuvant FOLFOX with Selective Use of 
Combined Modality Chemoradiation versus Preoperative Combined Modality Chemoradiation for 
Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total 
Mesorectal Excision 
** Pre-operative Radiation Or Selective Preoperative radiation and Evaluation before Chemotherapy and TME 
ClinicalTrials.gov Identifier: NCT01515787 
 
For any communications regarding this protocol, please contact the Protocol Coordinator on page 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
*Investigator having NCI responsibility for this protocol 
 
Drug Availability  
Commercial Agents:  Oxaliplatin, Leucovorin, Capecitabine, 5-Fluorouracil 
 
 
 
Participating Organizations 
Alliance / Alliance for Clinical Trials in Oncology,  
ECOG-ACRIN / ECOG-ACRIN Medical Research Foundation, Inc.,  
NRG / NRG Oncology foundation, Inc., SWOG / SWOG,  
CCTG / Canadian Cancer Trials Group 
 
 
 
  
 

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NCTN Group Champions: 
 
 
ECOG-ACRIN 
 
 
  
 
 
 
 
 
SWOG 
 
 
  
 
 
 
 
 
NRG 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
CCTG 
 
 
  
 
 
 
 
 
  
 
 
 
 
Study Statisticians: 
 
 
 
Clinical and Correlative Studies  
 
 
  
 
 
 
 
 
QOL and PRO-CTCAE Studies 
 
 
  
 
 
 
  
 
Alliance Statistics and Data Center 
 
 
  
  
 
    
 
 
 
 
 
 
                          
 
Study Co-Chairs: 
 
 
 
 
Medical Oncology 
  
  
Patient Reported Outcomes 
 
 
  
  
 
 
   
 
 
 
  
 
 
  
  
 
 
   
  
 
 
 
  
  
 
 
 
  
  
 
 
 
 
Correlative Sciences 
  
  
Quality of Life 
 
 
  
  
 
 
       
 
 
 
  
  
 
 
  
  
 
 
   
  
 
 
 
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 

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Surgery 
  
  
Pathology 
 
 
  
  
 
 
   
 
 
   
 
  
 
 
  
  
 
 
   
  
 
 
 
  
  
 
 
 
  
  
 
 
 
 
Radiology 
  
  
Radiation Oncology 
 
 
  
  
 
 
   
 
 
 
  
  
 
 
  
  
 
 
   
  
 
 
 
  
  
 
 
 
  
  
 
 
Alliance GI Committee Leadership: 
 
 
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
   
  
 
 
 
  
  
 
 
 
  
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
For regulatory requirements:  For patient enrollments:  
For study data submission:  
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 
 
 
  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
 
 to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
 for regulatory 
assistance. 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
 
Contact the CTSU Help Desk 
with any OPEN related 
questions by phone or email : 
 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the protocol 
for further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (
). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, pages 2, 3, 
& 5. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
 All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 

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Protocol Resources 
Questions: 
Contact Name: 
Test schedule, treatment 
delays/interruptions/adjustments, dose 
modifications, adverse events, forms 
completion and submission 
 
 
 
 
Drug administration, infusion pumps, 
nursing guidelines 
 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
 
 
 
Radiation quality control  
 
 
 
 
 
 
 
 
Radiology quality control 
 
 
 
 
 
 
 
 
Surgical Quality Assurance 
 
 
 
 
 
 
 
 
 
Send Surgical Quality Assurance materials to: 
                          
 
Paraffin-embedded tissue and 
non-paraffin biospecimens 
 
 
 
 
 
 
Biospecimen Management System 
(BioMS) 
 
 
 
Adverse Events (CTEP-AERS, 
MedWatch, Non-AER, AML/MDS) 
 
 
 
 
  
Note: There will be no waivers of eligibility per NCI. 

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Table of Contents 
1.0 
BACKGROUND 
10 
1.1 
Potential Role for Neoadjuvant FOLFOX 
10 
1.2 
Proposed Study Overview 
12 
1.3 
Clinical Correlative Studies (QOL and PRO-CTCAE) 
13 
1.4 
Biological Correlative Studies 
13 
2.0 
GOALS 
13 
2.1 
Treatment 
13 
2.2 
Clinical Correlative Studies 
14 
2.3 
Biological Correlative Studies 
15 
3.0 
PATIENT ELIGIBILITY 
16 
3.1 
Registration – Inclusion Criteria 
16 
3.2 
Registration – Exclusion Criteria 
17 
4.0 
SCHEDULE OF TESTS 
18 
4.1 
Pre-operative Testing Schedule: Group 1 (FOLFOX and Selective 5FUCMT) 
18 
4.2 
Pre-operative Testing Schedule: Group 2 (5FUCMT) 
20 
4.3 
Post-operative Testing Schedule: Groups 1 and 2 
22 
4.4 
Patient-Reported Outcomes 
23 
4.5 
Quality of Life Assessments 
26 
5.0 
STRATIFICATION AND GROUPING FACTORS 
27 
5.1 
Stratification Factors (Used for Randomization to Group 1 or Group 2) 
27 
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES 
27 
6.1 
CTEP Registration Procedures 
27 
6.2 
CTSU Registration Procedures 
28 
6.3 
Patient Enrollment and Randomization 
31 
6.4 
Treatment Assignment 
32 
6.5 
Correlative Studies 
32 
6.6 
Treatment Prior to Registration 
33 
6.7 
Prior to Treatment 
33 
7.0 
PROTOCOL TREATMENT 
33 
7.1 
Group 1 Pre-Operative Treatment Schedule (FOLFOX) 
33 
7.2 
Group 2 Pre-operative Treatment Schedule (5FUCMT) and Group 1 Pre-Op Treatment 
Schedule if Patient Receives Pre-operative 5FUCMT 
35 
7.3 
Radiation Therapy 
35 
7.4 
Radiologic Imaging 
42 
7.5 
Post-operative Therapy 
46 
8.0 
SUGGESTED DOSAGE MODIFICATION BASED ON ADVERSE EVENTS 
46 
8.1 
Radiation Therapy 
46 
8.2 
FOLFOX Chemotherapy and 5-FU Combined Modality 
47 
8.3 
Suggested FOLFOX Dose Modifications Based on Interval Adverse Events 
49 
8.4 
Suggested 5FUCMT Dose Modifications (with either IV 5-FU or capecitabine) 
50 
8.5 
Oxaliplatin-induced Pharyngolaryngeal Dysesthesia 
56 
8.6 
Dose Modifications Based on Body Weight 
57 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE 
59 
9.1 
Supportive Care 
59 
9.2 
Antiemetics 
59 

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9.3 
Blood Products 
59 
9.4 
Neulasta and Neupogen 
59 
9.5 
Diarrhea 
60 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING 
60 
10.1 
Adverse Event Characteristics 
60 
10.2 
Expected vs. Unexpected 
60 
10.3 
Assessment of Attribution 
61 
10.4 
Expedited Reporting Requirements 
63 
10.5 
Other Required Expedited Reporting 
65 
11.0 
TREATMENT EVALUATION 
66 
11.1 
Radiological Tumor Evaluation 
67 
11.2 
Clinical Tumor Evaluation 
71 
11.3 
Pathological Tumor Response 
72 
11.4 
Post-operative Bowel Surveillance 
78 
11.5 
Treatment Evaluation 
78 
12.0 
DESCRIPTIVE FACTORS AT BASELINE 
79 
13.0 
TREATMENT/FOLLOW–UP DECISION 
80 
14.0 
BIOSPECIMENS 
81 
14.1 
Biospecimens Acquisition Schedule 
81 
14.2 
Specimen Registration and Tracking 
81 
14.3 
Biospecimens Submission Schedule 
82 
14.4 
Blood Sample Submission 
83 
14.5 
Paraffin Block Submission 
83 
14.6 
Study Methodology and Storage Information 
83 
14.7 
Return of Genetic Testing Research Results 
84 
15.0 
DRUG INFORMATION 
84 
15.1 
Oxaliplatin (Eloxatin®, OXAL) 
84 
15.2 
Leucovorin Calcium (CF) 
93 
15.3 
Fluorouracil (Adrucil, Efudex, [5FU]) 
94 
15.4 
Capecitabine (Xeloda®) 
96 
16.0 
STATISTICAL CONSIDERATIONS AND METHODOLOGY 
99 
16.1 
Study Overview 
99 
16.2 
Sample Size, Accrual Time, and Study Duration 
99 
16.3 
Statistical Design for Primary Endpoints 
99 
16.4 
Supplementary Analysis Plans 
108 
16.5 
Adverse Event Stopping Rule 
109 
16.6 
Accrual Monitoring Stopping Rule 
110 
16.7 
Study Monitoring 
110 
16.8 
Women and Minorities Distributions 
110 
17.0 
RECORDS AND DATA COLLECTION PROCEDURES 
111 
17.1 
Data Submission Using RAVE 
111 
17.2 
Submission Timetable 
112 
18.0 
BUDGET 
112 
18.1 
Costs Charged to Patient 
112 
18.2 
Reimbursement 
113 
18.3 
MRI Reimbursement 
113 

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18.4 
Correlative Science Funding 
113 
19.0 
REFERENCES 
114 
APPENDIX I: PATIENT INFORMED CONSENT VISUAL PRESENTATION 
117 
APPENDIX II: PATIENT FAQ- PROSPECT RECTAL CANCER STUDY 
128 
APPENDIX III: OPTIONAL PATIENT CAPECITABINE MEDICATION DIARY 
112 
APPENDIX IV: SUGGESTED DOSE MODIFICATION OF CAPECITABINE 
114 
APPENDIX V: PATIENT-REPORTED OUTCOMES 
115 
APPENDIX VI: FUNCTIONAL OUTCOMES AND QUALITY OF LIFE 
121 
APPENDIX VII: SURGICAL CONSIDERATIONS AND QUALITY ASSURANCE 
146 
APPENDIX VIII: SUGGESTED MRI TECHNICAL AND QUALITY REQUIREMENTS 
151 
APPENDIX IX: SCHEDULE AND PROCEDURE FOR IMAGING SUBMISSION 
153 
APPENDIX X: GENOMIC CHARACTERIZATION 
155 
APPENDIX XI: INDICATORS OF IMMUNOLOGIC ACTIVATION 
161 
APPENDIX XII: ASSESSMENT OF GERMLINE VARIATION 
164 
APPENDIX XIII: AJCC 7TH EDITION RECTUM CANCER STAGING 
173 
APPENDIX XIV: INDEX OF ACRONYMS 
175 
APPENDIX XV: SITE PREPARATION CHECKLIST 
178 
APPENDIX XVI: IMAGE INTERPRETATION 
179 
APPENDIX XVII: SWISS SPECIFIC APPENDIX 
180 
 

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Schema 
 
 
 
 
 
 
 
 
 
Estimated Tumor Regression           No progression AND estimated tumor 
< 20% OR any progression3 
      
regression ≥ 20%3 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Cycle length = 14 days; 2 5FUCMT duration = 5.5 weeks; 5FUCMT = 5-fluorouracil OR capecitabine + radiation therapy.; 3  This is a clinical 
estimation as to whether there has been at least a 20% decrease in the tumor in response to neoadjuvant FOLFOX treatment made on the basis of 
both tumor imaging and clinical tumor response based on proctoscopy (see Section 11); 4 No patient will receive 5FUCMT more than once;.5 If 
there is progressive disease at the restaging of primary tumor after 6 cycles of FOLFOX, Group 1 patients proceed to 5FUCMT instead of event 
monitoring. If the patient refuses to receive 5FUCMT but will still undergo TME, the patient should be followed per protocol; 6May be initiated 
any time after restaging scan; 7 All operative and pathology reports must be submitted (see Section 11.3). 
Generic name:  Oxaliplatin 
Brand name(s):  Eloxatin® 
Abbreviation:  OXAL  
Availability:  Commercial   
Generic name:  Leucovorin 
Brand name(s):   
Abbreviation:  CF 
Availability:  Commercial  
Generic name: Capecitabine 
Brand name(s):  Xeloda® 
Abbreviation: CAPCIT 
Availability:  Commercial  
Generic name:   Fluorouracil 
Brand name(s):  Adrucil® 
Abbreviation:  5-FU 
Availability:  Commercial 
Progressive Disease 5 at any time 
 
 
 
  
Unacceptable adverse events 
 
 
  →   Event Monitoring 
Patient withdraws from study treatment 
 
 
Low Anterior Resection with Total Mesorectal Excision 
(LAR with TME)7 
Margins of surgical resection 
Restaging of primary tumor 
Group 1 
FOLFOX x 6 cycles1 
Group 2 
5FUCMT2 
Randomization 
5FUCMT6 
Observation with follow-up evaluations 
(Up to 5 years from randomization) 
Event Monitoring for recurrence/death 
(Up to 8 years from randomization) 
Chemo Suggested (regimen choice optional): 
Negative surgical margins (R0): FOLFOX x 6 cycles1  
Positive Surgical Margins (R1, R2): 5FUCMT2,4 & FOLFOX x 4 cycles1 
If patient already received 5FUCMT: Treatment is at physician 
discretion 
Chemo Suggested 
 (regimen choice 
optional): 
FOLFOX x 8 cycles1 

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1.0 
BACKGROUND 
1.1 
Potential Role for Neoadjuvant FOLFOX 
Potential Role for Neoadjuvant FOLFOX for Locally Advanced Rectal Cancer Patients 
Undergoing Low Anterior Resection with Total Mesorectal Excision 
The American Cancer Society estimates that about 40,000 new cases of rectal cancer are 
diagnosed in the US each year, and these are expected to cause about 22,000 deaths (American 
Cancer Society, 2009). Currently the standard of care for all Stage II (T3/T4N0) and Stage III 
(TanyN1/N2) rectal cancer is tri-modality therapy including chemotherapy, radiation, and 
surgery (NIH consensus conference, 1990). Numerous studies have revealed that pelvic 
radiation reduces local recurrence while systemic chemotherapy improves overall survival 
(Gastrointestinal Tumor Study Group, 1985; Fisher et al., 1988; Krook et al., 1991; Tepper et 
al., 1997; Wolmark et al., 1993). The purpose of radiotherapy is to decrease local recurrence 
rates and secondarily, to increase the potential for rectal sphincter preservation. Local recurrence 
is a major cause of morbidity and has a severe adverse impact on patients’ quality of life. For 
that reason, utilization of radiotherapy for rectal cancer treatment was an important advance 
when it was introduced in the 1980s. However, radiation also has the potential for adverse effects 
on patient-centered outcomes such as sphincter and bowel function, loss of fertility in young 
patients, as well as diminished bone marrow reserve which is disadvantageous in the event of 
distant metastatic disease.  
In a landmark German study, Sauer et al. compared preoperative with postoperative 
chemoradiation (50.4 Gy plus continuous infusion of fluorouracil) in 823 patients with resectable 
rectal cancer (Sauer et al., 2004). The local recurrence rate after five years was lower in the 
preoperative treatment group (6% v 13%; p = 0.006) while the frequency of distant metastases 
and survival showed no significant difference. The estimated 2 year disease free survival (DFS) 
from this trial was 82%.  Preoperative treatment was associated with an impressive decrease in 
toxicity (grade 3 or 4 toxic effects 27% v 40% postoperative). Validation for the role of 
neoadjuvant 5-FU based chemoradiation therapy vs. postoperative chemoradiation reported by 
Sauer et al was recently confirmed by the National Surgical Breast and Bowel Project (NSABP 
R-03). After a median follow up of 8.4 years, in a population at somewhat higher risk than will 
be enrolled onto our proposed study, the 2-yr incidence LRR rate was 8% and the 2-year DFS 
rate was 78% (Roh et al., 2009). For these reasons, pre-operative pelvic chemoradiation is now 
considered the standard of care for locally advanced rectal cancer. The contemporary US 
treatment paradigm consists of neoadjuvant 5FUCMT, followed by surgery and additional 8-10 
cycles of adjuvant 5-FU based chemotherapy.  
The proposed study does not use new agents, but rather sequences existing well established 
strategies in a different way to capitalize upon the progress achieved in each treatment modality 
since 1990 when the current treatment paradigm was established. It is therefore essential that 
we do not compromise the currently favorable outcomes that are typically achieved using tri-
modality therapy for all patients. The rationale for this concept stems from a confluence of 
factors related to contemporary management of locally advanced rectal cancer:  
Neoadjuvant radiation results in overtreatment of some patients.  
Although preoperative chemoradiation reduces toxicity compared to the previous standard of 
post-operative treatment, chemoradiation remains associated with significant short-term and 
long-term side-effects. This has resulted in considerable debate whether all Stage II and III rectal 
cancer patients require such an intensive treatment approach (Carne and Nelson, 2004). This 
dispute has been fueled by reports indicating significantly reduced local recurrence rates when 
the surgical technique is performed by mesorectal excision (Carlsen et al, 1998; Enker et al, 

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1999; MacFarlane et al., 1993). Some centers have therefore recommended that radiation can 
be eliminated in patients with disease limited to the perirectal tissue (i.e., T3N0/T3N1 patients) 
and without extensive nodal or contiguous organ involvement (Carne et al., 2004; Enker et al., 
1999; Merchant et al., 1999). However, radiation remains the standard of care and is 
recommended by most clinical practice guidelines. Moreover, a randomized trial led by the 
Dutch demonstrated that even when TME is performed, pelvic radiation decreases the rate of 
local recurrence. 
Pelvic radiation is associated with both short and long-term morbidity.  
Combined modality therapy is associated with considerable short term toxicity, which is seen in 
up to 50% of patients (Matzel et al., 2003). Treatment is time intensive for patients in that it 
requires 28 daily visits to receive treatment as well as additional visits to receive either oral or 
intravenous 5-fluorouracil. Most importantly, the long-term effects of pelvic radiation can be 
substantial, including fibrosis and autonomic nerve injury which may be manifested by 
increased fecal incontinence, urgency and frequency, and higher rates of bladder and sexual 
dysfunction when compared to outcomes for patients that do not receive pelvic radiation (Sauer 
et al., 2004.; Paty et al., 1994; Shibata et al., 2004; Glimelius et al., 2003.; Minsky et al., 1995; 
Temple et al., 2003). Following pelvic radiation for rectal cancer, the uterus is not competent to 
sustain pregnancy. In addition, because the pelvis is an active site of hematopoiesis, patients 
who undergo pelvic radiation may have diminished ability to withstand subsequent 
myelosuppressive therapy, a consideration that is more relevant in an era where a greater number 
of chemotherapeutic options are available for metastatic disease. Pelvic fracture after modest 
trauma such as an uncomplicated fall also occurs more commonly among patients whose pelvis 
has been irradiated.  
Patients with rectal cancer succumb to metastatic disease and neoadjuvant radiation delays 
initiation of systemic therapy. 
Current rectal cancer treatment paradigms do not deliver systemic chemotherapy for 14-18 
weeks from initiation of neoadjuvant chemoradiotherapy and this delay is potentially 
disadvantageous because it allows a window for metastatic dissemination of disease. The 
standard treatment timeline is as follows: 5.5 weeks of combined modality treatment; 4-6 week 
recovery; surgical resection; 4-6 week postoperative recovery; and then initiation of adjuvant 
therapy. As a result, no systemic therapy is delivered to treat micrometastases for over 3 months 
from treatment onset. This delay may allow a window of opportunity for growth of small volume 
disease outside the pelvis. On this basis, there is rationale for moving systemic treatment more 
proximally into the treatment regimen. 
Both systemic therapy and surgical technique have substantially improved in the last decade. 
Pelvic radiation treats residual disease left behind when either the mesorectal excision was 
incomplete or tumor was invading the mesorectal envelope. Local control is critically important 
because of the immense morbidity associated with pelvic recurrence. Traditional surgery, now 
outmoded, involved blunt digital dissection of the mesorectum which often resulted in tearing 
the mesorectal fascia and resulting in incomplete resection of the nodal basin around the rectum 
and a positive radial margin. In this setting, postoperative chemoradiation reduced local 
recurrence by sterilizing tumor deposits left in the pelvis from inadequate surgery. The 
introduction and acceptance of total mesorectal excision (TME) and the subsequent 
standardization of sharp dissection of the lymph node bearing tissue, resulted in low radial 
positive margin rates and therefore very low recurrence rates. This has spurred a debate about 
whether radiotherapy remains necessary in the patient who has undergone an appropriate and 
successful TME. 

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This question was addressed in the TME trial set up by the Dutch Colorectal Cancer Group that 
randomized between standardized and quality-controlled TME surgery alone and TME surgery 
preceded by short-term pre-operative radiotherapy. This study was reported in the New England 
Journal in 2001-- the Dutch TME trial (Kapiteijn et al., 2001). This study helped to clarify the 
contribution of neoadjuvant radiation to rectal cancer therapy and underscored the importance 
of surgical technique. This study demonstrated that neoadjuvant radiation does not influence 
long-term survival. Second, it confirmed that neoadjuvant radiation improves local control even 
when TME is performed. A third important message emerged indirectly from the Dutch study. 
The rate of local recurrence for patients treated in the control group without radiotherapy was 
substantially lower than the 25% local recurrence noted in the historical rectal cancer trials. The 
Dutch study thus provides us with indirect evidence that improved surgical technique (TME) 
itself has contributed to decreased local recurrence while noting that pelvic radiation still 
contributes to further decrease in pelvic recurrence. There have also been significant advances 
in systemic chemotherapy for patients with colorectal cancer that have emerged since 2002 
(Goldberg et al., 2004; Grothey et al., 2004; Saltz et al., 2000). Response rates for patients with 
primary and metastatic colorectal cancer treated with modern chemotherapy regimens such as 
5-FU, leucovorin, oxaliplatin (FOLFOX) have routinely exceeded 50% and are frequently as 
high as 60-70% (Goldberg et al.,2004; Grothey et al., 2004). In the context of improved surgical 
technique, improved chemotherapy and better radiologic staging, many have questioned 
whether rectal cancer treatment can be streamlined and/or simplified. Preliminary Work 
Supports the Selective Strategy 
This protocol builds on pilot work conducted by study leaders at Memorial Sloan-Kettering 
Cancer Center. In a single institution trial (MSKCC07-021) that started in March 2007, 32 
patients, of whom 22 had clinical node-positive disease, were treated according to the proposed 
schema with the exception that the regimen also included bevacizumab for the first 4 cycles of 
therapy. Two patients did not complete neoadjuvant FOLFOX secondary to cardiac 
complications likely attributable to and/or bevacizumab. Of 30 who did complete neoadjuvant 
treatment, all had R0 TME rectal resections. Eight of 30 have had pathologic CRs. There was 1 
post-operative death and there have been 3 patients with recurrence. All 3 recurrent patients 
have had pulmonary metastases without local recurrence. The results of this pilot trial were 
published in the Journal of Clinical Oncology in January 2014 (Schrag et al., 2014). We now 
seek to extend the strategy of selective use of combined modality therapy with 5FU (5FUCMT) 
and tailoring treatment based on tolerance of and response to induction FOLFOX and to 
establish its efficacy in the multi-center setting. In the pilot trial, bevacizumab was included for 
the first 4 cycles of therapy. However, based on more recent data from other studies indicating 
that bevacizumab does not increase response rate, and does not improve survival in the adjuvant 
setting (C-08 trial), it is not included in the proposed neoadjuvant regimen. 
1.2 
Proposed Study Overview 
The study investigators hypothesize that neoadjuvant FOLFOX can safely and efficaciously be 
delivered as an alternative 5FUCMT without compromising either the ability to perform a pelvic 
R0 resection, the local control rate or overall disease free survival for appropriately selected 
locally advanced rectal cancer patients who are treated with contemporary surgical technique 
including TME and contemporary FOLFOX chemotherapy. We further hypothesize that early 
administration of FOLFOX will provide optimal systemic therapy for any clinically occult 
micrometastases which may be present, and that pre-operative elimination of radiation to select 
patients will allow more complete delivery of post-operative FOLFOX. We anticipate that this 
strategy will minimize toxicity and optimize outcomes for appropriately selected locally 
advanced rectal cancer patients. 

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Addendum 10 
Specifically, this phase II/III trial seeks to determine whether 6 cycles of neoadjuvant FOLFOX 
followed by comprehensive restaging with selective use of 5FUCMT followed by total 
mesorectal excision (TME) achieves favorable outcomes for patients with locally advanced 
(clinical T3N0, T3N1, T2N1) rectal cancer. The current standard of care for locally advanced 
rectal cancer involves use of 5FUCMT for all patients. In the intervention group, 5FUCMT is 
used selectively and is administered to the subset of patients randomized to the intervention 
group who are either:1) unable to complete 6 cycles of FOLFOX; 2) have evidence of 
progression after 6 cycles of FOLFOX; 3) fail to undergo an pelvic R0 resection or 4) withdraw 
consent from the study.  
Eligible study subjects include adults who are candidates for curative intent sphincter-sparing 
surgery and lack high risk features such as tumor encroaching upon the mesorectal fascia or 
distal tumors.  
This study has the potential to dramatically influence our approach to rectal cancer treatment. 
Recognizing the small number of patients who participated in the pilot phase II study and their 
location at a single specialty center, a phase II component is regarded as essential to minimize 
risks associated with the intervention group that might only become manifest in the multi-center 
context. Moreover, the phase II component is randomized, which will permit meaningful 
comparisons and minimize the potential for selection bias. The design is highly efficient in that 
it proceeds from phase II directly to phase III. If the intervention compromises favorable 
outcomes, it will not proceed to phase III evaluation. The study strikes a balanced position 
between competing viewpoints and priorities in order to move the field forward and represents 
cooperation by a large number of investigators.  
1.3 
Clinical Correlative Studies (QOL and PRO-CTCAE) 
Clinical Correlative Studies (QOL and PRO-CTCAE) – for background, aims, and methodology 
see Appendices VII and VI; see Section 4.0 for test schedule and Section 17.0 for data 
submission. 
1.4 
Biological Correlative Studies  
Biological Correlative Studies (Genomic characterizations, Immunologic studies, and 
Pharmacogenomics) – See Appendices XII-XIV for background, aims, and methodology and 
see Section 14.0 for specimen logistics.  
2.0 
GOALS 
2.1 
Treatment 
2.1.1 Primary Objectives 
2.1.1.1 
Phase II component: To assure that neoadjuvant FOLFOX followed by selective 
use of 5FUCMT group (Group 1) maintains the current high rate of pelvic R0 
resection and is consistent with non-inferiority for time to local recurrence (TLR).  
2.1.1.2 
Phase III component: To compare neoadjuvant FOLFOX followed by selective 
use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the 
primary endpoint of Disease-free Survival (DFS). 

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2.1.2 Secondary Objectives 
2.1.2.1 
To compare time to local recurrence between the two treatment groups. 
2.1.2.2 
To compare the proportion of patients who achieve a pathologic complete response 
(pCR) at the time of surgical resection between the two treatment groups. 
2.1.2.3 
To compare overall survival between the two treatment groups. 
2.1.2.4 
To evaluate and compare the adverse event profile and surgery complications 
between the two treatment groups. 
2.1.2.5 
To estimate the proportion of patients in the selective group (Group 1) who 
receive: 1) pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or 
post-operative 5FUCMT. 
2.1.2.6 
To compare the neoadjuvant response scores (NAR) between the two treatment 
groups. 
2.2 
Clinical Correlative Studies 
2.2.1 Quality of Life (QOL) 
2.2.1.1 
Primary: To compare bowel function in patients randomized to the neoadjuvant 
FOLFOX followed by selective use of 5FUCMT vs. standard 5FUCMT at 
approximately 1 and 2 years post-operatively.  
2.2.1.2 
Secondary:  
2.2.1.2.1 To compare sexual function separately within men and within women between 
groups at approximately 1 and 2 years post-operatively. 
2.2.1.2.2 To compare bladder function between groups at  approximately 1 and 2 years 
post-operatively. 
2.2.1.2.3 To compare health-related quality of life between groups at 1 and 2 years post-
operatively. 
2.2.1.3 
Exploratory: To assess the correlation between bladder, bowel, and sexual function 
and quality of life; to investigate factors associated with bladder, bowel, and sexual 
dysfunction; to compare bladder and bowel function over time between genders; 
and to perform subgroup analyses based on other sociodemographic factors. 
2.2.2 Patient-Reported Outcomes Version of the Common Terminology Criteria (PRO-
CTCAE) 
2.2.2.1 
Primary: 
2.2.2.1.1 To evaluate the feasibility of implementing the PRO-CTCAE in an NCI-sponsored 
treatment trial. 
2.2.2.1.2 To evaluate the feasibility of implementing the PRO-CTCAE at Alliance sites. 
2.2.2.1.3 To evaluate the feasibility of patients self-reporting symptoms during treatment by 
using the PRO-CTCAE.  
2.2.2.2 
Secondary: 
2.2.2.2.1 To evaluate and compare patients’ self-reported symptom burden during treatment 
between groups using the PRO-CTCAE system 

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Addendum 10 
2.2.2.3 
Exploratory: 
2.2.2.3.1 To evaluate whether exposure to patient-reported symptoms influences CTCAE 
symptom reporting by research staff 
2.3 
Biological Correlative Studies 
2.3.1 Genomic Characterization of Rectal Tumors using Molecular Inversion Probe (MIP) 
Arrays and MALDI-TOF Mass Spectrometry. 
2.3.1.1 
Primary: To prospectively use MIP array technology and mass spectrometry-based 
genotyping to identify copy number aberrations and somatic mutations that 
mediate tumor formation using formalin-fixed, paraffin-embedded (FFPE) tumor 
tissue from patients participating in the current study.  
2.3.1.2 
Secondary: To correlate the MIP array copy number and mutational data from 
patients with locally advanced rectal cancer with clinical outcome in each 
treatment cohort. The clinical outcomes include pathologic complete response, 
time to recurrence, time to pelvic recurrence, and overall survival.  
2.3.2 Immunologic Studies – Indicators of Immunologic Activation in Locally Advanced 
Rectal Cancer. 
2.3.2.1 
To identify immune markers for response to neoadjuvant chemotherapy or 
chemoradiation using very well established, validated immunologic assays.  
2.3.2.2 
To investigate the ability of neoadjuvant FOLFOX or chemoradiation to augment 
anti-tumor immunity against rectal cancer. 
2.3.2.3 
To identify novel immune targets in rectal cancer. 
2.3.3 Pharmacogenomics: Assessment of Germline Variation as a Predictor of Response 
and Toxicity to Platinum-based Chemotherapy and to Radiation Therapy in Patients 
with Rectal Cancer.  
2.3.3.1 
Primary:  
2.3.3.1.1 To determine whether germline genetic variants in candidate genes of interest are 
associated with response and/or toxicity to platinum and 5FU-based 
chemotherapy.  
2.3.3.2 
Secondary: 
2.3.3.2.1 To determine whether germline genetic variants in candidate genes of interest are 
associated with response and/or toxicity to radiation therapy. 
2.3.3.2.2 To assess whether genetic risk variants identified in genome-wide association 
studies of colorectal cancer susceptibility are associated with rectal cancer clinical 
outcome and response to therapy.  
 
 

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Addendum 10 
3.0 
PATIENT ELIGIBILITY 
For SAKK sites, please refer to the Swiss Specific Appendix for instructions regarding patient 
screening, enrollment and identification. 
3.1 
Registration – Inclusion Criteria 
3.1.1 Age ≥ 18 years at diagnosis. 
3.1.2 Diagnosis of rectal adenocarcinoma.  
3.1.3 Radiologically measurable or clinically evaluable disease as defined in Section 11.0. 
3.1.4 ECOG Performance Status (PS): 0, 1 or 2. 
3.1.5 For this patient, the standard treatment recommendation in the absence of a clinical trial 
would be combined modality neoadjuvant chemoradiation followed by curative intent 
surgical resection. 
3.1.6 Candidate for sphincter-sparing surgical resection prior to initiation of neoadjuvant therapy 
according to the primary surgeon. 
3.1.7 Clinical Stage: T2N1, T3N0, T3N1.  
• 
N2 disease is to be estimated as four or more lymph nodes that are 10 mm. 
• 
Clinical staging should be estimated based on the combination of the following 
assessments: physical exam by the primary surgeon, CT or PET/CT scan of the 
chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS). If a pelvic MRI 
is performed, it is acceptable to perform CT of the chest/abdomen, omitting CT imaging 
of the pelvis. 
3.1.8a The following laboratory values obtained  28 days prior to registration. 
• 
Absolute neutrophil count (ANC) ≥ 1500/mm3 
• 
Platelet count  100,000/mm3 
• 
Hemoglobin > 8.0 g/dL 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
• 
SGOT (AST)  3 x ULN 
• 
SGPT (ALT)  3 x ULN 
• 
Creatinine 1.5 x ULN 
3.1.8b Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing 
potential only. 
3.1.8c Patient of child-bearing potential is willing to employ adequate contraception. Appropriate 
methods of birth control include abstinence, oral contraceptives, implantable hormonal 
contraceptives, or double barrier method (diaphragm plus condom).  
3.1.8d Provide informed written consent. 
3.1.8e Willing to return to enrolling medical site for all study assessments. 
 
 

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Addendum 10 
3.2 
Registration – Exclusion Criteria  
3.2.1 Clinical T4 tumors. 
3.2.2 Primary surgeon indicates need for abdominoperineal (APR) at baseline. 
3.2.3 Evidence that the tumor is adherent to or invading the mesorectal fascia on imaging studies 
such that the surgeon would not be able to perform an R0 resection (one with negative 
margins). Please reference the end of Section 7.4.2 for details. 
3.2.4 Tumor is causing symptomatic bowel obstruction (patients who have had a temporary 
diverting ostomy are eligible). 
3.2.5 Chemotherapy within 5 years prior to registration. (Hormonal therapy is allowable if the 
disease free interval is ≥ 5 years.) 
3.2.6 Any prior pelvic radiation. 
3.2.7 Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic polyps, 
non-melanoma skin cancer, ductal carcinoma in situ, bladder carcinoma in situ, or 
carcinoma-in-situ of the cervix.  
3.2.8 Any of the following because this study involves an agent that has known genotoxic, 
mutagenic and teratogenic effects. 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ adequate 
contraception  
3.2.9 Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician 
obtaining informed consent, would make the patient inappropriate for entry into this study 
or interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens. 

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Addendum 10 
4.0 
SCHEDULE OF TESTS 
4.1 
Pre-operative Testing Schedule: Group 1 (FOLFOX and Selective 5FUCMT) 
 
Active Monitoring Phase 
 
 
 
 
Tests and procedures 
≤ 28 
days 
prior to 
registra
tion 
≤ 60 days 
prior to 
registration 
OR after 
registration 
but before 
start of 
treatment 
At baseline  
(before start  
of 
treatment) 
Prior to 
each new 
cycle of 
FOLFOX 
(± 3 days) 
Restaging ≤ 
28 days after 
completion of 
FOLFOX (in 
other words, 
≤ 28 days 
after cycle 6 
day 14 of 
FOLFOX 
Weekly 
(W) or 
biweekly 
(every 2 
weeks; B) 
during 
5FUCMT 
Surgery12 
History and physical exam 
X 
 
 
X 
X 
X (B) 
 
Pulse, blood pressure and 
temperature 
X 
 
 
X 
X 
X (W) 
 
ECOG performance status 
(PS) 
X 
 
 
X 
X 
X (B) 
 
Weight 
 
 
X 
X 
X 
X (B) 
 
Height 
 
 
X 
 
 
 
 
Adverse event assessment1 
 
 
X 
X 
X 
X (B13) 
 
Hematology2 
X 
 
 
X 
 
X (W) 
 
Chemistry3 
X 
 
 
 
 
 
 
Carcinoembryonic antigen 
(CEA)  
 
X 
 
 
X 
 
 
Research blood sample  
(see Section 14.0)4 R 
 
 
X 
 
 
 
X 
Pregnancy test 5 
X 
 
 
 
 
 
 
Rectal exam and 
proctoscopy 
 
X6 
 
 
X 
 
 
Rectal tumor tissue biopsy 
(see Section 14.0) R  
 
X7 
 
 
 
 
X 
Pathologic confirmation of 
rectal adenocarcinoma 
 
X 
 
 
 
 
X 
MRI or ERUS of the 
pelvis (MRI preferred)  
X8 
 
 
 
X8 
 
 
CT of the Chest 
(contrast optional) 
X9 
 
 
 
 
 
 
CT of abdomen 
with contrast 
X9 
 
 
 
 
 
 
CT of this pelvis with 
contrast (Optional if pelvic 
MRI performed) 
X9 
 
 
 
X9 
 
 
Completion of PRO-
CTCAE  
by patient10 
(see Appendix V) 
 
 
X 
X 
 
X (W) 
 
QOL Assessment11 
(see Appendix VI) 
 
 
X14 
 
X14 
 
 
Photographs evaluating 
TME specimen for 
Surgical QA (see 
Appendix VII) 
 
 
 
 
 
 
X 
Shaded columns indicate Group 1 patients who were assigned to 5FUCMT based on restaging of primary tumor or inability to 
tolerate FOLFOX. 
NOTE: Time points specified in the footnotes below override time points listed above for the specific test or procedure. 

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Addendum 10 
Table 4.1 Footnotes  
1. 
Patients must have assessment at the time of progressive disease, study withdrawal, or removal.  
2. 
Hematology includes hemoglobin, platelets and absolute neutrophil count (ANC).  
3. 
Chemistry includes SGOT (AST), SGPT (ALT), total bilirubin, creatinine. Additional chemistries (e.g., 
Mag, Phos, LDH) are not required and should be performed in accordance with clinical necessity. Blood 
work does not have to be performed at the trial site; it can be performed at other locations. 
4. 
Mandatory research blood draws will be collected at baseline (≤ 28 days of start of FOLFOX) and ≤ 28 
days prior to surgery. 
5. 
Pregnancy test required for females of childbearing potential ≤ 7 days of registration.  
6. 
Rectal exam and proctoscopy are ideally to be performed by the primary surgeon. Proctoscopy should be 
performed ≤ 60 days prior to registration or after registration but before the start of treatment. Ideally, the 
surgeon should perform pre and post induction treatment proctoscopies. A gastroenterologist may perform 
proctoscopy in lieu of the surgeon, but then must also perform the follow-up exam. Proctoscopy may be 
accomplished using rigid proctoscopy or as part of a flexible sigmoidoscopy or colonoscopy.  
7. 
If a rectal tumor tissue biopsy was performed at an outside facility and can be obtained for confirmation 
of the diagnosis and for submission of the research specimen, it is adequate, and a repeat biopsy is not 
necessary. If a biopsy is performed at the accruing site, the following procedure is suggested: Obtain four 
large pinch biopsies in a viable section of the tumor (leading edge) and fix in formalin and embed in 
paraffin as per standard pathology practice. These specimens can be processed as routine clinical 
specimens by pathology. Samples from this biopsy must later be sent to the pathology core (at Ohio 
State) for correlative science. Rectal tumor biopsy may be performed within 60 days before registration 
OR between registration and the start of treatment. See Section 14.0 for submission instructions.  
8. 
Scan is to be performed within 60 days prior to registration. Use same imaging modality throughout the 
study. Radiology scans do not have to be performed at the trial site; they can be performed at other 
locations as long as images are available for review. (See Appendix VIII for suggested MRI Technical 
and Quality Requirements.) 
9. 
A PET/CT scan may be performed in lieu of a CT scan with contrast, but a CT scan is preferred. Scans do 
not have to be performed at the trial site; they can be performed at other locations as long as images are 
available for review. Scan is to be performed within 60 days prior to registration. Contrast is preferred but 
not required for the CT of the chest. Contrast is REQUIRED for the CT of the abdomen. If pelvic MRI is 
performed, omission of the CT scan of the pelvis is acceptable. If pelvic MRI is not performed, restaging 
pelvic CT scan is required. 
10. 
The PRO-CTCAE is required for patients enrolled at US and Canadian sites who are fluent in reading and 
speaking English or Spanish; patients will be asked by PRO-CTACE staff to use the website or Interactive 
Voice Response System by telephone to report once at baseline and, once every week during pre-op active 
treatment. Following surgery, patients will report once every six months for three years. See Appendix V. 
11. 
The QOL is required for patients who are fluent in reading and speaking English accrued at US and English-
speaking Canadian sites; sites must administer pre-printed booklets to patients (photocopies not 
acceptable). Sites may order these booklets by filling out and submitting the “CTSU Supply Request Form” 
available at 
 (Please be sure to order both male and female QOL booklets from CTSU). 
Booklet should be administered by the site research staff in clinic at the following time points: baseline, 1-
2 weeks prior to surgery and 12 months +/- 6 weeks and 24 months +/- 6 weeks after rectal resection. In 
the event that a patient is not seen in clinic at 12 and 24 months +/- 6 weeks after rectal resection, the site 
research staff will follow-up with the patient via telephone and/or mail. See Section 4.5 and Appendix VI  
12. 
Recommendation: Surgery should be performed within 3-6 weeks of the 6th dose of neoadjuvant FOLFOX 
therapy or within 5-8 weeks of the last dose of RT if 5FUCMT is required. Actual timing of surgery is at 
the discretion of the treating clinician. Tissue block submission from surgical resection is mandatory (see 
Section 14.0 for submission instructions). 
13. 
Adverse Events form to be completed at the start of week 1 of 5FUCMT, at the start of week 3 of 5FUCMT 
and at the start of week 5 of 5FUCMT. 
14. 
For patients enrolled after 02/01/2016, QOL is no longer needed as the accrual goal has been reached.  
R. 
Research funded (see Section 18.0). 
For SAKK sites, please refer to the Swiss Specific Appendix for instructions regarding Precaution. 

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Addendum 10 
4.2 
Pre-operative Testing Schedule: Group 2 (5FUCMT) 
 
 
 
 
Tests and procedures 
Active Monitoring Phase 
≤ 28 days 
prior to 
registratio
n 
≤ 60 days prior to 
registration OR after 
registration but 
before start of 
treatment 
At baseline 
(before start of 
treatment) 
Weekly 
(W) or 
biweekly 
(every 2 
weeks; B) 
during 
5FUCMT 
≤ 28 days 
after 
completion 
of 5FUCMT 
Surgery12 
History and physical exam 
X 
 
 
X (B) 
X 
 
Pulse, blood pressure and 
temperature 
X 
 
 
X (W) 
X 
 
ECOG performance status 
(PS) 
X 
 
 
X (B) 
X 
 
Weight 
 
 
X 
X (B) 
X 
 
Height 
  
 
X 
 
 
 
Adverse event assessment1 
 
 
X  
X (B13) 
X 
 
Hematology2 
X 
 
 
X (W) 
 
 
Chemistry3 
X 
 
 
 
  
 
Carcinoembryonic antigen 
(CEA)  
 
X 
 
 
X 
 
Research blood sample  
(see Section 14.0)4 R 
 
 
X 
 
 
X 
Pregnancy test 5 
X 
 
 
 
 
 
Rectal exam and 
proctoscopy 
 
X6 
 
 
 
 
Rectal tumor tissue biopsy 
(see Section 14.0) 7 R 
 
X 
 
 
 
X 
Pathologic confirmation of 
rectal adenocarcinoma 
 
X7 
 
 
 
X 
MRI or ERUS of the 
pelvis  
(MRI preferred)  
X8 
 
 
 
 
 
CT of the Chest (contrast 
optional) 
X9 
 
 
 
 
 
CT of the abdomen with 
contrast 
X9 
 
 
 
 
 
CT of the pelvis with 
contrast (optional if pelvic 
MRI performed) 
X9 
 
 
 
 
 
Completion of PRO-
CTCAE  
by patient10 
(see Appendix V) 
 
 
X 
X (W) 
 
 
QOL Assessment11 
(see Appendix VI) 
 
 
X14 
 
X14 
 
Photographs evaluating 
TME specimen for 
surgical QA (see Appendix 
VII) 
 
 
 
 
 
X 
Note: Post-operative test schedule appears in Section 4.3 
NOTE: Time points specified in the footnotes below override time points listed above for the specific test 
or procedure. 
 

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Addendum 10 
Table 4.2 Footnotes  
1. 
Patients must have assessment at the time of progressive disease, study withdrawal, or removal.  
2. 
Hematology includes hemoglobin, platelets and absolute neutrophil count (ANC).  
3. 
Chemistry includes SGOT (AST), SGPT (ALT), total bilirubin, creatinine. Additional chemistries (e.g., Mag, Phos, LDH) are 
not required and should be performed in accordance with clinical necessity. Blood work does not have to be performed at the 
trial site; it can be performed at other locations. 
4. 
Mandatory research blood draws will be collected at baseline (≤ 28 days of start of 5FUCMT) and ≤ 28 days prior to surgery. 
5. 
Pregnancy test required for females of childbearing potential ≤ 7 days of registration.  
6. 
Rectal exam and proctoscopy should be performed by the primary surgeon. Proctoscopy should be performed ≤ 60 days prior 
to registration or after registration but before the start of treatment. A gastroenterologist may perform proctoscopy in lieu of 
the surgeon. Proctoscopy may be accomplished using rigid proctoscopy or as part of a flexible sigmoidoscopy or colonoscopy.  
7. 
If a rectal tumor tissue biopsy was performed at an outside facility and can be obtained for confirmation of the diagnosis and 
for submission of the research specimen, it is adequate, and a repeat biopsy is not necessary. If a biopsy is performed at the 
accruing site, the following procedure is suggested: Obtain four large pinch biopsies in a viable section of the tumor (leading 
edge) and fix in formalin and embed in paraffin as per standard pathology practice. These specimens can be processed as 
routine clinical specimens by pathology. Samples from this biopsy must later be sent to the pathology core (At Ohio State) for 
correlative science. Rectal tumor biopsy may be performed within 60 days before registration OR between registration and 
the start of treatment. See Section 14.0 for submission instructions.  
8. 
Scan is to be performed within 60 days prior to registration. Use same imaging modality throughout the study. Radiology 
scans do not have to be performed at the trial site; they can be performed at other locations as long as images are available for 
review. (See Appendix VIII for suggested MRI Technical and Quality Requirements.) 
9. 
A PET/CT scan may be performed in lieu of a CT scan with contrast, but a CT scan is preferred. Scans do not have to be 
performed at the trial site; they can be performed at other locations as long as images are available for review. Scan is to be 
performed within 60 days prior to registration. Contrast is preferred but not required for the CT of the chest. Contrast is 
REQUIRED for the CT of the abdomen. Contrast CT of the pelvis is required for patients who have ERUS. If pelvic MRI is 
performed CT scan of the pelvis is optional. 
10. The PRO-CTCAE is required for patients enrolled at US and Canadian sites who are fluent in reading and speaking English 
or Spanish; patients will be asked by PRO-CTCAE staff to use the website or Interactive Voice Response System by telephone 
to report once at baseline and, once every week during pre-op active treatment. Following surgery, patients will report once 
every six months for three years. See Appendix V. 
11. The QOL is required for patients who are fluent in reading and speaking English accrued at US and English-speaking Canadian 
sites; sites must administer pre-printed booklets to patients (photocopies not acceptable). Sites may order these booklets by 
filling out and submitting the “CTSU Supply Request Form” available at 
 (Please be sure to order both male 
and female QOL booklets from CTSU). Booklet should be administered by the site research staff in clinic at the following 
time points: baseline, 1-2 weeks prior to surgery and 12 months +/- 6 weeks and 24 months +/- 6 weeks after rectal resection. 
In the event that a patient is not seen in clinic at 12 and 24 months +/- 6 weeks after rectal resection, the site research staff will 
follow-up with the patient via telephone and/or mail. See Section 4.5 and Appendix VI. 
12. Recommendation: Surgery should be performed within 5-8 weeks of the last dose of RT. Actual timing of surgery is at the 
discretion of the treating clinician. Tissue block submission from surgical resection is mandatory (see Section 14.0 for 
submission instructions). 
13. Adverse Events form to be completed at the start of week 1 of 5FUCMT, at the start of week 3 of 5FUCMT and at the start of 
week 5 of 5FUCMT. 
14. For patients enrolled after 02/01/2016, QOL is no longer needed as the accrual goal has been reached.  
R. 
Research funded (see Section 18.0). 
 
For SAKK sites, please refer to the Swiss Specific Appendix for instructions regarding Precaution. 
 
 

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Addendum 10 
4.3 
Post-operative Testing Schedule: Groups 1 and 2 
Tests and procedures 
At completion 
of post 
operative 
treatment 
9 months from 
randomization 
± 1 month 
Annually 
starting at 15 
months from 
randomization 
until 5 years 
after 
randomization ± 
1 month 
Every 6 months 
starting at  
15 months until 
5 years after 
randomization ± 
1 month 
At PD, 
withdrawal 
or removal8 
History and physical exam 
 
X 
 
X 
X 
Pulse, blood pressure and 
temperature 
 
X 
 
X 
X 
ECOG performance status (PS) 
 
X 
 
X 
X 
Weight 
 
X 
 
X 
 
Adverse event assessment 1 
X 
X 
 
X 
X 
Carcinoembryonic antigen 
(CEA) 2 
 
X 
 
X q3 months for 
1st year of 
surveillance, 
then q6 months. 
Deviations are 
not violations 
 
Colonoscopy 3 
 
 
X at months 15 
and 51 after 
randomization 
 
 
Proctoscopy 4 
 
 
X 
 
 
Surveillance CT scan with 
contrast (chest/abdomen/pelvis) 5 
 
 
X 
 
X 
Completion of PRO-CTCAE by 
patient 6 (see Appendix V) 
 
 
 
X After surgery, 
complete once 
every 6 months 
for 3 years 
 
QOL Assessment 7  
(see Appendix VI) 
 
 
X Until 2 years 
after 
randomization 
only 
 
 
Laboratory testing during post-operative treatment is at discretion of treating physician 
NOTE: Time points specified in the footnotes below override time points listed above for the specific test or procedure. 
Table 4.3 Footnotes  
1. 
Patients must have assessment at the time of progressive disease, study withdrawal, or removal.  
2. 
Blood work does not have to be performed at the trial site, it can be performed at other locations. 1st year of surveillance = 1st 
post-treatment year.  
3. 
A full surveillance colonoscopy should be performed at approximately 15 and 51 months after randomization. More frequent 
evaluation may be indicated based on findings such as adenomatous polyps or genetic predisposition. Surveillance 
colonoscopy does not need to be performed every 6 months. For the assessments when colonoscopy is performed, because it 
includes visualization of the rectum, proctoscopy does not also need to be performed. Deviations in the timing of colonoscopy 
will not constitute a study violation. 
4. 
Rectal exam and proctoscopy should be performed annually starting 15 months from randomization. 
5. 
A PET/CT scan may be performed in lieu of a CT scan with contrast, but a CT scan with contrast is preferred. Scans do not 
have to be performed at the trial site; they can be performed at other facilities as long as data are available for review by the 
site. Contrast is preferred but not required for the CT of the chest. Contrast is required for the CT of the abdomen and pelvis. 
6. 
See Appendix V. 
7. 
Postoperatively sites must administer pre-printed booklets with QOL survey at 12 months +/- 6 weeks (~15-18 months after 
randomization) and 24 months +/- 6 weeks (~27-30 months after randomization) after rectal resection. In the event that a 
patient is not seen in clinic at 12 and 24 months +/- 6 weeks after rectal resection, the site research staff will follow-up with 
the patient via telephone and/or mail. See Section 4.5 and Appendix VI. For patients enrolled after 02/01/2016, QOL is no 
longer needed as the accrual goal has been reached.  
8. 
Upon identification and confirmation of PD per Section 11.1.4.2.3 or withdrawal from the Section 4.3 observation follow-up, 
patients should proceed to the annual Event Monitoring Phase (Section 4.3.1) until a total of 8 years post-randomization. 

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Addendum 10 
For SAKK sites, please refer to the Swiss Specific Appendix for instructions regarding Precaution. 
4.3.1 Event Monitoring Folow-up Phase 
Event Monitoring Phase1 
After completion of Section 4.3 
Post-operative Observation Schedule 
Every 12 Months 
After PD 
Every 12 Months 
Withdrawal 
Every 12 Months 
Death 
X2 
X2 
X2 
X2 
Table 4.3.1 Footnotes: 
1. Patients who stop treatment early, withdraw from observation follow-up, progress per 
Section 11.1.4.2.3, or complete the Section 4.3 Post-operative observation schedule 
will proceed to annual Event Monitoring (i.e. Survival Follow-up) until a total of 8 
years post-randomization. If a patient is still alive 8 years after registration, then no 
further follow-up is required.  
2. Clinical assessments (i.e. disease status evaluations) are not required in Event 
Monitoring per protocol. However, site research staff should review patient electronic 
health records and/or contact the treating institution if the patient moved, to obtain 
disease status evaluation data. Recurrent disease data is crucial to the primary endpoint 
of this protocol which is disease-free survival. 
4.4 
Patient-Reported Outcomes 
Patient-Reported Outcomes Versions of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE) Assessment (see Appendix V). 
For SAKK sites, PRO-CTCAE assessments are not applicable as outlined in the Swiss Specific 
Appendix. 
4.4.1 Study Site Staff PRO-CTCAE Credentialing 
Note: At least one staff personnel from the site study team should credentialed to perform 
patient PRO-CTCAE training and registration prior to the first patient’s baseline visit.  
PRO-CTCAE Training and Registration 
To obtain credentialing to perform PRO-CTCAE patient training, send an email request to 
the PRO-CTCAE Coordinator at 
The coordinator will contact you 
to schedule a date and time for live interactive training using the telephone. Please note 
that the training does not require viewing of an instructional video; a PRO-CTCAE training 
video is not posted on the CTSU website. Training will require about 30 minutes and is 
required only once. 
Training will include: 1) how to register a patient to PRO-CTCAE reporting by either 
telephone using the interactive voice response system (IVRS) or by computer using the 
PRO-CTCAE website; 2) how to explain and demonstrate the PRO-CTCAE telephone and 
computer systems to patients; 3) how to monitor your patients’ PRO-CTCAE reporting. 
The PRO-CTCAE Coordinator will email notice of the certification to the site, and the site 
must submit the confirmation of certification form to the CTSU Regulatory Office via the 
Regulatory Submission Portal (see Section 6.2). The CTSU will list the certification on the 
CTSU Regulatory Support System (RSS). Study teams may check the status of their 
certification by logging into the CTSU website, clicking the blue ‘Regulatory’ tab, then 

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24 
Addendum 10 
clicking the beige ‘Site Registration’ tab, then entering their CTEP site number and 
protocol number N1048 in the text boxes and clicking ‘Go.’ 
For any questions or concerns, please send email to 
 
 
4.4.2 Patient PRO-CTCAE Training  
All patients enrolled at U.S. and Canadian sites who can read and speak English or Spanish 
will be required to participate in PRO-CTCAE reporting by either telephone using the 
interactive voice response system (IVRS) or by computer using the PRO-CTCAE website. 
Patients may choose their reporting mode. Site study staff will train the patient how to use 
the IVRS or website; this training will require about 10 to 20 minutes per patient. 
Because patients will self-report PRO-CTCAE symptoms from home, patients will not 
require access to a telephone or a computer during regularly scheduled clinic visits. 
However, in order for site personnel to train patients who choose telephone reporting, 
access to a telephone will be required. If this is not possible, the site study staff may provide 
this training over the telephone by calling the patient after s/he leaves the clinic. Likewise, 
for patients who choose computer reporting, access to an Internet-enabled computer is 
necessary. 
Patients choosing to report by telephone will call telephone number 
enter 
userID and PIN, then answer the verbal questions concerning symptoms and health 
concerns. This will require about 5 minutes. 
Patients choosing to report by computer will go to the PRO-CTCAE website at 
 enter username and password, and then answer the questions. 
This will require about 5 minutes.  
Reference cards for both the telephone IVRS system and the computer website will be 
provided to the patient as shown below. These reference cards, available in English and 
Spanish, are available on the CTSU website for sites to print for patients. Both a help line 
and website are listed on the cards; should a patient have difficulties, s/he may call 
telephone number 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROSPECT RECTAL CANCER STUDY (N1048) 
Automated Telephone [IVRS] System Reference Card 
 
1. To access your survey by phone, please call toll-free 
 
 
2. You will need your ID number and PIN to access your survey.  
____________________________ 
3. Please answer the questions about your symptoms; this will require less than 5 minutes 
 
If you have any questions, please either: call your doctor’s office at ____________________, send 
an email to 
 
 
Please remember that the information you report through PRO-CTCAE goes only to the 
research team. Always discuss your symptoms with your doctor or nurse during regular 
visits 
 
Thank you for agreeing to participate in the PROSPECT study! 

N1048 
Version Date:08/25/2022 
 
25 
Addendum 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROSPECT RECTAL CANCER STUDY (N1048) 
Website Reference Card 
1. To access your survey, please type this link into your browser: 
 
 
2. You will need your username and password   
____________________________ 
3. Please answer the questions about your symptoms; this will require less than 5 minutes 
 
If you have any questions, please either: call your doctor’s office at ____________________, send 
an email to 
 
 
Please remember that the information you report through PRO-CTCAE goes only to the 
research team. Always discuss your symptoms with your doctor or nurse during regular visits 
 
Thank you for agreeing to participate in the PROSPECT study! 

N1048 
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Addendum 10 
4.4.3 Patient PRO-CTCAE Reporting 
Note: Site study staff must clearly convey to the patient that the information regarding 
symptoms collected by the PRO-CTCAE self-report are for research purposes only and are 
not monitored by a physician. Study staff must advise patients to directly contact their 
doctor for any concerning symptoms. 
During the pre-operative period, patients will be required to use either the telephone IVRS 
system or the computer website to self-report symptoms once weekly on a day and time 
pre-arranged by the patient and the site study personnel. This reporting should require 
about 5 minutes and should occur approximately 3 days prior to the scheduled clinic visit.  
Patients will be asked by site study personnel to provide a telephone number and an active 
email address if they have one for contact. Patients who do not self-report as scheduled 
will receive an automated reminder call or email. If there is no response to two successive 
reminders, an automatic email notification will be sent to the PRO-CTCAE Coordinator 
who will then call the patient to administer the PRO-CTCAE items verbally and enter the 
patient’s verbal responses into the PRO-CTCAE web system.  
Data reported by patients into the PRO-CTCAE electronic platform will be stored in a 
secure database on a server hosted at the National Cancer Institute. This NCI database will 
be available electronically to the cooperative group statistical center for remote access.  
4.4.4 Study Site PRO-CTCAE Reporting 
Sites will be randomly assigned at the time of training by the PRO-CTCAE Coordinator to 
report adverse events either by: (a) using the Solicited AE Form from the paper forms 
packet posted on the CTSU or Alliance website, or (b) using a Solicited AE Form generated 
from the PRO-CTCAE system which contains the patient’s PRO-CTCAE scores. Details 
of the randomization can be found in Appendix V. For sites assigned to (a), the AE form 
should be printed by site study staff from the paper forms packet posted on the CTSU or 
Alliance website. For sites assigned to (b), the AE form should be printed from the PRO-
CTCAE system (instructions will be provided during PRO-CTCAE training). Both forms 
are entered into RAVE.  
Six months (+/- 1 month) after registering the first patient to the PRO-CTCAE web system, 
and optionally again at 12 months (+/- 1 month), site study personnel will be asked to 
complete a very brief questionnaire about the PRO-CTCAE system via email from the 
PRO-CTCAE Coordinator. 
4.5 
Quality of Life Assessments 
For SAKK sites, QOL assessments are not applicable, as outlined in the Swiss Specific 
Appendix. 
Note: The sample size for the QOL component was reached on 02/01/2016. Therefore, 
patients registered to this study after 02/01/2016 will not be required to participate in the 
Quality of Life Assessment component of the study and will not complete the paper Quality 
of Life (QOL) questionnaire booklets. Patients registered prior to 02/01/2016 should 
continue to complete the QOL questionnaire booklets per the schedule found below. 
The QOL study is required for all eligible patients randomized in the phase II or phase III 
component of the study until the maximum number of 460 patients has been accrued.  Patients 
must use pre-printed questionnaire booklets ordered from the CTSU website (Note: There are 2 
versions of the QOL booklet. One for males and one for females. Be sure to order both male and 
female booklets from CTSU). Patients who can read and speak English are eligible to participate 
in the QOL portion of the study. QOL questionnaire booklets will be completed by the patients 
at regularly scheduled clinic visits occurring at: 

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Addendum 10 
1. Baseline (before start of treatment at time of randomization) 
2. 1-2 weeks prior to surgery (after neoadjuvant treatment e.g. at time of surgical consent) 
3. 12 months +/- 6 weeks (corresponds to ~15-18 months after randomization)  
4. 24 months +/- 6 weeks (corresponds to ~27-30 months after randomization) after rectal 
resection  
If the patient was not seen in clinic at 12 and 24 months ± 6 weeks after rectal resection and/or 
a QOL questionnaire booklet is not completed by the patient during a scheduled clinic visit at 
one of the specified time points, the site study staff should follow-up with the patient by 
telephone and/or mail in order to minimize missing data. The mode of QOL administration 
(paper vs. telephone) and the date of completion will be noted on the form.  If a patient chooses 
to complete the survey via telephone, sexual function questions (IIEF for men and FSFI for 
women) will not be administered due to their sensitive nature. 
To assess bowel function, the 19 item Bowel Function Index (Temple et al., 2005) will be used. 
To assess sexual function, gender specific questionnaires will be used, specifically the 
International Index of Erectile Function (Rosen et al., 1997) and the Female Sexual Functioning 
Index (Rosen et al., 2000). Bladder function will be assessed using two items from validated 
questionnaires. We will assess global HRQL using the EuroQOL5D-5L which evaluates 
domains of pain, anxiety, physical function, ambulation and activities of daily living as well as 
the linear analogue scale. These instruments have been embedded in many prior NCCTG and 
CALGB clinical trials and reproducibly assess health related quality of life in a succinct manner. 
The entire functional assessment can be completed in less than 30 minutes with an average of 
10-20 minutes per patient. Refer to Appendix VI for more details. 
5.0 
STRATIFICATION AND GROUPING FACTORS 
5.1 
Stratification Factors (Used for Randomization to Group 1 or Group 2)   
5.1.1 ECOG Performance Status: (0 or 1) vs. 2 
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES  
All Site Staff (Alliance and CTSU institutions). This study is supported by the NCI Cancer Trials 
Support Unit (CTSU). 
For SAKK sites, please refer to the Swiss Specific Appendix for activation instructions, including 
copies of the physician agreements. 
6.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 

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Addendum 10 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
 
   
6.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 

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Addendum 10 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
• 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the Regulatory 
section of the CTSU website. Acceptable documentation of local IRB/REB approval 
includes:Local IRB documentation; 
• 
 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
• 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed:Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 

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Addendum 10 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents:   
• 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and 
staff on a participating roster. To view/download site registration forms: Log in to the 
CTSU members’ website (
) using your CTEP-IAM username and 
password; 
• 
Click on Protocols in the upper left of the screen: 
• 
Enter the protocol number in the search field at the top of the protocol tree; or 
• 
Click on the By Lead Organization folder to expand, then select Alliance, and protocol 
number #N1048. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided. (Note: For 
sites under the CIRB, IRB data will load automatically to the CTSU.)  
Requirements for N1048 Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
Protocol Specific Requirements that are required but not necessary for CTSU approval 
(site can open N1048 and register patients PRIOR to completing the 2 following items): 
1. PRO-CTCAE Credentialing (should be completed before the first study participant’s 
baseline visit; see Section 4.4.1) 
2. IMRT and/or 3D Conformal Radiation Therapy Credentialing (should be completed 
before the first study participant starts radiation therapy; see Section 7.3.2) 
a. For applicable NCTN studies with a radiation and/or imaging (RTI) 
component, the enrolling site must be aligned to a RTI provider. To manage 
provider associations access the Provider Association tab on the CTSU 
website at 
to add or 
remove associated providers. Sites must be linked to at least one IROC 
credentialed provider to participate on trials with an RT component. 
Enrolling sites are responsible for ensuring that the appropriate agreements 
are in place with their RTI provider, and that appropriate IRB approvals are 
in place.   
b. IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to 
IROC to begin the modality credentialing process. 
 
 

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Addendum 10 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 
 or 
 in order to receive further instruction and support.Checking Site’s 
Registration Status: 
• 
Site registration status may be verified on the CTSU members’ website. Click on 
Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go: 
• 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
6.3 
Patient Enrollment and Randomization 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
• 
Requirements for OPEN access:  A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 

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Addendum 10 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
 For any additional questions, contact the CTSU 
Help Desk at 
To receive site reimbursement for 
specific tests and/or bio-specimen submissions, completion dates must be entered in the OPEN 
Funding screen post registration. Please refer to the protocol specific funding page on the CTSU 
members’ website for additional information. Timely entry of completion dates is recommended 
as this will trigger site reimbursement. 
6.4 
Treatment Assignment 
Treatment assignment will be calculated using a dynamic allocation procedure that balances the 
marginal distributions of the stratification factors between the two treatment groups. ECOG 
performance status, defined in Section 5.0, together with the randomizing site, will be used as 
stratification factors. 
6.5 
Correlative Studies  
For SAKK sites, please refer to the Swiss Specific Appendix for details regarding translational 
research. 
6.5.1 Acquisition of Rectal Tumor Tissue 
This is mandatory for pathologic confirmation of diagnosis and correlative research 
component that are part of this study and the patient will be automatically registered onto 
this component. Patients may have had a previous biopsy acquired prior to study 
registration. This outside specimen may be used in lieu of a repeat tumor biopsy at the 
registering site. However, in some cases, the outside tumor specimen will be suboptimal. 
In this context, the primary surgeon or gastroenterologist at the study site should perform 
a rectal tumor biopsy at the time of proctoscopy. In addition to submission for routine 
clinical processing and confirmation of the diagnosis of rectal adenocarcinoma, a portion 
of the tumor should be submitted to the Ohio State Pathology Lab for research purposes 
(see Section 14.0). If a tumor biopsy specimen is not obtained at the registering site, an 
adequate tumor specimen that confirms the diagnosis of rectal adenocarcinoma should be 
obtained from the outside pathology source. A sample of this tumor specimen should be 
submitted to the Ohio State Pathology lab. Specific instructions and mailing addresses are 
in Section 14.0. 
Rectal tumor biopsy may be performed within 60 days of registration OR between 
registration and the start of treatment. 
The suggested method for rectal tumor acquisition is to obtain four biopsies from the 
leading edge of the primary rectal tumor. The leading edge should be sampled so as to 
avoid the center of the tumor which is more often necrotic. The use of alligator forceps 
though a rigid proctoscope is recommended. Pinch biopsies via a flexible endoscope are 
an alternative but are often associated with lower yield of adequate tissue specimen. This 
tissue should be embedded into a formalin fixed paraffin embedded block and processed 
as routine clinical specimens by pathology. Samples from this biopsy should later be sent 
to the pathology core (at Ohio State) for correlative science. See Section 14.0 for 
instructions. 
6.5.2 Acquisition of Blood Samples 

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Addendum 10 
The patient will be automatically registered onto the correlative research component (see 
Section 14.0). The correlative study will attempt to understand the molecular events related 
to tumor response to either FOLFOX or 5FUCMT. 
6.5.3 Informed Consent for Correlative Studies 
At the time of registration, the following will be recorded (found on the informed consent 
document): 
1. 
Patient has given permission to the Alliance to store and use his/her blood 
samples for use in future research to learn about, prevent, or treat cancer. 
2. 
Patient has given permission to the Alliance to store and use his/her blood 
samples for use in future research to learn about, prevent, or treat other health 
problems (for example: diabetes, Alzheimer’s disease, or heart disease). 
3. 
Patient has given permission to the Alliance to give his/her stored blood samples 
for use in future research to outside researchers. 
4. 
Patient has given permission to the Alliance to store and use his/her tissue 
samples for use in future research to learn about, prevent, or treat cancer. 
5. 
Patient has given permission to the Alliance to store and use his/her tissue 
samples for use in future research to learn about, prevent, or treat other health 
problems (for example: diabetes, Alzheimer’s disease, or heart disease). 
6. 
Patient has given permission for the Alliance to give his/her stored tissue 
samples for use in future research to outside researchers. 
6.6 
Treatment Prior to Registration 
Treatment cannot begin prior to registration and must begin  21 days after registration. 
6.7 
Prior to Treatment 
6.7a Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified in the test schedule. 
6.7b All required baseline conditions (see Section 10.5.1) must be documented and 
graded. 
6.7c Treatment on this protocol must commence at the accruing membership site under 
the supervision of an Alliance or CTSU member physician. 
6.7d After informed consent is obtained from the patient and prior to starting the 
treatment, baseline PRO-CTCAE assessments and QOL questionnaires must be 
completed. Blood and tissue samples should be obtained prior to treatment. 
7.0 
PROTOCOL TREATMENT 
For SAKK sites, please refer to the Swiss Specific Appendix for information on drug supply and 
handling, including drugs / radiotherapy / surgery in protocol. 
NOTE: The primary physician must see the patient at the initial visit and assume responsibility for 
adherence to protocol treatment. Subsequent visits and participation in shared care models with 
RNPs/PAs/etc. is acceptable provided that all protocol procedures are followed and all reports are 
submitted. 
7.1 
Group 1 Pre-Operative Treatment Schedule (FOLFOX) 
FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) 
Agent1 
Dose6 
Route 
Day2 
Retreatment3,4 
Oxaliplatin 
85 mg/m2 
IV over  
2 hours  
Day 1 
Repeat every 14 
days for a total of 6 

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Addendum 10 
 
cycles 
Leucovorin5 
400 mg/m2 bolus 
 
IV over  
2 hours 
Day 1 
 
 
Repeat every 14 
days for a total of 6 
cycles 
5FU 
400 mg/m2 bolus over 5-
15 minutes then 2400 
mg/m2 continual over 
46-48h total dose  
IV 
Day 1 
 
Days 1 to 2 
Repeat every 14 
days for a total of 6 
cycles 
1. Oxaliplatin is administered first, prior to leucovorin; alternatively leucovorin may be administered (via 
separate infusion containers) concurrently with oxaliplatin. 
2. FOLFOX cycle = 14 day cycles for 6 cycles. 
3. If necessary to accommodate holidays, patient schedule or other justified circumstance, the schedule 
may be modified by ± 7 days. 
4. Patients who cannot tolerate six cycles of FOLFOX or those that require dose modification below dose 
level -2 will receive preoperative 5FUCMT. There are no restrictions on dose modifications for the 6th 
cycle of neoadjuvant FOLFOX. If for example, a patient has dose limiting neuropathy or a 
hypersensitivity reaction that precludes administration of the 6th dose of FOLFOX or any one of its 
component agents, the patient should proceed to undergo restaging as per the directives for Group 1.  
5. Alternate folinic acids (i.e., levo-leucovorin) may be substituted for Leucovorin if Leucovorin is not 
available. Note: Levo-leucovorin is twice as potent as leucovorin; dosages should be adjusted 
accordingly. Dosages are at the discretion of the treating physician. Dose modifications of leucovorin 
up to and including omission of leucovorin or its analogues imposed by drug shortages will not 
constitute protocol violations. 
6. The dose modification schema for FOLFOX (see Section 8.0) is suggested. Oncologists may use 
clinical judgment in making dose modifications that deviate from the suggested schema. These 
will not constitute protocol violations. 
 
 

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Addendum 10 
7.2 
Group 2 Pre-operative Treatment Schedule (5FUCMT) and Group 1 Pre-Op Treatment 
Schedule if Patient Receives Pre-operative 5FUCMT 
5FUCMT (5-fluorouracil OR capecitabine + radiation therapy) 
Agent 
Dose 
Route 
Day 
5FU 
225 mg/m2 
per day 
Continuous IV infusion 
administered 
concurrently with RT 
Continuous IV infusion either 5 or 7 
days per week during RT 
 
Capecitabine1,2,3 
825 mg/m2 
BID 
Orally administered 
concurrently with RT 
5 days per week on days of planned 
RT 
Radiation Therapy 
(RT) 
see 
Section 7.3.3 
 
5 days per week 
1. Capecitabine is an acceptable alternative to 5-FU for chemosensitization during radiotherapy.  
2. Patients must be counseled about the importance of compliance with capecitabine. A 
capecitabine diary is provided for convenience but does NOT need to be submitted. 
Compliance, with mention of missed doses, must be documented in the patient’s medical record 
by site study personnel.  
3. Patients should take their doses of capecitabine orally daily, one dose in the morning and one 
dose in the evening, about 12 hours apart for 5 days per week during radiation therapy. Patients 
should swallow capecitabine tablet(s) whole with a full glass of water, about 8 ounces of water, 
within 30 minutes after a meal. Patients should not try to make up a missed or vomited dose, 
never double up on a dose and tell their doctor if they miss a dose. Patients must return any 
remaining capecitabine tablets at the end of the 5.5 week long period to their doctor.  
7.3 
Radiation Therapy 
7.3.1 Quality Assurance Monitoring Program 
Radiation Therapy facilities participating in NCI sponsored protocols must be active in the 
IROC Houston (RPC) Quality Assurance monitoring program. 
7.3.2 Radiation Therapy Credentialing 
This protocol allows physician discretion as to the use of Intensity Modulated Radiation 
Therapy (IMRT) or 3D conformal planning techniques.  
Sites using only IMRT need only complete item 1 below. Sites using only 3D Conformal 
need only complete item 2 below. Sites using both IMRT and 3D conformal need to 
complete both items 1 and 2 below. Items 1 and/or 2 only need to be completed ONCE for 
each radiation therapy planning technique that will be used for this study. Items 1 and/or 2 
must be completed before the first study participant starts radiation therapy; sites may 
enroll patients prior to completing items 1 and/or 2. 
1. 
Sites using Intensity Modulated Radiation Therapy (IMRT) planning techniques 
in this study must complete either the IMRT benchmark on the IROC Rhode Island 
(QARC) website (
 under the tab labeled “Benchmarks”); or 
the IMRT head and neck phantom study on the IROC Houston (RPC) website 
(
). The IMRT facility questionnaire located on the IROC 
Houston website must also be completed. 
2. 
Sites using 3D conformal radiation therapy in this study must complete the 3D 
conformal benchmark and questionnaire located on the IROC Rhode Island 
(QARC) website (
 under the tab labeled “Benchmarks”).  
OR 

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Addendum 10 
To determine if your site is already credentialed for use of 3D Conformal planning and/or 
IMRT, send an email to 
 or call 
or visit the IROC 
Houston website at 
 and click ‘credentialing’ as it appears in 
red text on the top web banner, then click credentialing status inquiry. 
In addition to items 1 and 2 above, radiation therapy quality assurance documentation must 
be submitted to IROC RI (QARC) for each study patient; detailed instructions can be found 
in Section 7.3.9. 
7.3.3 Radiation Therapy Characteristics 
Note: If protocol radiotherapy is delayed by more than 14 days or discontinued early, IROC 
RI (QARC) must be notified of the reason(s) and the date(s). Notification is not required 
for shorter delays due to toxicity, weather, linac maintenance problems, or similar logistical 
reasons. The notification must be submitted via email to 
 or fax 
 
Field 
Dose 
(Gy) 
Number of 
Fractions 
Fraction 
Size 
Rx Length 
Rx Days 
Initial 
45 
25 
 
1.8 Gy 
5 weeks 
Monday 
through 
Friday 
Boost 
5.4 
3 
3 days 
Total 
50.4 
28 
Group 2: Radiation begins on Day 1 of neoadjuvant chemotherapy and continues for 28 
consecutive weekdays. The trial administers 1.8 Gy per day without a break except for 
weekends and holidays.  
Equipment 
Modality: Linear accelerator-based photons with a minimum energy of 6 MV will be used. 
IMRT is allowed, for which inverse-planning capable software is required. IMRT may be 
delivered either at fixed gantry angles with a multileaf collimator or in rotational mode 
using a multileaf collimator or tomotherapy. 
Geometry: Teletherapy units with a source-to-axis distance of 100cm. Calibration: 
Teletherapy units used in this study shall have their calibration verified by the Radiological 
Physics Center (RPC). 
7.3.4 Target Volume Definitions for Conformal Therapy or IMRT 
ICRU-50 and ICRU-62 prescription methods and nomenclature shall be utilized for this 
study. The volumes are to be defined by planning CT/MRI techniques as well as PET scans 
when clinically appropriate. While PET scans are not mandated as part of the protocol, for 
those patients who have PET scans available, the information may be used to aid in 
treatment planning. The inferior extent of palpable tumors should be determined by 
physical examination. 
Gross Tumor Volume (GTV): This includes the primary tumor and any pelvic nodes felt 
involved grossly with metastatic disease. Assessment of the primary tumor and nodal 
disease may be made on the basis of endoscopy, CT, PET-CT, MRI, or transrectal 
ultrasonography. The entire rectal circumference at the level of the tumor should be 
included as GTV. 
Clinical Target Volume (CTV): This includes the GTV and the following nodal groups: 
perirectal nodes; presacral nodes; internal iliac; and common iliac nodes below the L5-
sacral junction.  
 
 
 

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Planning Target Volume 1 (PTV 1): This will provide a margin around the CTV to 
compensate for the inter- and intra-fraction uncertainty consequent to daily setup 
uncertainty and to potential internal organ motion. By definition, the PTV will consist of a 
symmetrical 7 mm expansion around the CTV. In the event that a PTV extends outside of 
the skin surface, the clinician should manually trim the PTV contours to be 3-5 mm inside 
the outer skin (unless there is direct skin involvement). 
The following are guidelines for generating CTV and a unified PTV: 
• 
Rectal GTV (+1.5 cm radially, +2.5 cm craniocaudally) = CTV 
• 
Nodal GTV + 1.5cm symmetrical expansion = CTV 
• 
Uninvolved iliac vessels + 1.0 cm = CTV  
• 
Presacral lymphatic CTV is generated by contouring the entire sacral hollow from 
mid S1-S5 and 8 mm tissue anterior to the anterior border of the sacral bone 
• 
The mesorectum and perirectal lymphatic CTV is generated by utilizing anatomic 
landmarks: 
o Posterior Border: anterior border of the sacrum and gluteus maximus 
o Lateral Border: ileum, piriformis and obturator muscles 
o Anterior Border: should include the interface with the bladder, vagina, 
uterus or prostate 
o Inferior Border: the levators 
The PTV 1 is generated by expanding all of the above structures by 0.7 cm symmetrically 
and unifying them into one 3-dimensional volume for planning purposes. 
Planning Target Volume 2 (PTV 2): The PTV for the cone down volume is an expansion 
of the GTV by 3 cm and the presacrum, provided the small bowel does not receive more 
than 5,000 cGy. This volume should not extend beyond PTV1. 
Examples of contoured patients (anorectal atlas) are available for review on the ATC 
website (
 or at the RTOG website (
). These 
examples are excellent resources for the contouring of normal structures as well as GTV, 
CTV and PTV design, and their use is strongly encouraged. 
Suggested Field Borders for 3-D Conformal Treatment 
For the first course, use of PA and opposed laterals is recommended. An AP field may be 
used at the discretion of the treating radiation oncologist if it results in improved dose 
homogeneity without increasing the small bowel dose unnecessarily. 
 
Standard PA (and AP if used) Field: 
Inferior 
The minimum would be at least a 3 cm margin from 
the inferior extent of the cancer, or at the anal verge 
for cancers within 5 cm of the verge on digital 
rectal examination. The anal verge should be 
identified by a marker on simulation. 
Lateral 
2 cm lateral to the bony pelvis taken at its widest 
point. 
Superior 
L5-S1 junction. 
 
 

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Standard Opposed Lateral Portals: 
Superior 
To correspond to PA fields. 
Inferior 
To correspond to PA fields. 
Anterior 
This will cover the lower common and internal 
iliacs as defined on CT scans. Anatomically this 
will extend anteriorly to approximately the 
anterior one-third of the acetabulum. 
Posterior 
This must include 2 cm posterior to the 
presacrum. 
The cone down field shall have a minimum 3 cm margin around the GTV but must include 
the whole of the sacral hollow. It is acceptable to use only opposed lateral fields, or to 
include a PA field, for the cone down treatment. 
7.3.5 Localization, Simulation, and Immobilization 
A custom immobilization device (such as Alpha Cradle for supine patients and an Alpha 
Cradle with bowel displacement device for prone patients) is suggested to minimize set-up 
variability. Simulation may be done with the patient in the supine "arms up" position for 
patients with very thin body habitus or the prone "arms up" position for patients of 
moderate or large body habitus, using a CT-simulator with a slice thickness ≤ 5 mm. Oral 
CT contrast is strongly suggested. An anal marker at the verge is required. 
Weekly portal imaging is required; more frequent portal imaging is encouraged for patients 
being treated in the prone position on a bowel displacement device.  
Portal imaging is the most common system used to verify patient position, in particular 
when the target volume is believed to possess a fixed spatial relationship with visualized 
bony anatomy. Orthogonal paired (AP and lateral) portal images (MV or kV) are required 
for IMRT and 3-D CRT to verify that the isocenter is in correct alignment relative to the 
patient position. 
Volumetric imaging is allowed in this study. This includes in-room kV or MV cone beam 
or conventional CT imaging. If volumetric imaging is used (including tomotherapy), a 
screen capture of the fused CT images can be printed to demonstrate in room verification. 
Treatment planning CT scans will be required to define gross target volume and clinical 
target volumes. The treatment planning CT scan should be acquired with the patient in the 
same position and using the same immobilization device as for treatment.  
All tissues to be irradiated must be included in the CT scan. CT scan thickness should be 
0.5 cm or smaller slices through the region that contains the primary target volumes. The 
regions above and below the target volume may be scanned also with slice thickness of 0.5 
cm.  
7.3.6 Organs at Risk (OARs) 
Small Bowel: This is defined on planning CT study. Only the small bowel encompassed 
in the fields is to be included as part of the DVH. Bowel exclusion techniques are permitted. 
No portion of the small bowel shall receive a dose in excess of 5,000 cGy. It is recognized 
that there will be significant patient heterogeneity regarding the volume of the bladder and 
bowel that overlaps with the PTV. When a choice must be made between target coverage 
and sparing normal tissue, the priority should be given to target coverage. The constraints 
listed below are intended as guidelines; exceeding the recommended constraints will not 
be considered a protocol violation. 
 

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Addendum 10 
Constraints for Conformal or IMRT Planning: 
Small bowel: 
• No more than 150 cc above 3,500 cGy 
• No more than 70 cc above 4,000 cGy 
• No more than 35 cc above 4,500 cGy 
• None above 5,000 cGy 
Femoral heads: 
• No more than 50% above 3,000 cGy 
• No more than 40% above 4,000 Gy 
• No more than 5% above 4,500 cGy 
• No femoral head volume should receive 5000 cGy 
Bladder: 
• Mean dose < 4,000 cGy 
7.3.7 Target Dose 
Prescription Dose and Fractionation: 
PTV1 
The total dose to the PTV1 will be 4,500 
cGy in 25 fractions (180 cGy to the PTV1 
each day). 
PTV2 
A cone down dose of 540 cGy will be 
delivered to PTV2 in 3 fractions of 180 cGy 
per day (total dose 5,040 cGy). 
Fractionation: 
Treatment shall be given 5 days per week. 
Prescription Isodose Surface: 
Dose is to be prescribed to an isodose surface that encompasses the PTV and that satisfies 
the dose uniformity guidelines below. The minimum dose to PTV1 and PTV2 shall be no 
less than 95% of the protocol specified dose for that volume. 
Dose Definition: 
Dose is to be specified in cGy to muscle. 
Tissue Heterogeneity: 
Calculations shall take into account the effect of tissue heterogeneities. 
Dose Uniformity: 
PTV1 and PTV2 shall both be encompassed within the isodose surface corresponding to 
95% of the prescription dose for that volume. The maximal dose should be no more than 
110% of the prescription dose; the maximal volume to receive 110% of the prescription 
dose should be kept below 10% of the PTV, as evaluated by dose volume histogram. 
IMRT Plan Verification: 
If IMRT is used, the monitor units generated by the IMRT planning system must be 
independently checked prior to the patient’s first treatment. Measurements in a QA 
phantom can suffice for a check as long as the plan’s fluence distributions can be 
recomputed for a phantom geometry. 
 
 

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Addendum 10 
7.3.8 Rests and Interruptions 
Uninterrupted radiation treatment is intended. Treatment may be interrupted for the 
development of acute toxicity. The specific reason(s) for any treatment interruption must 
be recorded in the treatment chart. Treatment interruptions exceeding fourteen (14) days 
will be considered a major protocol deviation. See Section 7.3.10 for definitions of major 
and minor protocol deviations. Treatment interruption is mandated for severe diarrhea or 
other regional symptoms of severity > Grade 3 by Common Terminology Criteria. No 
modifications in dose will be made for interruptions in therapy. 
NOTE: If protocol radiation therapy is delayed or interrupted for more than 14 days, 
IROC RI (QARC) must be notified of the reason(s) and date(s) that radiotherapy was 
held. It is not necessary to report single-day breaks that are required for logistical 
reasons such as weather or linac maintenance. 
Patient Monitoring During Treatment: 
During radiation therapy, all patients should be seen by a healthcare provider for radiation 
therapy management visits at least once weekly with standard supportive care measures.  
Treatment Interruptions: 
Treatment interruptions that are required because of treatment-related adverse events, 
patient noncompliance or refusal, major intervening illness, or major holidays will not 
result in protocol violation. See Section 8.1 for additional information concerning treatment 
interruptions and adverse events. 
7.3.9 Quality Assurance Documentation 
Digital Submission: 
Submission of treatment plans in digital format as DICOM RT is required. Digital data 
must include CT scans, structures, plan, and dose files. Submission may be by either 
SFTP or CD. Instructions for data submission are on the IROC Rhode Island Web site at 
Any items on the list below that are not part of the digital 
submission may be included with the transmission of the digital RT data via sFTP or 
submitted separately. Digital format is preferred. 
Within one week of the completion of radiotherapy, the following data for all patients 
shall be submitted for review: 
 
External Beam Treatment Planning System  
 
1. 
Digitally reconstructed radiographs (DRR) for each treatment field, showing the 
collimator and beam aperture. Please include two sets, one with and one without 
overlays of the target volumes and organs at risk. When using IMRT, orthogonal 
setup DRR’s are sufficient.  
2. 
RT treatment plans including CT, structures, dose, and plan files. These items are 
included in the digital plan.  
3. 
Dose volume histograms (DVH) for the composite treatment plan for all target 
volumes and required organs at risk. A DVH shall be submitted for all required 
organs at risk. When using IMRT, a DVH shall be submitted for a category of 
tissue called “unspecified tissue.” This is defined as tissue contained within the 
skin, but which is not otherwise identified by containment within any other 
structure. DVHs are included in the digital plan. 
4. 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest dose 
statistics. 
 
 

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Supportive Data 
1. 
A copy of the patient’s radiotherapy record including prescription, and the daily 
and cumulative doses to all required areas 
2. 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by IROC and the radiation oncology reviewers. 
Forms 
1. 
QARC RT-1 Dosimetry Summary Form 
2. 
QARC RT-2 Form 
These forms may be completed electronically in PDF format at 
 
 
Supportive Data and Forms may be included with the transmission of the digital RT data 
via sFTP or submitted separately via e-mail to DataSubmission@QARC.org or mailed to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questions regarding the completion of the RT-1/IMRT Dosimetry Summary Form and 
RT-2 data forms, dose calculations or documentation should be directed to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questions regarding the radiotherapy section of this protocol should be directed to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
7.3.10 Quality Assurance Reviews 
The Radiation Study Co-Chair, Harvey Mamon, MD, PhD, will perform RT Quality 
Assurance Reviews of completed cases on a regular basis.   
 
Definitions of Protocol Deviations 
1. Prescription Dose 
Minor Deviation: The dose to the prescription isodose surface differs from that in 
the protocol by between 6% and 10%. 
Major Deviation: The dose to the prescription isodose surface differs from that in 
the protocol by more than 10%. 

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2. Dose Uniformity 
Minor Deviation: Less than 95% of the PTV (PTV1 or PTV2) receives at least 
95% of its protocol specified dose, or more than 10% of PTV2 receives more than 
110% of the protocol dose. 
Major Deviation: Less than 95% of the PTV (PTV1 or PTV2) receives at least 90% 
of its protocol specified dose, or more than 10% of PTV2 receives more than 120% 
of the protocol dose. 
3. Volume 
Minor Deviation: Margins less than specified or fields excessively large as deemed 
by the study. 
Major Deviation: Transection of tumor or potentially tumor bearing area (CTV). 
4. Treatment Interruptions 
No Deviation: Treatment interruptions less than 8 treatment days 
Minor Deviation: Treatment interruptions of 8 to 14 treatment days 
Major Deviation: Treatment interruptions exceeding 14 treatment days 
7.4 
Radiologic Imaging 
7.4.1 Imaging Equipment and Technical Specifications 
For further information regarding required imaging equipment and technical specifications, 
please refer to Appendix VIII. 
7.4.2 Radiology Review at the Primary Treatment (Accrual) Site 
All imaging studies are to be interpreted by radiology staff at the patient’s primary 
treatment site. Imaging staff at the primary treatment site will interpret scan, make 
determinations about eligibility, clinical staging and treatment response and prepare reports 
as part of standard practice. These assessments will be recorded and used to assess 
response as well as outcomes. 
When results of staging studies do not agree, the study that identifies the most advanced 
stage disease should be used to make determinations about staging and/or eligibility. 
The primary interpretation of all imaging studies will occur at each site, and each site will 
make the initial determination for each patient as to: 
1. Study eligibility  
2. Initial MRI study adequacy  
3. Baseline TNM status  
4. Post-treatment MRI Response categorized as >=20% or <20% (Group 1 only) 
Acceptable Images: 
In cases where ERUS is the modality selected to evaluate the primary rectal tumor, an 
accompanying CT for complete pelvic disease staging should also be interpreted by the on 
site radiologist. The CT images obtained during a PET/CT scan are often suboptimal but 
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Addendum 10 
Review Images: 
Radiologists at the sites will assess the following image attributes in conjunction with 
treating physicians and record the information on case report forms. The central review 
will complete a parallel process (not in real-time) but will also evaluate the image quality. 
• 
Did the patient meet baseline eligibility criteria?  
• 
Did the primary rectal tumor decrease in size by an estimated 20% or more after 
neoadjuvant FOLFOX? (GROUP 1 only)  
• 
Did the patient’s restaging studies show evidence of progression in either the 
primary rectal tumor or target lymph nodes? (GROUP 1 only) 
• 
Did patient restaging studies show new evidence of advanced disease? (GROUP 1 
only) 
Estimated Radiographic T Stage (Using AJCC 7th Edition Definitions): 
This should be estimated as T1, T2, or T3.  
T4 tumors are ineligible. 
Estimated Radiographic N Stage: 
For purposes of achieving consistent interpretation in this protocol: 
Node positivity determination: Entry criteria nodes will be measured in short-axis 
diameter and for the purposes of study entry will be considered positive if 5mm in 
short axis.  
Radiographic N2 status is estimated as: 4 or more nodes that measure 10mm or 
more in short-axis.  
Radiographic N1 status is estimated as: fewer than 4 lymph nodes that measure 10 
mm or greater in short axis but 1 or more lymph nodes that measure 5 mm or 
greater 
Presence of Distant Disease: 
Nodal stations considered suspicious for metastatic disease (M1) for rectal cancer are: 
common iliac, external iliac and inguinal nodes.  
Distance of the Tumor from the Mesorectal Fascia Reflection: 
Patients with tumors with a distance of 1mm or less from the mesorectal fascia reflection 
have threatened radial margins. These patients are typically not amenable to curative intent 
sphincter-sparing TME resection and therefore are ineligible. As per exclusion criteria 
3.2.3, patient eligibility is based on lack of evidence of tumor that is adherent to the 
mesorectal fascia and the ability to perform a curative intent sphincter-sparing TME 
resection at diagnosis. This determination is made by the primary surgeon. 
7.4.3 Central Radiology Review (Quality Assurance) 
Central Radiology Review is to ensure consistency of study implementation across sites 
given the complexities of radiologic staging of locally advanced rectal cancer. Central 
radiology review may share feedback about image interpretation with the primary site. 
However, decisions about clinical management based on interpretation of baseline 
images and decisions about treatment and estimation of clinical response to 
neoadjuvant FOLFOX (Group 1) are to be made by the primary treating physician(s) 
at the accruing site. 

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Addendum 10 
Central radiology review (quality assurance) in this trial has four essential purposes: 
1. To confirm that registered patients met eligibility criteria; 
2. To ensure consistency of baseline clinical staging; 
3. To estimate as to whether Group 1 patients achieve a 20% reduction in primary 
tumor size in response to neoadjuvant FOLFOX; 
4. To understand the location and nature of locally recurrent rectal cancer. 
Baseline MRI (or CT if MRI is not available; MRI preferred) will be reviewed by the 
central radiologist in order to confirm that patients met eligibility criteria.  
Restaging MRI (or CT if MRI is not available; MRI preferred) performed after induction 
FOLFOX will be reviewed for patients randomized to Group 1 to estimate response. The 
imaging review of the post-treatment imaging for Group 1 patients will indicate whether 
the estimated clinical response to FOLFOX was equal to or greater than a 20% reduction 
in tumor area (cm2) per MRI criteria. 
The Central Radiology review team may communicate to the sites (by email) if evidence 
of major protocol violations (e.g., presence of metastatic disease) are identified. Decisions 
about clinical management based on interpretation of images rest with the accruing 
site and primary clinical team based on the best clinical interests of the patient. Final 
decisions and adjudication of discrepant interpretations rest with the sites and the primary 
physicians. 
Difference between Site Review and Central Review: 
The information recorded by central radiology reviewer includes all of the information 
recorded by the site plus some supplemental information about image quality. Information 
recorded by central imaging review is also more granular in order to advance the science 
of imaging. 
Image Quality: Because assessment of the quality of images is of critical importance, the 
quality of each image will be assessed. Quality ratings will include ‘Suboptimal’ (some 
motion or lower than optimal signal or resolution) or ‘Optimal’ (optimal resolution and 
signal). 
7.4.4 Submitting Images to the Imaging Core Lab for Central Review  
Central Radiology Review is for quality assurance purposes and is not done in “real-time.”  
As such, sites should submit images to the Imaging Core Lab at Ohio State University as 
soon as feasible. (See Appendix IX for more detailed information.) 
Banking of MRI and/or CT images, according to the patient consent permission, is for 
future research. As protocols are developed, they will be presented for IRB review and 
approval. 
 
 

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Addendum 10 
Schedule of Submission of Imaging Scans for Central Radiologic Review 
 
Submit electronically at 
 
For help, email 
 
Study Type 
Group 1: FOLFOX 
Group 2: 5FUCMT 
If the patient receives an MRI and a 
CT at baseline, submit the Baseline 
MRI to Central Radiology for 
review 
Submit as soon as feasible. 
Submit as soon as feasible. 
If the patient receives an ERUS and 
a CT at baseline, submit the 
Baseline CT to Central Radiology 
for review 
Submit as soon as feasible. 
Submit as soon as feasible. 
If the patient receives an MRI at 
restaging*, submit the Restaging 
MRI to Central Radiology for 
review 
Submit as soon as feasible. 
Scan not required. If scan was 
performed, submit 
If the patient receives an ERUS and 
a CT at restaging*, submit the 
Restaging CT to Central 
Radiology for review 
Submit as soon as feasible. 
Scan not required. If scan was 
performed, submit 
Surveillance Imaging: 
MRI, CT, PET-CT to identify 
recurrent disease  
Submit as soon as feasible. 
Submit as soon as feasible. 
*Note: At restaging, use the same imaging modality that was used at baseline for a given patient. ERUS studies 
do not need to be submitted. 
 
NOTE: Central Radiology Review is for quality assurance purposes and is not done in "real-time"; Decisions 
about clinical management based on interpretation of images rest with the accruing site and primary clinical team 
based on the best clinical interests of the patient. 
Images should be de-identified and transmitted electronically from each participating site 
to the Imaging Core Lab at The Ohio State University as soon as feasible. The website 
for uploading these images is 
 If your site does not yet have 
an account/log-in information, please email 
to request an 
account/log-in information.  
7.4.5 Postoperative Images for Event Monitoring 
Pelvic imaging (MRI or CT) for all patients who are identified as having local recurrence 
should be submitted for central review. This information will facilitate ascertainment of 
the location of recurrent disease in relation to the radiation field. 
7.4.6 Surveillance Images  
Study outcomes of local and distal recurrence will often be ascertained based on routine 
surveillance imaging performed long after all chemotherapy, radiation and surgery have 
been completed. Studies that identify recurrences should also be submitted for central 
review. The central radiology reader will categorize whether there is evidence of local 
recurrence (cancer in the pelvis), distant recurrence, both or neither. The Central Radiology 
PI interpretation will stand as the final interpretation in cases of disagreement with the site 
radiologist regarding determination of local and/or distant recurrence. 
 
 

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7.5 
Post-operative Therapy 
Post-operative therapies outlined here are suggestions and may be modified at the 
discretion of the treating physician. There are no specific timing rules for initiating post-
operative therapy. All post-operative treatments (whether they follow the suggestions 
outlined here or not) must be reported on the Post-Operative Treatment Form. 
Suggested Post-Operative Treatment Regimens: 
• 
If participant is in Group 1 and has margins of surgical resection of R0, the suggested 
post-op treatment regimen is to administer 6 cycles of FOLFOX chemotherapy.  
• 
If participant is in Group 1 and has margins of surgical resection of R1 or R2, the 
suggested post-op treatment regimen is to administer 5.5 weeks of 5FUCMT 
chemoradiation and 4 cycles of FOLFOX chemotherapy (sequence is at the discretion 
of the treating physician).  
• 
If a participant had received 5FUCMT prior to surgery, then the participant should not 
receive 5FUCMT after surgery. 
• 
If participant is in Group 2, the suggested post-op treatment regimen is to administer 8 
cycles of FOLFOX chemotherapy.  
The above post-operative treatment regimens are suggested. If a physician administers a 
different or modified post-operative treatment regimen, it will not be a protocol violation. 
Post-operative treatment is discretionary. Therefore post-operative care may be performed at 
an institution other than the registering institution (if it is delivered). However, the primary 
recruiting site remains responsible for completion of all study forms and reporting follow-up 
and patient outcomes. Participation in shared care models (ex: staggered follow-up at the 
primary recruiting site and a more convenient site) is acceptable provided that documentation is 
available. The primary recruiting site remains responsible for reporting of and adherence to all 
protocol requirements. Please refer to the Alliance policy and procedures document posted 
on the Alliance website for the policy on engagement in research by non-registering 
institutions. If the NCTN Group credited for enrollment is a non-Alliance Group, then 
other requirements from the credited Group may apply.  
8.0 
SUGGESTED DOSAGE MODIFICATION BASED ON ADVERSE EVENTS   
8.1 
Radiation Therapy 
Treatment interruptions are discouraged; however, they may be necessitated by uncontrolled 
diarrhea or other acute complications. The reason for and length of any such interruption must 
be documented. If the sum total of such interruptions exceeds 7 normally scheduled treatment 
days for reasons other than toxicity, this would be a minor treatment violation. For further 
information about major and minor protocol deviations, please refer to Section 7.3. 
A minimum of 4 daily radiation therapy treatments are required in any given week. Any missed 
radiation treatments will be made up at the end of the treatment schedule such that the total 
number of delivered 1.8 Gy fractions remains 28. 
If chemotherapy is held, radiation therapy will continue. If radiation is held, chemotherapy is 
also held. Radiation therapy may be held for grade 4 cellulitis of the perineum or grade 4 
neutropenia or other radiation-associated toxicity. Radiation should be restarted subsequent to 
recovery at the discretion of the radiation oncologist as per standard practice. 
 
System/Organ/Class 
(SOC) 
 
Adverse Event 
 
Suggested Dosage Change 
 
 
Grade 2 – Continue at current dose 

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Addendum 10 
Blood and lymphatic 
system disorders 
Thrombocytopenia 
 
Grade 3 – Hold until recovery ≤ grade 1 then resume 
Grade 4 – Hold until recovery ≤ grade 1 (platelets ≥ 
75 x 109/L) then resume 
 
Neutropenia 
 
Grade 3 or 4 - Hold until recovery ≤ grade 1 then 
resume 
 
 
Febrile 
Neutropenia 
Grade 3 or 4 - Hold until resolution of fever and 
neutropenia ≤ grade 1. Hold until the ANC ≥ 1200 
/mm3 and fever has resolved then resume 
 
Gastrointestinal 
disorders 
 
Diarrhea 
Grades 1 or 2 – Continue at current dose 
Grade 3 – If grade 3 for > 4 days, hold until 
recovery ≤ grade 1 then resume 
Grade 4 - Hold until recovery ≤ grade 1 then resume 
8.2 
FOLFOX Chemotherapy and 5-FU Combined Modality  
Guidelines for dose modifications are suggested recommendations based on standard 
practice and prior NCI protocols that use these regimens.  
Variations in dose modifications strategies will not be considered major protocol violations. 
There are several exceptions to this flexibility for Group 1 neoadjuvant FOLFOX 
administration; these are described in the following paragraphs. 
The dose modification guidelines listed in this section include: 
Group 1 
Neoadjuvant FOLFOX; 
Neoadjuvant 5FUCMT (if it is administered); 
Adjuvant 5FUCMT (if it is administered); 
Adjuvant FOLFOX (if it is administered) 
Group 2 
Neoadjuvant 5FUCMT; 
Adjuvant FOLFOX (if it is administered) 
To facilitate a standardized approach across sites, tables with suggested dose modification 
criteria are provided. FOLFOX, 5-FU during radiation and capecitabine during radiation are all 
regimens that have been widely used in treatment of rectal cancer for many years. Investigators 
should refer to package inserts and local pharmacy practices for complete set of potential 
toxicities and adhere to best practices. Guidelines are repeated here to foster consistency across 
trial sites. 
Group 1 patients (neoadjuvant and adjuvant FOLFOX) and Group 2 patients (adjuvant 
FOLFOX): 
The following criteria are specific to Group 1 neoadjuvant FOLFOX: These criteria for dose 
reduction and dose delay for Group 1 neoadjuvant FOLFOX are mandatory and failure to adhere 
will constitute a protocol violation. 
1. Dose reduction: If a Group 1 patient requires a dose reduction below level -2 (level -
2 is allowed) during cycles 1-5 preoperative therapy, the patient will discontinue 
FOLFOX and be referred for preoperative 5FUCMT. 
2. Dose delay: For Group 1 patients, if FOLFOX is held due to toxicity for more than 
30 days from day one of the previous cycle, the patient will discontinue FOLFOX 
and be referred for preoperative 5FUCMT. This does not apply for cycle #6. 

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The following criteria are applicable to both Groups 1 and 2 and apply to both 
neoadjuvant and adjuvant therapy: the precise dose modification schema used and the 
symmetry of dose modification (e.g., reduce both 5FU and oxaliplatin symmetrically, or one 
preferentially) may be left to the discretion of the treating oncologist. The modification schema 
in Table 8.1 is a guideline.  
Leucovorin dose may be decreased in concert with bolus 5-FU dose. If 5-FU is not administered, 
also do not administer leucovorin. 
ALERT: ADR reporting may be required for some adverse events (see Section 10.0). 
Table 8.1 Dose Levels of FOLFOX 
 
Dose Level* 
5-FU infusion 
 
5-FU bolus 
 
 
Oxaliplatin 
 
  
0 
1200 mg/m2/day x 2 days  
 
(2400 mg/m2 
over 46-48 hours) 
400 mg/m2 
85 mg/m2 
-1 
960 mg/m2/day x 2 days  
 
(1920 mg/m2 
over 46-48 hours) 
320 mg/m2 
65 mg/m2 
-2 
800 mg/m2/day x 2 days  
 
(1600 mg/m2 
over 46-48 hours) 
270 mg/m2 
50 mg/m2 
-3** 
680 mg/m2/day x 2 days  
 
(1360 mg/m2 
over 46-48 hours) 
230 mg/m2 
 
40 mg/m2 
 
*  Dose level 0 refers to the starting dose. 
** If dose reduction below level -2 is required during cycles 1-5 of neoadjuvant therapy 
for a Group 1 patient, FOLFOX should be discontinued and the patient referred for 
5FUCMT. Dose reduction to level -3 is only permitted during cycle 6. 
 
 
All Group 2 patients and Select Group 1 patients (5FUCMT): 
During pelvic radiation therapy, providers should administer either intravenous infusional 5-
fluorouracil or alternatively oral capecitabine. If infusional 5-FU is selected, it should be started 
at a dose of 225 mg/m2 per day to run continuously during radiation, either 5 or 7 days is 
acceptable. If capecitabine is selected, the starting dose should be 1650 mg/m2 per day 
administered as two doses per day each at 825 mg/m2. Rounding capcitabine doses that coincide 
with available tablet sizes is expected and encouraged. An optional capecitabine diary is 
included in Appendix III to facilitate medication compliance and reporting. Sites may use their 
own practice specific tracking systems. 

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Table 8.2 Dose Levels of 5FUCMT 
 
Dose Level1 
5-FU infusion2 
 
Capecitabine2,3,4 
 
0 
 
225 mg/m2/day 
825 mg/m2 bid 
-1 
175 mg/m2/day 
 618.5 mg/m2 bid 
-2 
 
135 mg/m2/day 
412.5 mg/m2 bid 
-3 
100 mg/m2/day 
325 mg/m2 bid 
1 
Dose level 0 refers to the starting dose.  
2 
Note: There are no dose level restrictions for either infusional 5-FU or capecitabine 
during 5FUCMT; in other words, the patients will remain active in the study and on 
schedule irrespective of any dose modifications to 5-FU and capecitabine made by 
the treating physician.  
3 
Rounding to accommodate capecitabine tablet formulation is expected and 
acceptable. Sites may use their institutional rounding guidelines if preferred. Tablets 
are not be split or crushed.  
4 
For additional information on modifying the dose of capecitabine during 5FUCMT 
according to BSA, please refer to Appendix IV. 
8.3 Suggested FOLFOX Dose Modifications Based on Interval Adverse Events 
Dose modifications during FOLFOX are at the discretion of the primary site. Modifications 
should be reported on study case report forms. Consistent with standard oncology practice, in 
the event of grade 3 toxicity, treatment should be delayed until recovery/resolution to <Grade 2 
toxicity. Suggested dose modification guidelines are presented below for guidance. Adherence 
to institutional guidelines or standard algorithms included in electronic chemotherapy order 
entry systems is acceptable. These dose modification guidelines are applicable to Group 1 and 
Group 2 adjuvant and Group 1 neoadjuvant FOLFOX administration. 
1. Patients should be assessed every 2 weeks for toxicity during FOLFOX. 
2. Erythropoietin stimulating agents should not be administered at any point during this 
protocol. 
3. Use of G-CSF (Neulasta or Neupogen) is at the discretion of clinicians but is not usually 
necessary. Pegylated GCSF (Neulasta) may be given on day of disconnection from 5FU 
infusion to FOLFOX patients who have previously experienced dose delays secondary 
to neutropenia as an alternative to dose reduction. 

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Addendum 10 
Table 8.3 Suggested FOLFOX Dose Modifications Based on Interval Adverse Events 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
 BASED ON INTERVAL ADVERSE EVENT (Occurring before Day 1 of Cycle) 
Blood and 
lymphatic 
Systemic 
disorders 
Neutropenia 
ANC < 1200  
 
 
and/or 
 
 
Thrombocytopenia 
Grade ≥ 2 
5-FU 
Oxaliplatin 
 
Hold up to 16 days until ANC ≥ 1200. If 
recovered in ≤ 16 days, resume at next 
lower dose level or resume at same dose 
level and administer pegylated GCSF 6 
mg subcutaneously on day of 5FU 
disconnection. 
 
Hold up to 16 days until platelets ≥ 
75,000. If recovered in ≤ 16 days, 
resume at next lower dose level.  
Other  
Non-hematologic  
Grade ≥ 2 
(excluding alopecia) 
5-FU 
Oxaliplatin 
 
Hold treatment until ≤ grade 1 then 
resume at next lower dose level.  
*Located at h
 
 
The following describe actions in the Dosage Change column: 
➢ Omit = Treatment is not given for this cycle 
➢ Hold = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped  
8.4 Suggested 5FUCMT Dose Modifications (with either IV 5-FU or capecitabine) 
Dose modifications during 5FUCMT are presented here for guidance and to foster consistency 
in protocol implementation across study sites. Several points are important to emphasize: 
1. Patients should be assessed weekly for toxicity during 5FUCMT. 
2. There is no limit on dose reductions; in other words, the patients will remain active in 
the study and on schedule irrespective of any dose modifications made by the treating 
physician. 
3. Erythropoietin stimulating agents should not be administered at any point during 
5FUCMT. 
4. Use of G-CSF (Neulasta or Neupogen) is permitted at the discretion of the treating 
physician. 
5. If toxicity has not improved to ≤ grade 1 within 16 days of last treatment with 
5FU/capecitabine, radiation should be completed without 5FU/capecitabine 
chemosensitization. 
6. For criteria for holding radiation therapy, please see Section 8.1. 
 

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Table 8.4 5FUCMT Dose Modifications Based on Interval Adverse Events 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used  unless 
otherwise specified     
SYSTEM/ORGAN/
CLASS (SOC)  
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
 BASED ON INTERVAL ADVERSE EVENT 
 (Occurring before Day 1 of Each Week of the 5.5 Weeks of Radiation Treatment) 
Blood and lymphatic 
Systemic disorders 
Neutropenia  
 grade ≥ 2  
 
 
 
and/or 
 
 
 
Thrombocytopenia 
Grade ≥ 2 
5-FU 
Capecitabine 
Hold up to 16 days until ANC ≥ 1200. 
If recovered in ≤ 16 days, resume at 
next lower dose level. Note: there is no 
limit on dose reductions. If not 
recovered in 16 days (corresponding to 
16 days from previous 
5FU/capecitabine), complete radiation 
without 5FU/capecitabine sensitization.  
 
Hold up to 16 days until platelets ≥ 
75,000. If recovered in ≤ 16 days, 
resume at next lower dose level. Note: 
there is no limit on dose reductions. If 
not recovered in 16 days 
(corresponding to 16 days from 
previous 5FU/capecitabine), 
discontinue 5FU/capecitabine and 
complete radiation without 
5FU/capecitabine sensitization. 
Other  
Non-hematologic  
Grade ≥ 2 
(excluding alopecia) 
5-FU 
Capecitabine 
Hold treatment until ≤ grade 1 then 
resume at next lower dose level. Note: 
there is no limit on dose reductions. If 
not recovered in 16 days 
(corresponding to 16 days from 
previous 5FU/capecitabine), 
discontinue 5FU/capecitabine and 
complete radiation without 
5FU/capecitabine sensitization. 
 
*Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
 
The following describe actions in the Dosage Change column: 
➢ Omit = Treatment is not given for this cycle 
➢ Hold = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped  
 
Table 8.5 FOLFOX Dose Modifications Based on Toxicities that Occur on Days 2-14 During 
Previous Cycle 
Dose modifications during FOLFOX are presented here for guidance and to foster consistency 
in protocol implementation across study sites. Several points are important to emphasize: 
1. Patients should be assessed every 2 weeks for toxicity during FOLFOX 
2. Dose reductions are limited and must not be lower than dose level -2 during cycles 1-5. 

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Addendum 10 
a. Dose level-2 corresponds to an oxaliplatin dose <50mg/m2 and an infusional 
5FU dose<800 mg/m2/day x 2 days (i.e., 1600 mg/m2 over 46-48 hours) 
b. Dose reductions below level-2 including withholding either 5FU or oxaliplatin 
during cycle 6 are permissible. 
c. If a patient requires a FOLFOX reduction that is lower than level -2 for cycles 
1 through 5, then discontinue FOLFOX and refer the patient for 5FUCMT. 
3. If a patient has not recovered within 28 days of treatment during cycles 1 through 5, 
reassign patient to 5FUCMT instead. 
4. If a patient has not recovered within 28 days of treatment during cycle 6, refer for 
restaging. 
5. Erythropoietin stimulating agents should not be administered. 
6. Use of G-CSF (Neulasta or Neupogen) is discouraged. 
 
Table 8.5 FOLFOX Dose Modifications Based on Toxicities that Occur on Days 2-14 During 
Previous Cycle 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 1-14 during cycle) 
Gastrointestinal 
disorders 
Nausea grade 2 
 
 
 
 
 
 
Nausea grade 3 
 
 
 
 
 
 
 
 
 
Nausea grade 4 
 
 
 
 
 
 
 
 
 
Oxaliplatin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5-FU 
Intensify antiemetic therapy and proceed with 
FOLFOX at current dose level. Maximal 
antiemetic therapy includes a 5HT inhibitor (i.e., 
granisteron, odansetron, palonestron) as well as 
compazine, lorazepam, aprepitant, and decadron 
 
 
If resolved to < grade 2 on day of treatment, may 
proceed with intensification of antiemetic 
therapy and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of therapy, 
intensify antiemetic regimen and proceed with 
FOLFOX when resolved to < grade 2. May 
decrease oxaliplatin one dose level if not 
responsive to maximal antiemetic support. 
 
 
If resolved to < grade 2 on day of treatment, may 
proceed with intensification of antiemetic 
therapy and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of therapy, 
intensify antiemetic regimen and proceed with 
FOLFOX when resolved to < grade 2. Decrease 
oxaliplatin one dose level if not responsive to 
maximal antiemetic support. 
 
 

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Addendum 10 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 1-14 during cycle) 
Vomiting grade 
2 
 
 
 
 
Vomiting grade 
3 
 
 
 
 
 
 
 
 
Vomiting grade 
4 
 
 
 
 
 
 
 
 
 
Diarrhea grade 2  
 
 
 
 
 
 
 
Diarrhea grade 3 
 
 
 
 
 
 
 
Diarrhea grade 4 
 
 
Oxaliplatin 
 
 
 
 
 
5-FU 
Oxaliplatin 
 
 
 
 
 
 
 
 
 
 
 
 
Intensify antiemetic therapy and proceed with 
FOLFOX at current dose level. Maximal 
antiemetic therapy includes a 5HT inhibitor (i.e., 
granisteron, odansetron, palonestron) as well as 
compazine, lorazepam, aprepitant, and decadron.  
 
If resolved to < grade 2 on day of treatment, may 
proceed with intensification of antiemetic 
therapy and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of therapy, 
intensify antiemetic regime and proceed with 
FOLFOX when resolved to < grade 2. May 
decrease oxaliplatin one dose level if not 
responsive to maximal antiemetic support. 
 
If resolved to < grade 2 on day of treatment, may 
proceed with intensification of antiemetic 
therapy and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of therapy, 
intensify antiemetic regimen and proceed with 
FOLFOX when resolved to < grade 2. Decrease 
oxaliplatin one dose level if not responsive to 
maximal antiemetic support. 
 
 
If resolved to < grade 2, intensify antidiarrheal 
therapy and proceed with FOLFOX at current 
dose level. If not resolved to < grade 2, HOLD 
FOLFOX, intensify antidiarrheal therapy and 
proceed with FOLFOX when resolved to < grade 
2. 
 
If resolved to < grade 2, intensify antidiarrheal 
therapy and proceed with FOLFOX, decreasing 
5FU and oxaliplatin one dose level. If not 
resolved to < grade 2, HOLD FOLFOX, intensify 
antidiarrheal therapy and proceed with FOLFOX 
decreasing 5FU and oxaliplatin one dose level 
when resolved to < grade 2 
 
If resolved to < grade 2, intensify antidiarrheal 
therapy and proceed with FOLFOX, decreasing 
5FU and oxaliplatin one dose level. If not 
resolved to < grade 2, HOLD FOLFOX, intensify 
antidiarrheal therapy and proceed with FOLFOX 
decreasing 5FU and oxaliplatin one dose level 

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Addendum 10 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 1-14 during cycle) 
 
 
 
 
 
 
Oral mucositis, 
Esophagitis, 
gastritis, 
pharyngeal 
mucositis, small 
intestinal 
mucositis, 
colitis, rectal 
and/or anal 
mucositis  grade 
3 
 
Oral mucositis, 
Esophagitis, 
gastritis, 
pharyngeal 
mucositis, small 
intestinal 
mucositis, 
colitis, rectal 
and/or anal 
mucositis  grade 
4 
when resolved to < grade 2 
 
Hold FOLFOX until mucositis improves to < 
grade 2 then resume with one dose level 
reduction of 5-FU and the previous dose level of 
oxaliplatin  
  
 
 
 
Hold FOLFOX until mucositis improves to < 
grade 2 then resume with two dose level 
reduction of 5-FU and the previous dose level of 
oxaliplatin  
 
Blood and 
lymphatic system 
disorders 
Neutropenia 
  ANC 1000-
1199 
 
Neutropenia 
  ANC < 1000 
 
 
 
Febrile 
neutropenia 
 ANC <1000 
and  
 temp ≥ 38.5o C 
 
 
 
5-FU 
Oxaliplatin 
 
Hold FOLFOX until ANC ≥ 1200 then resume at 
previous dose levels.  
 
Hold FOLFOX until ANC ≥ 1200 then resume 
with one dose level reduction of both 5-FU and 
oxaliplatin for all subsequent cycles or at same 
dose level with pegylated GCSF given at a dose 
of 6 mg/kg on day of 5FU disconnection. 
 
Hold FOLFOX until fever has resolved and ANC 
≥ 1200 then resume with one dose level 
reduction of both 5-FU and oxaliplatin for all 
subsequent cycles or at same dose level with 
pegylated GCSF given at a dose of 6 mg/kg on 
day of 5FU disconnection. 
 
Hold FOLFOX until platelets ≥ 75,000 then 

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Addendum 10 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 1-14 during cycle) 
 
Thrombocytope
nia 
 Platelets 50,000 
–  74,999 
 
Thrombocytope
nia 
 Platelets < 50, 
000 
resume at previous dose levels.  
 
Hold FOLFOX until platelets ≥ 75,000 then 
resume FOLFOX with one dose level reduction 
of both 5-FU and oxaliplatin for all subsequent 
cycles.  
ENT 
Pharyngola
ryngeal 
dysesthesia 
 
Oxaliplatin 
Increase the duration of oxaliplatin infusion to 
six hours for all subsequent cycles.  
Pulmonary 
disorders 
Cough, 
dyspnea, 
hypoxia, 
pneumonitis or 
pulmonary 
infiltrates, grade 
≥ 3. 
5-FU 
Oxaliplatin 
Hold oxaliplatin until interstitial lung disease is 
ruled out. Continue 5-FU/leucovorin. 
Discontinue study if interstitial lung disease is 
confirmed. 
Thrombotic 
microangiopathy 
Hemolytic 
uremic 
syndrome 
(HUS) ≥ grade 3 
5-FU 
Oxaliplatin 
Discontinue oxaliplatin. Continue  
5-FU/leucovorin. 
Immune system 
disorders 
Allergic 
reaction 
  grade 1 
 
Allergic 
reaction 
 grade 2 
 
 
 
 
 
Allergic 
reaction 
 grade 3 or 4 
Oxaliplatin 
Leucovorin 
Decrease infusion rate by 50% until symptoms 
resolve, then resume at initial planned rate. 
 
Stop FOLFOX infusion. Administer H1 and/or 
H2 blockers and/or steroids according to local 
medical site policy. Restart infusion when 
symptoms resolve and pretreat before all 
subsequent doses. Treat according to local 
medical site policy. 
 
Stop the infusion. Discontinue FOLFOX. Treat 
according to local medical site policy. 
Skin and 
subcutaneous 
tissue 
disorders 
 
Extravasation 
 
 
 
Oxaliplatin 
 
 
 
Extravasation of oxaliplatin has been associated 
with necrosis. If extravasation is suspected, stop 
the FOLFOX infusion and restart at another site. 
Treat according to local medical site policy. 

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Addendum 10 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used unless 
otherwise specified     
SYSTEM/ORG
AN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 1-14 during cycle) 
Other  
Non-hematologic 
Grade 3 or 
Grade 4  
 
5-FU 
Oxaliplatin 
Leucovorin 
 
Hold FOLFOX until toxicity ≤ grade 1 then 
resume with one dose level reduction of both 5-
FU and oxaliplatin 
Neurological 
Neurotoxicity 
grade 2 
persisting 
between 
treatment cycles 
 
Neurotoxicity 
grade 3 
resolving to ≤ 
grade 2 between 
treatment cycles 
 
Neurotoxicity 
grade 3 
persisting 
between 
treatment cycles 
 
 
Neurotoxicity 
grade 4 
Oxaliplatin 
 
Continue FOLFOX with previous dose level of 
5-FU and one dose level reduction of oxaliplatin 
for all subsequent cycles. 
 
Continue FOLFOX with previous dose level of 
5-FU and one dose level reduction of oxaliplatin 
for all subsequent cycles. 
 
 
Discontinue oxaliplatin. Continue 5-
FU/leucovorin. Reassign to 5FUCMT if has not 
completed at least 5 cycles of FOLFOX.  
 
Discontinue oxaliplatin. Continue 
5FU/leucovorin. Reassign to 5FUCMT if has not 
completed at least 5 cycles of FOLFOX.  
Cardiovascular 
Cardiac 
ischemia or 
infarction grade 
3 or 4 
 
Cerebrovascular 
ischemia grade 
3 or 4 
 
Discontinue all study therapy. 
 
 
Discontinue all study therapy. 
*Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
The following describe actions in the Dosage Change column: 
➢ Omit = Treatment is not given for this cycle 
➢ Hold = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped  
8.5 
Oxaliplatin-induced Pharyngolaryngeal Dysesthesia 
If a patient develops oxaliplatin-induced pharyngolaryngeal dysesthesia, evaluate the oxygen 
saturation with a pulse oximeter; if normal, an anxiolytic agent may be given and the patient 
observed in clinic until the episode has resolved. Increase the duration of infusion of oxaliplatin 
to six hours for all subsequent treatment cycles.  
Pharyngolaryngeal dysesthesia may appear similar to a hypersensitivity reaction.  

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Addendum 10 
The table below compares the two. 
Table 8.6 Comparison of the symptoms and treatment of pharyngolaryngeal dysesthesias 
and platinum hypersensitivity 
Clinical Symptoms 
Pharyngolaryngeal dysesthesias 
Platinum hypersensitivity 
Dyspnea 
Present 
present 
Bronchospasm 
Absent 
present 
Laryngospasm 
Absent 
present 
Anxiety 
Present 
present 
O2 saturation 
Normal 
decreased 
Difficulty swallowing 
present (loss of sensation) 
absent 
Pruritis 
Absent 
present 
Urticaria/rash 
Absent 
present 
Cold-induced symptoms Yes 
no 
Blood pressure 
normal or increased 
normal or decreased 
Potential treatments 
Anxiolytics, observation in a 
controlled clinical setting until 
symptoms abate or at the 
physician’s discretion 
Oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
8.6 
Dose Modifications Based on Body Weight 
All dosing is to be determined solely by actual weight. This will eliminate the risk of calculation 
error and the possible introduction of variability in dose administration. Failure to use actual 
body weight in the calculation of drug dosages will be considered a major protocol deviation.  
The actual weight on the day of registration or the first day of treatment may be used for cycle 
1 unless the change in the weight results in a change in calculated dose ≥10%, in which case the 
weight on the day of treatment should be used. Over the course of treatment it is not required to 
change the doses of 5-FU, leucovorin or oxaliplatin due to changes in weight unless the 
calculated dose changes by ≥10%. 
 
 

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Addendum 10 
Table 8.7 
5FUCMT Dose Modifications Based on Retreatment 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used  unless 
otherwise specified     
SYSTEM/OR
GAN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT   
(Occurring on Day 1-5 of Each Week of the 5.5 Weeks of Radiation Treatment)  
Gastrointestinal 
disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
disorders 
Nausea grade 3 
 
 
 
Vomiting grade 
3 
 
 
 
Vomiting grade 
4 
 
 
 
Diarrhea grade 3 
 
 
 
Diarrhea grade 4 
 
 
 
Oral mucositis  
grade 3   
 
 
 
 
Oral mucositis 
grade 4 
 
 
 
 
 
 
Esophagitis, 
gastritis, 
pharyngeal 
mucositis, small 
intestinal 
mucositis, 
colitis, rectal 
and/or anal 
5-FU 
Capecitabine 
 
 
5-FU 
Capecitabine 
 
 
 
 
 
 
5-FU 
Capecitabine 
 
 
 
 
 
 
5-FU 
Capecitabine 
 
 
 
 
 
 
 
 
 
 
 
 
5-FU 
Capecitabine 
Hold 5-FU or capecitabine until nausea improves 
to ≤ grade 1 then resume 5-FU or capecitabine 
with one dose level reduction. 
 
Hold 5-FU or capecitabine until vomiting 
improves to ≤ grade 1 then resume 5-FU or 
capecitabine at the previous dose level.  
 
Hold 5-FU or capecitabine until vomiting 
improves to ≤ grade 1 then resume 5-FU or 
capecitabine with one dose level reduction.  
 
Hold 5-FU or capecitabine until diarrhea 
improves to ≤ grade 2 then resume 5-FU or 
capecitabine with one dose level reduction.  
 
Hold 5-FU or capecitabine until diarrhea 
improves to ≤ grade 1 then resume 5-FU or 
capecitabine with two dose level reductions. 
 
Hold 5-FU or capecitabine until mucositis 
improves to ≤ grade 1. Omit 5-FU or 
capecitabine for remainder of cycle. Resume 5-
FU or capecitabine with one dose level reduction 
for next cycle.  
 
Hold 5-FU or capecitabine until mucositis 
improves to ≤ grade 1. Omit 5-FU or 
capecitabine for remainder of cycle. Resume 5-
FU or capecitabine with two dose level 
reductions for next cycle.  
 
 
 
Hold 5-FU or capecitabine until mucositis 
improves to ≤ grade 1. Omit 5-FU or 
capecitabine for remainder of cycle. Resume 5-
FU or capecitabine with one dose level reduction 
for next cycle.  
 
 
Hold 5-FU or capecitabine until mucositis 
improves to ≤ grade 1. Omit 5-FU or 
capecitabine for remainder of cycle. Resume 5-

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Addendum 10 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* is used  unless 
otherwise specified     
SYSTEM/OR
GAN/CLASS 
(SOC)  
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT   
(Occurring on Day 1-5 of Each Week of the 5.5 Weeks of Radiation Treatment)  
mucositis  grade 
3 
 
Esophagitis, 
gastritis, 
pharyngeal 
mucositis, small 
intestinal 
mucositis, 
colitis, rectal 
and/or anal 
mucositis  grade 
4 
FU or capecitabine with two dose level 
reductions for next cycle.  
Skin and 
subcutaneous 
tissue 
disorders 
Palmer-plantar 
erythrodysesthes
ia syndrome 
grade 3 
5-FU 
Capecitabine 
 
 
Hold 5-FU or capecitabine for remainder of 
cycle. Decrease 5-FU or capecitabine by one 
dose level for the next cycle 
Other  
non-
hematologic 
Grade 3  
 
 
 
Grade 4 
5-FU 
Capecitabine 
Hold 5-FU or capecitabine until toxicity ≤ grade 
1 then resume 5-FU or capecitabine with one 
dose level reduction.  
 
Discontinue 5-FU or capecitabine for remainder 
of cycle. Restart next cycle with one dose level 
reduction of 5-FU or capecitabine.  
 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE 
9.1 
Supportive Care 
Patients should receive routine supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions.  
9.2 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.3 
Blood Products  
Blood products are permissible. The use of erythropoietin is strongly discouraged in the adjuvant 
setting and is not permitted in this trial. 
9.4 
Neulasta and Neupogen 
Neulasta and Neupogen should not be started as part of initial therapy and are not usually 
necessary with neoadjuvant FOLFOX or chemoradiation, but may be used to support 
maintenance of dose delivery and schedule according to physician discretion. ASCO guidelines 
for the use of growth factors are described in “2006 Update of Recommendations for the Use of 

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Addendum 10 
White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guidelines” J Clin 
Oncol 24(19): 3187-3205, 2006. 
9.5 
Diarrhea 
Diarrhea should be managed with loperamide. The recommended dose of loperamide is 4 mg at 
first onset, followed by 2 mg every 2-4 hours until diarrhea free (maximum 16 mg/day). 
Use of alternative agents such as Lomotil and tincture of opium is permissible. 
10.0 ADVERSE EVENT (AE) REPORTING AND MONITORING  
For SAKK sites, please refer to the Swiss Specific Appendix for information regarding safety 
reporting and SAEs. 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. However, CTCAE version 5.0 must be used for serious AE reporting 
through CTEP-AERS as of April 1, 2018. All appropriate treatment areas should have access to 
a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website:
 
10.1.1 Adverse event monitoring and reporting is a routine part of every clinical trial. First, 
identify and grade the severity of the event. Next, determine whether the event is expected 
or unexpected (see Section 10.2) and if the adverse event is related to the medical treatment 
or procedure (see Section 10.3). With this information, determine whether the adverse 
event must be reported as an expedited report (see Section 10.4). Important: Expedited 
adverse event reporting requires submission of a CTEP Adverse Event Reporting System 
(CTEP-AERS) report(s) using CTCAE v5.0. Expedited reports are to be completed within 
the timeframes and via the mechanisms specified in Section 10.4 and 10.5. All AEs 
reported via expedited mechanisms must also be reported via the routine data reporting 
mechanisms defined by the protocol (see Section 10.4 and Section 17.0). 
10.1.2 Each CTCAE term in the current version is a unique representation of a specific event used 
for medical documentation and scientific analysis and is a single MedDRA Lowest Level 
Term (LLT). Grade is an essential element of the Guidelines and, in general, relates to 
severity for the purposes of regulatory reporting to NCI. 
Note: A severe AE, as defined by the above grading scale, is NOT the same as serious AE 
which is defined in the table in Section 10.4. 
10.2 
Expected vs. Unexpected  
The determination of whether an AE is expected is based on the agent-specific information 
provided in Section 15.0 of this protocol. 
Unexpected AEs are those not listed in the agent-specific information provided in Section 15.0 
of this protocol. 
Note: “Unexpected adverse experiences” means any adverse experience that is neither identified 
in nature, severity, or frequency of risk in the information provided for IRB review nor 
mentioned in the consent form.  
 
 

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10.2.1 Comprehensive Adverse Events and Potential Risks (CAEPR) List 
Information contained in the CAEPR is compiled from the Investigator’s Brochure, the 
Package Insert (for those investigational agents that are available commercially) as well as 
company safety reports, AEs submitted through CTEP-AERS, and peer-reviewed 
publications that contain safety information not contained in the current IB or Package 
Insert. The safety profile for an investigational agent is reviewed at least annually in 
accordance with current Good Clinical Practice (cGCP) guidelines. It may be amended 
more frequently in response to an emerging safety profile for the agent/intervention, e.g., 
in conjunction with an Action Letter. 
• 
Protocol specific exceptions to expedited reporting of serious adverse events are 
found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion 
of the CAEPR (see Section 15.1.7). 
10.2.2 Studies Requiring the Inclusion of a CAEPR:   
NCI requires the inclusion of a CAEPR in studies described below. Other studies can utilize 
the NCI CAEPR as well. 
• 
For all studies conducted under a NCI IND. 
• 
For all studies reviewed by CTEP/CIP that includes agents/interventions for which NCI 
has a CAEPR. 
10.2.3 As the CAEPR is updated the SPEER is also revised and the revisions will be sent to all 
Principal Investigators registered to NCI-approved studies using the agent(s). A copy of 
the current CAEPR (containing the SPEER) may also be obtained via email from 
 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
Definite -  
The adverse event is clearly related to the agent(s). 
Probable -  
The adverse event is likely related to the agent(s). 
Possible -  
The adverse event may be related to the agent(s). 
Unlikely -  
The adverse event is doubtfully related to the agent(s). 
Unrelated -  
The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a medical treatment 
suggest there is evidence to indicate a causal relationship between the drug and the adverse 
event.  
10.3.1  Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormalities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent since they are considered to be a serious AE and must 
be reported to the sponsor as specified in 21 CFR 312.64(b). 
10.3.2 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention requires expedited reporting within 24-hours. 
Any death occurring greater than 30 days with an attribution of possible, probable, or 
definite to an agent/intervention requires expedited reporting within 24-hours. 

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Reportable Categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term associated 
with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the onset of 
symptoms) or an unobserved cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and administration 
site conditions.” Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
10.3.3 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g. 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent be 
reported via CTEP-AERS. Three options are available to describe the event: 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
Myelodysplastic syndrome (MDS) 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
10.3.4 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
reporting via CDUS. 
10.3.5 Pregnancy 
Pregnancy occurring in a female patient should be reported via CTEP-AERS, using the 
even term and severity grade “pregnancy, puerperium and perinatal conditions – other, 
pregnancy (grade 3). 
• 
Pregnancy should be followed until the outcome is known 
• 
CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). 
Pregnancy loss 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” 
under the Pregnancy, puerperium and perinatal conditions SOC. 
• 
A Pregnancy loss should not be reported as a Grade 5 event under the Pregnancy, 
puerperium, and perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
 
 

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10.4 
Expedited Reporting Requirements  
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial 
within 30 Days of the Last Administration of a Commercial Agent 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 

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• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but 
rather should be reported via routine reporting methods (e.g., CDUS and/or CTMS). 
Refer to Section 10.4.2 for NCI Contact Information or Technical Help regarding CTEP-
AERS reporting.  
In the rare event when internet connectivity is disrupted, a 24 hour notification must be 
made to NCI by telephone. An electronic report must be submitted immediately upon 
establishment of internet re-connection.  
Please see Section 10.2 for more details regarding reporting of adverse events. 
Please refer to Section 15.1.7 for the CAEPR and protocol specific exceptions to expedited 
reporting of serious adverse events.  
10.4.1 Additional Instructions or Exclusions to CTEP-AERS Reporting 
• 
All adverse events reported via AERS (i.e. serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
• 
Grade 1-3 nausea or vomiting and hospitalization resulting from such do not 
require AERS reporting, but should be reported via routine AE reporting. 
• 
Grade 3 nausea or vomiting does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 diarrhea and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 3 diarrhea does not require AERS reporting, but should be reported via 
routine AE reporting 
• 
Grade 1-3 mucositis and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 3 mucositis does not require AERS reporting, but should be reported via 
routine AE reporting 
• 
Grade 1-3 hand foot syndrome and hospitalization resulting from such do not 
require AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 hand foot syndrome does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 dehydration and hospitalization resulting from such do not require 
AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 dehydration does not require AERS reporting, but should be reported via 
routine AE reporting 
• 
Grade 1-3 fatigue and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting. 
• 
Grade 3 fatigue does not require AERS reporting, but should be reported via 
routine AE reporting 
• 
Grade 1-3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, 
and thrombocytopenia) with hospitalization resulting from such do not require 
AERs reporting, but should be reported via routine AE reporting 

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• 
Grade 3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and 
thrombocytopenia) does not require AERs reporting, but should be reported via 
routine AE reporting 
10.4.2 Contact Information for NCI Safety Reporting 
Website for submitting expedited reports 
 
CTEP-AERS-MD Help Phone (for 
CTEP)* 
 Monday through Friday,  
7:00 AM to 7:00 PM (US Eastern Time) 
Cancer Imaging Program (CIP) Help 
Phone for SAE reporting* 
 Monday through Friday,  
7:00 AM to 7:00 PM (US Eastern Time) 
Fax for expedited report supporting 
Medical Documentation for CTEP trials 
  
 
Fax for expedited report supporting 
Medical Documentation for CIP trials 
 
CTEP-AERS-MD Help Email 
  
CIP SAE Reporting Email 
 
Technical (e.g., IT or computer issues 
ONLY) Help Phone* 
 
CTEP-AERS Technical Help Email 
  
CTCAE v4 Help/Questions Email 
  
CTEP-AERS FAQs link 
 
CTEP-AERS Computer Based Training 
link 
 
 
*Office phone and fax are accessible 24 hrs per day 7 days a week. The CTEP-AERS -MD phone 
line is staffed from Monday through Friday, 7:00 AM to 7:00 PM ET. Any phone call after these 
hours will go to voicemail. Please leave contact information and the phone call will be returned 
the following business day. 
10.5 
Other Required Expedited Reporting 
 
EVENT TYPE 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
 
Complete an electronic-CRF Notification Form: Grade 4 or 5 Non-
AER Reportable Events/Hospitalization Form (via RAVE) within 5 
working days of the date the clinical research associate (CRA) is 
aware of the event(s) necessitating the form. 
If a CTEP-AERS report has been submitted, this form does not 
need to be submitted. 
 
 
 

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10.5.1 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
evaluate at baseline per CTCAE v4.0 grading unless otherwise stated in the table below: 
            
System Organ 
Class (SOC) 
 
 
Adverse event/Symptoms 
 
 
Baseline 
 
Each  
evaluation 
Gastrointestinal 
disorders 
Dysphagia 
Diarrhea 
Constipation 
Nausea 
Vomiting 
Mucositis oral 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
Dyspnea 
 
x 
 
x 
Nervous system 
disorders 
Peripheral sensory neuropathy 
x 
x 
General disorders 
and 
administration 
site conditions 
 
Pain 
Fatigue 
 
 
x 
x 
 
x 
x 
Metabolism and 
nutrition 
disorders 
 
Anorexia 
 
 
x 
 
x 
Psychiatric 
disorders 
Anxiety 
Depression 
x 
x 
x 
x 
 
10.5.2 Submit via electronic Case Report Forms the following AEs experienced by a patient and 
not specified in Section 10.5.1: 
10.5.2.1 
Grade 4 AEs regardless of attribution to the study treatment or procedure. 
10.5.2.2  
Grade 5 AEs (Deaths) 
10.5.2.2.1 Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
10.5.2.2.2 Any death more than 30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 
10.5.3 Refer to the instructions in the Case Report Forms Packet (or electronic data entry screens, 
as applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
11.0 TREATMENT EVALUATION  
Guidance for Evaluation after Neoadjuvant Treatment 
Group 2 patients (5FUCMT) are not required to undergo repeat tumor imaging or proctoscopy 
after chemoradiation. Reevaluation prior to surgery is at the discretion of the primary treating 
clinicians.  
 

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Group 1 patients (FOLFOX) 
• 
Are required to undergo repeat tumor imaging after 6 cycles of FOLFOX. Repeat imaging 
should include the same modality that was used at baseline. 
o If a baseline MRI was performed, a post-FOLFOXx6 MRI should be repeated. 
o If a baseline ERUS was performed, a post-FOLFOXx6 ERUS should be repeated. 
• 
Are required to undergo repeat clinical assessment of the primary tumor by proctoscopy 
• 
The decision as to whether Group 1 patients proceed directly to TME or alternatively, receive 
5FUCMT and only then undergo TME, will be made on the basis of both tumor imaging and 
clinical tumor response based on proctoscopy. This is a clinical estimation as to whether 
there has been at least a 20% decrease in the tumor in response to neoadjuvant 
FOLFOX treatment. In the event of clinical disagreement, the surgeon who will 
perform the TME decides if there has been an estimated 20% clinical response. 
Group 1 patients who do receive 5FUCMT are not required to undergo repeat tumor imaging 
after chemoradiation. 
Note: Proctoscopic assessment of whether there has been a 20% response is based on the 
performing clinician’s estimation. This information should be combined with careful 
radiologic review of the baseline and post neoadjuvant FOLFOX images in order to estimate 
whether there has been a 20% clinical response. These assessments are clinical estimations 
due to the challenges inherent in clinical rectal cancer staging.  
11.1 
Radiological Tumor Evaluation  
11.1.1 Timing of Restaging Evaluations: Group 1 Patients  
Patients should be reevaluated within 4 weeks after completion of six cycles of pre-
operative FOLFOX.  
11.1.2 Definitions of Measurable and Non-Measurable Disease 
11.1.2.1 
Measurable Disease (RECIST adaptation)  
Metastatic disease focus is considered measurable if its longest diameter can be 
accurately measured as 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT or MRI. This criteria will be used to identify distant 
recurrence. 
11.1.2.2 
A lymph node is considered measurable for purpose of estimating clinical nodal 
status if its short axis is ≥ 5.0 mm when assessed by CT scan or pelvic MRI. For 
this study, internal target iliac lymph nodes must measure ≥ 10 mm. 
11.1.2.3 
A malignant lymph node is considered measurable for purposes of ascertaining 
metastatic recurrence if its short axis is ≥ 1.5cm when assessed by CT scan or 
pelvic MRI 
11.1.2.4 
Non-Measurable Disease (Standard definition per RECIST) 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm). This 
includes: Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non measurable 
as well. 

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Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis < 1.0 
cm are considered non-pathological (i.e., normal) and should not be recorded or 
followed. 
11.1.3 Guidelines for Evaluation of Measurable Disease 
11.1.3.1 
Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers.  
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
11.1.3.2 
Acceptable Modalities for Measurable Disease:  
• 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. 
• 
Evaluation of the primary rectal tumor by pelvic MRI is preferred. However, 
for patients who are not able to undergo a pelvic MRI or for clinicians who 
prefer it, an ERUS is acceptable. If ERUS is performed as an alternative to 
pelvic MRI at baseline, then an ERUS must also be performed at the time of 
restaging.  
• 
In cases where ERUS is the modality selected to evaluate the primary rectal 
tumor, an accompanying CT for complete pelvic disease staging will also be 
interpreted by the on-site radiologist. A standard CT of the chest, abdomen and 
pelvis is required. For CT scans of the chest, contrast is preferred but not 
required. For CT scans of the abdomen and pelvis, contrast is required. In the 
event that radiologic studies yield inconsistent interpretation of T stage or N 
stage the modality that assigns the highest T stage or the highest N stage should 
be used for purposes of protocol eligibility.  
11.1.3.3 
Measurement at Follow-up Evaluation: 
• 
Cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). 
 
 

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11.1.4 Measurement of Effect – Imaging Tumor Response to Neoadjuvant FOLFOX (Group 
1 only) 
Note: “Adapted RECIST” (as defined in this protocol) is used and consists of the following: 
11.1.4.1 
Target Lesions & Target Lymph Nodes: 
• 
The Rectal Primary tumor is the primary target lesion. In addition, 
associated pelvic lymph nodes should be recorded and measured at baseline.  
• 
In order for the patient to proceed directly to TME, there should be NO 
evidence of progression and there should be evidence of clinical response that 
is estimated as ≥20%. 
• 
The primary rectal lesion is measured and followed as a bi-dimensional 
product to avoid measurements that include the GI tract lumen whether 
collapsed or filled with air, feces or contrast material which does not represent 
tumor tissue. The Bi-Dimensional Product (BDP) is the product of the longest 
diameter for the rectal primary tumor and the thickest wall. The BDP will be 
used as reference to further characterize any objective tumor response in the 
measurable dimension of the disease.  
• 
Post-Baseline Bi-Dimensional Product (PBDP): The product of the longest 
diameter of the rectal primary tumor multiplied by the thickest wall will be 
calculated and reported as the post-bi-dimensional product (PBDP).  If the 
radiologist is able to provide an actual measure for the target even if it is 
below 0.5 cm. If the target is believed to be present and is faintly seen but too 
small to measure, a default value of 0.5 cm should be assigned. If it is the 
opinion of the radiologist that the rectal primary has likely disappeared, the 
measurement should be recorded as 0 cm. 
• 
Given increased error in measuring smaller structures, and given differing 
qualities of MRI and their resolution, diminutive nodes are those measuring 
0-4mm. These will not be considered evaluable for change. Evaluable nodes 
are those 5mm or greater in the mesorectal and superior hemorrhoidal 
location.  
• 
To be labeled as a target lymph node: up to 4 nodes in the mesorectal, 
superior hemorrhoidal and internal iliac regions may be considered “target” 
lymph nodes. Mesorectal and superior hemorrhoidal regions must measure 5 
mm or greater in the short axis. Internal iliac lymph nodes must measure 10 
mm or greater in short axis. 
• 
To categorize the primary tumor as consistent with clinical stage N2 
disease, ≥4 lymph nodes must measure >10mm in short axis. 
11.1.4.2 
Imaging Response Criteria:  
11.1.4.2.1 For purpose of restaging, a target lymph node must measure 5 mm or more in short 
axis. 
• 
Target lymph nodes, which at baseline measure between 5 and 10mm short 
axis inclusive, must increase 3mm in size to be considered PD. Nodes 
between 11 and 20 mm short axis inclusive must increase in size 4mm to be 
considered PD. Nodes 20mm and greater in short axis must increase in size 
by 25%, (e.g., 20mm to 25mm, or 25mm to 31mm) to be considered PD. 
• 
An internal target iliac lymph node (“obturator,” etc.), must be greater than 
or equal to 10 mm in short axis diameter to be considered evaluable and will 

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follow the same rules as above for absolute increase in size. 
11.1.4.2.3 Evaluation of the Rectal Primary and Target Lymph Nodes 
1. Complete Response (CR): 
All of the following must be true: 
a.    Disappearance of the rectal primary.  
b.    Each target lymph node must have decreased 
short axis to <5mm. 
c.    No new sites of disease. 
2. Partial Response (PR): 
At least a 20% decrease in PBDP 
(bi-dimensional product of primary rectal lesion)  
No new sites of disease. No PD of any target 
lymph nodes 
3. Stable disease (SD): 
Defined as neither sufficient shrinkage to qualify 
for PR nor sufficient increase to qualify for PD.   
4. Progression (PD): 
At least one of the following must be true: 
a. 
At least one new malignant lesion, which 
also includes any lymph node that was 
normal at baseline (< 1.5 cm short axis) and 
increased to ≥ 1.5 cm short axis during 
follow-up. 
b. At least a 20% increase in PBDP (bi-
dimensional product of rectal primary lesion) 
taking as reference the BDP. 
11.1.4.3 
Overall Radiologic Tumor Response Status after Neoadjuvant FOLFOX 
The radiologic tumor response status after neoadjuvant FOLFOX for Group 1 
patients is determined by combining the patient’s status on primary rectal tumor, 
target lymph nodes, and new disease as defined in the following tables:  
For Patients with Measurable Disease:  
Primary Rectal Tumor 
& 
Target Lymph Nodes 
New Sites of 
Disease 
Overall Radiologic 
Tumor Response 
Status 
CR 
No 
CR 
PR 
No 
PR 
SD 
No 
SD 
Not all Evaluated 
No 
Not Evaluated (NE) 
PD 
Yes or No 
PD 
 
 

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11.2 
Clinical Tumor Evaluation  
11.2.1 Schedule and Record Information for Proctoscopy and Rectal Examination 
Proctoscopy 
Assessment 
Group 1 
Group 2 
Record Group 1 
Information 
Record Group 2 
Information 
Baseline-
pretreatment 
Prior to first 
dose of 
FOLFOX 
Prior to first 
dose of pelvic 
radiation 
On Study Form 
On Study Form 
Reevaluation after 
initial neoadjuvant 
treatment 
≤ 28 days after 
completion of 
FOLFOX (in 
other words, ≤ 
28 days after 
cycle 6 day 14 
of FOLFOX) 
Not required. 
Performed at 
clinician’s 
discretion 
Reevaluation After 
Pre-Operative 
FOLFOX (Group 1 
Only) Form for 
Group 1: AFTER 
FOLFOX, 
BEFORE 
5FUCMT-Surgery 
N/A 
15 months from 
randomization 
+/- 1 month 
+/- 1 month 
Disease Status 
Follow-up Form 
Disease Status 
Follow-up Form 
Annually (Every 12 
months +/- 1 
month) starting with 
15 month 
reassessment 
Continue until 
whichever 
comes first: any 
recurrent 
disease or 5 
years from 
randomization 
Continue until 
whichever 
comes first: any 
recurrent disease 
or 5 years from 
randomization 
Disease Status 
Follow-up Form 
Disease Status 
Follow-up Form 
 
Rectal 
Examination 
Group 1 
Group 2 
Record Group 1 
Information 
Record Group 2 
Information 
Baseline-
pretreatment 
Prior to first 
dose of 
FOLFOX 
Prior to first 
dose of pelvic 
radiation 
On Study Form 
On Study Form 
Reevaluation after 
initial neoadjuvant 
treatment 
≤ 28 days after 
completion of 
FOLFOX (in 
other words,  
≤ 28 days after 
cycle 6 day 14 
of FOLFOX) 
Not required. 
Performed at 
clinician’s 
discretion 
Reevaluation After 
Pre-Operative 
FOLFOX (group 1 
Only) Form for 
Group 1: AFTER 
FOLFOX, 
BEFORE 
5FUCMT-Surgery 
N/A 
 
 

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11.2.2 Guidelines for Evaluation of Clinically Evaluable Disease 
11.2.2.1 
Measurement Methods: 
• All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• The same method of assessment must be used to characterize each identified 
and reported lesion at baseline and at the follow up evaluation. 
• Proctoscopy with direct visualization is the accepted clinical evaluation. 
• Virtual colonoscopic assessments are not acceptable. 
 
11.2.3 Definition of Clinically Evaluable Disease 
To be clinically evaluable, a tumor must be directly visualized at proctoscopy and 
estimated to have a Clinical Bidimensional Product (BDP) of ≥ 1 centimeter. 
11.2.4 Clinical Tumor Response Based on Proctoscopy Can be Classified as the Following: 
• 
Complete response (100%) 
• 
Major response (51% to 100% smaller) 
• 
Moderate response (21% to 50% smaller) 
• 
Minimal response (0% to 20% smaller) 
• 
Progression (tumor has enlarged) 
• 
Unable to determine 
11.2.5 Treatment Decision for Group 1 Patients after Re-evaluation Following 6 Cycles of 
Neoadjuvant FOLFOX 
• 
If there is any evidence of progressive disease (PD) on either imaging or 
clinical assessment, the patient proceeds to 5FUCMT. 
• 
If there is an estimated ≥ 20% response on imaging OR if there is an 
estimated response of ≥ 20% on proctoscopy, the patient proceeds 
directly to TME. 
• 
Otherwise, the patient proceeds to 5FUCMT. 
• 
The primary surgeon adjudicates decision making in the event of clinical 
inconsistency or disagreement among clinical team members. 
11.3 
Pathological Tumor Response 
All operative and pathology reports for the TME resection must be submitted. Reports must 
contain information about microscopic involvement of surgical resection margins.  
De-identified reports may be submitted via iMedidata RAVE using the Supporting 
Documentation Form. 
If site is unable to electronically submit the reports, de-identified operative and pathology 
reports may be submitted to the Alliance Statistics and Data Center, Attention N1048 Data 
Manager via: 
Fax:  
 
or 
Postal Mail: 
 
 
 
 
11.3.1 Definition of Surgical Margin Status 

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11.3.1.1 
Margin Type:  
 
Proximal Margins 
The proximal surgical margin refers to the most 
cephalad portion of the specimen (closest to patient's 
head). 
 
Distal Margins 
The distal margin refers to the most caudad portion 
(closest to anal canal). 
 
Radial Margins 
The radial margin, synonymously termed 
circumferential margin refers to the outer 
circumference of the rectal specimen. 
 
11.3.1.2 
Margin Positivity: 
 
Positive 
A surgical margin is POSITIVE if the pathologist notes 
tumor within ≤ 1mm of any edge of the primary tumor 
specimen. 
 
Close 
A surgical margin is CLOSE if the pathologist notes 
tumor > 1 but ≤ 3mm of any edge of the primary tumor 
specimen. 
 
Negative 
A surgical margin is NEGATIVE if the pathologist 
notes that there is NO tumor within 3mm of any edge 
of the primary tumor specimen. 
11.3.2 Overall Completeness of TME Resection 
The AJCC 7th edition criteria will be used to categorize the completeness of the TME 
resection. This categorization schema should focus on the pelvic resection of the TME 
specimen. If distant tumor is appreciated intraoperatively (for example, a liver metastasis), 
the pelvic resection may still be considered R0. 
 
R0 resection 
All gross disease has been removed, and microscopic 
examination reveals all surgical margins free of tumor. This 
must include the proximal, distal and radial margin.   
Tumor > 1mm from the tumor resection margins is considered 
R0. In some cases, intraoperatively, a surgeon may biopsy a liver 
nodule or retroperitoneal node. Resection will still be considered 
curative if pathologic examination reveals positive lymph nodes 
as long as the nodes were completely resected, unless there is 
also evidence of positive margins. 
R1 resection 
There is evidence of tumor manifest at 1 or more surgical 
resection margins based on microscopic pathologic assessment 
of the tumor specimen but there is no macroscopic evidence of 
tumor at any resection margin nor is there macroscopic evidence 
of residual tumor based on the surgeon's operative report. 
R2 resection 
The surgical pathologist identifies any macroscopic evidence of 
tumor at any of the surgical resection margins or there is 
macroscopic evidence of residual tumor based on the surgeon's 
operative report. 
No resection 
Removal of the primary tumor was not performed. 
 
 
 

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Pathologic TNM Staging: After TME resection, patients will be staged according to 
the AJCC7th edition schema. 
T describes how far the main (primary) tumor has grown into the wall of the intestine and 
whether it has grown into nearby areas. Because this information will be ascertained from 
the surgical pathology report it is denoted with a prefix “p”. Because it is ascertained after 
neoadjuvant treatment, the prefix “y” is also added (e.g., ypT3). 
 
Tx 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ: intraepithelial or invasion of lamina propria  
T1 
Tumor invades submucosa 
T2 
Tumor invades muscularis propria 
T3 
Tumor invades through the muscularis propria into pericolorectal tissues 
 
IMPORTANT: T4 PATIENTS ARE NOT ELIGIBLE FOR THIS STUDY AT 
BASELINE. T4A VERSUS T4B DISEASE CANNOT BE RELIABLY 
DISTINGUISHED RADIOGRAPHICALLY. This categorization is included below 
because it is obtained from the AJCC 7th Edition schema. In rare cases, a patient may 
progress despite neoadjuvant treatment; a reassessment could indicate T4 disease. In this 
case, the radiologist should record the best clinical estimate using the AJCC criteria 
listed below:   
T4a 
Tumor penetrates to the surface of the visceral peritoneum 
T4b 
Tumor directly invades or is adherent to other organs or structures 
 
N describes the extent of spread to nearby (regional) lymph nodes based on the 
rectal resection specimen. The prefix “yp” is added as described for T status. 
 
Nx 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in 1-3 regional lymph nodes  
N2 
Metastasis in 4 or more regional lymph nodes 
 
To have clinical N1 disease, a patient must have fewer than 4 lymph nodes that measure 
10 mm or greater in short axis but 1 or more lymph nodes that measure 5 mm or greater. 
 
The following table illustrates hypothetical results of MRI staging studies and works 
through examples to guide patient eligibility. It is recognized and widely known that MRI 
based clinical rectal cancer staging is imperfect. These criteria are included to foster 
consistency across study sites. 
 
Lymph Node Number/Size 
Clinical Node + Disease 
Eligibility 
Five 7 mm lymph nodes 
Estimated cN1 
Eligible 
Six lymph nodes 
Two 12 mm lymph nodes 
Two 8 mm lymph nodes 
Estimated cN1 
Eligible 
Six lymph nodes 
Four 12 mm lymph nodes 
Estimated cN2 
Ineligible 
 
 
 

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M describes the extent of spread to distant sites outside of the pelvis. 
 
M0 
No distant metastasis outside the pelvis 
M1 
M1a: 
M1b:  
Distant metastasis outside the pelvis 
Confined to one organ or site 
In more than one organ/site 
 
Summary pathologic stage will be coded using the AJCC7th edition system. Each of the 
component TNM features based on information available from surgical pathology will be 
grouped according to this schema; the prefix “y” is used to connote that pathology must be 
interpreted in the context of neoadjuvant treatment and the “p” connotes pathologic stage. 
See Appendix XIII for the AJCC 7th Edition schema for colorectal cancer staging. 
  
Pathologic AJCC7 Summary Staging: 
 
Stage 
ypT 
ypN 
M 
0 
Tis 
N0 
M0 
I 
T1 
T2 
N0 
N0 
M0 
M0 
IIA 
T3 
N0 
M0 
IIB 
T4a 
N0 
M0 
IIC 
T4b 
N0 
M0 
IIIA 
T1-T2 
T1 
N1 or N1c 
N2a 
M0 
M0 
IIIB 
T3-T4a 
T2-T3 
T1-T2 
N1 or N1c 
N2a 
N2b 
M0 
M0 
M0 
IIIC 
T4a 
T3-T4a 
T4b 
N2a 
N2b 
N1-N2 
M0 
M0 
M0 
IVA 
Any T 
Any N 
M1a 
IVB 
Any T 
Any N 
M1b 
 
11.3.3 Degree of Pathological Treatment Response 
Pathological response will be made based on assessment of the surgical specimen at the 
primary treatment site. All pathology reports from the primary treatment site will be 
reviewed and evaluated for major and minor discordances in interpretation. A randomly 
selected sample of 15% of the pathologic TME specimens will be reviewed by the Alliance 
Central Pathologist. If ≥ 5% but < 20% of the TME specimens are interpreted as having a 
major difference in outcome upon central review, then 30% of the TME specimens will be 
reviewed by the Alliance Central Pathologist. The Alliance will provide funding for the 
central review of 30% of the pathologic TME specimens. Irrespective of whether the 
Central Pathologist reviews 15% or 30% of TME specimens, if ≥ 20% of the TME 
specimens reviewed by the Central Pathologist result in a major discordance in 
interpretation, additional resources will be requested from the Alliance and NCI to review 
additional TME specimens. If this occurs, a protocol amendment will be submitted to the 
NCI for review and approval specifying whether 100% of the TME specimens require 
central review or whether the Central Pathologist’s review will target specific sites with 
high rates of discordant interpretations.  
 

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A major discordance in treatment response will consist of a change from: 
• 
R0 to R1/R2 
• 
R1/R2 to R0 
• 
Path CR to non-CR 
• 
Non-CR to path CR 
• 
Identification of a histology that is inconsistent with rectal adenocarcinoma (e.g. 
squamous cell) 
A minor discordance in treatment response will exist if there is a change in interpretation 
such as: 
• 
Change in N status 
• 
Change in the number of involved nodes in the TME specimen 
• 
Change in T status 
• 
All other changes in treatment response, not defined above as a major discordance  
This assessment is made in addition to the AJCC 7th edition summary staging. 
11.3.3.1 
Pathological Complete Response (pCR):  
A pCR must include no gross or microscopic tumor identified anywhere within the 
surgical specimen. This must include: 
• 
No evidence of malignant cells in the primary tumor specimen 
AND 
• 
No lymph nodes that contain tumor. 
11.3.3.2 
Pathological Response other than a Complete Response: 
The definition of a non-pCR will include any surgical specimen that has any 
evidence of residual tumor manifest in the primary or regional lymph nodes. 
For patients who do not meet criteria for a pCR, the extent of response to pre-
operative therapy will be graded using the Tumor Regression Grade (TRG) schema 
that is included in the AJCC 7th edition. This was also used by Rodel in the 
pre/postoperative rectal cancer study and was subsequently adopted by the AJCC 
[Rodel (JCO 2005; 23:8688-8696)]. This schema evaluates the degree to which the 
primary rectal tumor specimen has responded to neoadjuvant treatment. 
Tumor Regression Coding Based on AJCC 7th Edition 
Tumor Regression Grade 
(TRG) 
Response 
Categorization 
Description 
TRG-0 
Complete  
No viable cancer cells 
TRG-1 
Moderate  
Single cells or small groups of cancer cells 
TRG-2 
Minimal  
Residual cancer outgrown by fibrosis 
TRG-3 
Poor  
Minimal or no tumor kill; extensive residual cancer 
 
Source: AJCC Cancer Staging Manual, 7th Edition (2010) published by Springer New York, Inc. 
 
11.3.3.3 
Neoadjuvant Response Score 
The Neoadjuvant Response Score (NAR) in rectal cancer has been used as a 
predictor of outcomes in locally advanced rectal cancer (George et al., 2015). It 

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remains controversial whether this predictor is superior to T and N staging (Imam 
et al., 2021; van der Valk et al., 2019). The NAR will be calculated for all 
participants and between group differences will be compared.  The NAR as 
formulated by George, Allegra, and Yothers in 2015 will be used (George et al., 
2015). Should there be updated versions of the formula, these updates will be 
incorporated. The NAR formula is estimated as: 
 
 

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11.4 
Post-operative Bowel Surveillance 
A full colonoscopy is suggested at 15 and 51 months after randomization. More frequent 
evaluation may be indicated based on findings such as adenomatous polyps or the presence of 
genetic predisposition. It is suggested that patients who did not undergo a complete colonoscopy 
to the cecum prior to initiation of preoperative treatment, undergo colonoscopy to evaluate for 
secondary colonic lesions prior to surgical resection.  
For proctoscopy and rectal examination, follow the schedules outlined in Section 11.2.1. Note 
that colonoscopy includes proctoscopy so that a colonoscopic surveillance examination also 
“counts” as a proctoscopic assessment. 
11.5 
Treatment Evaluation 
Treatment evaluation for Group 1 and 2 patients after completion of surgery and post-operative 
chemotherapy (and possible radiation) 
11.5.1 Patients will be evaluated as per the schedule of tests noted in Section 4.0 
11.5.2 At the time of reevaluation, patients will be classified in the following manner: 
11.5.2.1 
No evidence of disease (NED) 
11.5.2.2 
Recurrence of disease (REC) 
The appearance of rectal carcinoma in the primary site, nodal basin or distant organ 
sites during follow-up will be classified as recurrence cancer. Recurrence will be 
classified as local or distant.  
 
Patients may have local recurrence, distant recurrence, both or neither. Imaging 
should be used to document the extent of local and distant disease 
recurrence. Pathological confirmation of suspected distant metastasis should be 
performed based on clinical judgment and is not mandated. 
Although pathologic confirmation of recurrence is not mandated, local and distant 
recurrences will be categorized based on supporting evidence. Recurrences will be 
categorized based on whether they are evident from: 
 
11.5.2.3 
Second primary colorectal cancer (2PC) 
Second primary cancers are those that arise anywhere in the colon. Tumors 
involving the surgical anastamosis or arising from the pelvis are to be categorized 
as recurrent disease. 
Local recurrence 
Any tumor located in the pelvis or the perineal scar 
Distant recurrence 
Any tumor outside the pelvis and the perineal scar 
Pathology: 
Use this category if there is any pathology or cytology demonstrating recurrent 
rectal cancer. 
Serial Imaging: 
Use this category is for recurrences that have not been confirmed by pathology 
but where serial imaging studies (serial is defined as similar scans performed 
more than 30 days apart) indicate tumor. 
Clinical Evaluation: 
Use this category for recurrences that have not been confirmed by pathology or 
serial imaging studies but are manifest on physical exam or compelling imaging 
studies (absent serial images). 

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12.0 DESCRIPTIVE FACTORS AT BASELINE  
• 
Clinical Stage at Baseline Based on Pelvic MRI: cT2N1 vs. cT3N0 vs. cT3N1 vs. pelvic MRI 
not done 
• 
Clinical Stage at Baseline Based on ERUS and Pelvic CT: cT2N1 vs. cT3N0 vs. cT3N1 vs. 
ERUS and pelvic CT not done 
• 
History of Diabetes: Yes vs. No 
• 
History of Cardiovascular Disease: Yes vs. No 
• 
Highest Education Level: Less than high school vs. High school graduate or GED vs. Some 
college vs. College graduate or more 
 
 

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13.0 TREATMENT/FOLLOW–UP DECISION  
This section describes how to follow patients who are deemed ineligible, refuse treatment 
assignments; withdraw consent or who have violations or progression/recurrent disease. 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason 
before any study treatment is given. On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study 
entry. The patient may continue treatment off-protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly 
registered. The patient will go directly to the event-monitoring phase of the study. If 
the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. If the patient undergoes surgery, the surgery data 
must be submitted. Event monitoring will be required per Section 17.0 of the 
protocol. If the patient never received treatment, on-study material must be 
submitted. Event monitoring will be required per Section 17.0 of the protocol. 
Refusal 
Patients who refuse a treatment assignment after started the study treatment will go to 
the event-monitoring phase of the study. All data up until the point of refusal and 
surgery data (if the patient undergoes surgery) must be submitted. End of Active 
Treatment/Cancel Notification Form must be submitted. 
Withdrawal From 
Study Treatment 
but Not Consent 
Patients who withdraw from study treatment will go to event monitoring. If the 
patient undergoes surgery, the surgery data must be submitted. 
Withdrawal of 
Consent for 
Participation 
Patients who withdraw consent completely will be taken off study; study staff cannot 
collect any more study data on patient. If/when this occurs, site should notify the 
Data Manager (see Protocol Resources). 
Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end 
point is questionable. All data up until the point of confirmation of a major violation 
must be submitted. The patient will go directly to the event-monitoring phase of the 
study.  The patient may continue treatment off-protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly 
registered. Event monitoring will be required per Section 17.0 of the protocol. 
Minor Violation  
A patient is deemed a minor violation, if protocol requirements regarding treatment 
in cycle 1 of the initial therapy were violated such that evaluability for primary end 
point is nevertheless reasonable. For example, if baseline blood test fell outside the 
prescribed range, but all other criteria were met, the violation would be deemed 
minor. For minor violations, protocol directed treatment and observation should 
proceed. 
Progression Before 
Surgery 
Patients with disease progression preoperatively will continue with evaluation and 
treatment as outlined in Section 4.0. All patients should continue treatment per 
protocol and will continue to undergo observation. 
Persistent Disease 
at Surgery 
Rare patients in this study will have persistent disease at surgery. Persistent disease is 
defined as R1 or R2 resection. Patients who have persistent disease should continue 
observation until if and when there is progressive disease. 
Recurrence or 
Progression After 
Surgery 
Patients in this study will be rendered disease free after surgical resection. Patients 
who develop progression after surgery, which is new evidence of disease should be 
categorized as having local or pelvic recurrence. Subsequent to recurrence, patients 
should undergo event monitoring for survival. 
Failure to 
Complete 
Treatment 
Group 1 patients who fail to complete neoadjuvant FOLFOX x 6 will go to 
5FUCMT. 
Group 2 patients who fail to complete neoadjuvant 5FUCMT will go to surgery. 
Group 1 or Group 2 patients who do not complete any component of postoperative 
therapy will go to observation. If the patient undergoes surgery, the surgery data must 
be submitted. 

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14.0 BIOSPECIMENS  
For SAKK sites, please refer to the Swiss Specific Appendix for information regarding 
translational research. 
14.1 
Biospecimens Acquisition Schedule 
Type of 
biospecimen 
to submit 
Indicate if 
specimen is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number of 
tubes to be 
collected) 
Both 
Groups 1 
and 2: 
baseline 
(≤ 28 days 
prior to start 
of treatment) 
Both 
Groups 1 
and 2: after 
completion 
of 
neoadjuvant 
treatment 
Shipment 
precautions 
Tumor block1 
from baseline 
proctoscopic 
biopsy or 
outside tissue 
specimen 
 
Mandatory 
FFPE 
 
X4 
 
 
Tumor block1 
from TME 
surgical 
resection 
 
Mandatory 
FFPE 
 
 
X 
(at surgery) 
 
Whole blood2 
Mandatory 
 Red/grey or 
gold-topped 
Serum 
Separator 
Tube 
10 mL (1) 
X 
X 
(pre-op) 
Cool pack 
Whole blood3 
Mandatory 
EDTA 
(purple top) 
10 mL (1) 
X 
X 
(pre-op) 
Cool pack 
 
 
 
 
 
 
 
1. If tumor block is unavailable, the site may instead submit 4 2mm tissue cores, 15 unstained slides at 
4 microns thick, 4 unstained slides at 10 microns, and 1 H&E. If the site cannot send this many 
slides, the site may submit a total of 10 slides –5 slides at 4 microns thick, 4 slides at 10 microns, 
and 1 H&E stained slide. Submission of a block (or alternative) from the surgical resection is 
required even if no residual tumor is found in the resected specimen. 
2. For serum to be isolated from whole blood and used for immunology studies. 
3. For DNA to be isolated from whole blood and used for genotyping. 
4. Rectal tumor biopsy may be performed within 60 days before registration OR between registration 
and the start of treatment 
14.2 
Specimen Registration and Tracking 
Use of the Alliance Biospecimen Management System (BioMS) is mandatory and all 
specimens must be logged and shipped via this system.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. 
Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL:  
 using most standard web browsers (Safari, 
Firefox, and Internet Explorer). For information on using the BioMS system, please refer to the 
‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training 

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videos. To report technical problems, such as login issues or application errors, or for assistance 
in using the application, or questions or problems related to specific specimen logging, please 
contact: 855-55BIOMS. 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
Instructions for the collection of samples are included below. 
14.3 
Biospecimens Submission Schedule 
Label all biospecimens with the following identification: 
1) N1048 Protocol 
2) N1048 Protocol Study Number 
3) Date of Specimen Collection 
4) Patient’s Initials 
5) Type of Specimen Collected 
6) Institutional Surgical Pathology # (for Pathology Specimens) 
Whole blood specimens need to be mailed as soon as feasible following blood draw (preferably 
within 24 hours of collection; preferably mailed in a cool pack; no additional processing is 
required prior to shipment). Tumor blocks from the proctoscopic biopsy and the TME surgical 
specimen may be batched and sent together as soon as is feasible postoperatively. Tumor blocks 
should be sent within 4 weeks of TME resection. 
Biospecimens Submission Instructions 
Kits will NOT be provided for this study; sites should use institutional supplies. Instructions for 
the collection of samples are included below. Please be sure to use a method of shipping that is 
secure and trackable. Extreme heat precautions should be taken. Corresponding de-identified 
pathology reports should accompany any tissue specimen submitted. 
Shipment on Monday through Friday by overnight service to assure receipt is encouraged. Do 
not ship specimens the day before a holiday. The Alliance Biorepository at OSU does not accept 
Saturday deliveries. 
Ship all specimens with BioMS shipping manifest and pathology reports (if applicable) to the 
following address: 
  
 
 
 
  
 
 
For Argentine Sites: 
In addition to utilizing BioMS for specimen registration and tracking (as described in Section 
14.2), the N1048 Study-Specific Requisition Form must be completed. The local Courier 
Company “MARKEN” will perform shipment of samples. 
 
 

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14.4 
Blood Sample Submission 
The samples collected in 1) red/grey or gold top tubes (Serum Separator) and 2) purple top 
(EDTA) tubes should be collected at baseline (≤ 28 days of start of FOLFOX [Group 1] or 
5FUCMT [Group 2]) and ≤ 28 days prior to surgery for both Groups 1 and 2. Collect 10mL 
peripheral venous blood in a non-heparinized “red/grey or gold top” tube. Also collect 10 mL 
of peripheral venous blood in an EDTA “purple top” tube. The tubes should be refrigerated until 
shipped on cool pack by overnight mail to the Alliance Biorepository at OSU. The samples 
should be shipped as soon as is feasible, ideally, the same day that the blood is drawn; no 
additional processing is required prior to shipment. 
14.5 
Paraffin Block Submission 
Submit one formalin fixed paraffin embedded tissue block with representative primary tumor 
from the pre-treatment proctoscopic biopsy and one FFPE tissue block with representative 
primary tumor from the TME surgical specimen.  
The Alliance has instituted special considerations for institutions whose policies prohibits 
release or long-term storage of tissue blocks. If, due to institutional policy, a block cannot be 
sent, please submit 4 2mm cores, 15 unstained slides at 4 microns thick, 4 unstained slides at 10 
microns, and 1 H & E slide. If the site cannot send this many slides, the site may submit a total 
of 10 slides – 5 slides at 4 microns thick, 4 slides at 10 microns thick, and 1 H & E stained slide. 
The goal of the Alliance Biorepository at OSU is to provide investigators with quality histology 
sections for their research while maintaining the integrity of the tissue. All paraffin blocks that 
are to be stored at the Alliance Biorepository at OSU will be vacuum packed to prevent oxidation 
and will be stored at 4ºC to minimize degradation of cellular antigens. For these reasons it is 
preferred that the Alliance Biorepository at OSU bank the tissue block until the study 
investigator requests thin sections. Please contact the Alliance Biorepository at OSU if 
additional assurances are required. 
14.6 
Study Methodology and Storage Information 
14.6.1 Analysis of Tissue Samples 
FFPE tumor tissue blocks will be collected in order to assess correlation of responses to 
treatment with FOLFOX by genome sequencing. Banking of tumor tissue, according to the 
patient consent permission, is for future research. As protocols are developed, they will be 
presented for Alliance IRB review and approval.  
Genomic Characterization of Rectal Tumors Using Molecular Inversion Probe (MIP) 
Assay and Mass Spectrometry based Genotyping 
The MIP array technology will be used to identify prognostic and/or predictive, potentially 
druggable mutations involving MEK, AKT, PIK3CA, and BRAF, as well as others, and 
copy number alterations, such as ERBB2 amplification, using FFPE material. Mutations in 
KRAS, NRAS, BRAF and PIK3CA will be detected using the iPLEX assay and analyzed 
by the MassARRAY system is based on matrix-assisted laser desorption/ionization-time 
of flight mass spectrometry (MALDI-TOF MS). In these assays, the mutant and germline 
alleles for a given point mutation produce single-allele base extension reaction products of 
different masses that are then resolved by MALDI-TOF MS. For further information, refer 
to Appendix X. 
 
 

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14.6.2 Analysis of Blood Samples 
Indicators of Immunologic Activation 
Measurement of serum cytokines (IFN- γ, IL-2, IL-4, IL-5, IL-10, tumor necrosis factor-α, 
VEGF, basic fibroblast growth factor (bFGF), and IL-8 may be performed using bead array 
and ELISA kits. ELISA will also be used to measure antibody response to classes of cancer-
testes antigens notably LAGE-1, MAGE, CT-7, CT-47, Sox-2, XAGE-1 or others. Last, 
specifically bound serum IgG will be assayed by protein microarrays. For further 
information, refer to Appendix XI. 
Assessment of Germline Variation as a Predictor of Response and Toxicity to Platinum-
based Chemotherapy and Radiation Therapy 
We will perform genotyping of DNA on all patients randomized to receive neoadjuvant 
chemotherapy with FOLFOX using genetic variants to evaluate if germline genetic variants 
in candidate genes of interest are associated with response and/or toxicity to platinum and 
radiation therapy. We will also evaluate whether genetic risk variants identified in genome-
wide association studies of colorectal cancer susceptibility are associated with rectal cancer 
clinical outcome and response to therapy. For further information, refer to Appendix XII. 
14.7 
Return of Genetic Testing Research Results 
Because the results generated by the genetic testing included in this section are not currently 
anticipated to have clinical relevance to the patient or their family members, the genetic results 
will not be disclosed to the patients or their physicians. 
If at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA-certified setting will be required. Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and testing has 
been done in CLIA-approved laboratories. 
15.0 DRUG INFORMATION 
For SAKK sites, please refer to the Swiss Specific Appendix for information regarding drug supply 
and handling. 
15.1 
Oxaliplatin (Eloxatin®, OXAL) 
15.1.1 Background: Oxaliplatin, a platinum derivative, is an alkylating agent. Following 
intracellular hydrolysis, the platinum compound binds to DNA forming cross-links which 
inhibit DNA replication and transcription, resulting in cell death. Cytotoxicity is cell-cycle 
nonspecific. 
15.1.2 Formulation: Commercially available for injection as: Solution [preservative free]: 5 
mg/mL (10 mL, 20 mL, 40 mL) 
15.1.3 Preparation, Storage, and Stability: Refer to package insert for complete preparation and 
dispensing instructions. Store intact vials in original outer carton at room temperature and 
do not freeze. According to the manufacturer, solutions diluted for infusion are stable up 
to 6 hours at room temperature or up to 24hours under refrigeration. Oxaliplatin solution 
diluted with D5W to a final concentration of 0.7 mg/mL (polyolefin container) has been 
shown to retain > 90% of its original concentration for up to 30 days when stored at room 
temperature or refrigerated; artificial light did not affect the concentration (Andre, 2007). 
As this study did not examine sterility, refrigeration would be preferred to limit microbial 
growth. Do not prepare using a chloride-containing solution (e.g., NaCl). Dilution with 

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D5W (250 or 500 mL) is required prior to administration. Infusion solutions do not require 
protection from light. 
15.1.4 Administration: Refer to the treatment section for specific administration instructions. 
Administer as I.V. infusion over 2-6 hours. Flush infusion line with D5W prior to 
administration of any concomitant medication. Patients should receive an antiemetic 
premedication regimen. Cold temperature may exacerbate acute neuropathy. Avoid 
mucositis prophylaxis with ice chips during oxaliplatin infusion. 
15.1.5 Pharmacokinetic Information: 
Distribution: Vd: 440 L 
Protein Binding: > 90% primarily albumin and gamma globulin (irreversible 
binding to platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive 
derivatives 
Half-life Elimination: Terminal: 391 hours; Distribution: Alpha phase: 0.4 hours, 
Beta Phase: 16.8 hours 
Excretion: Primarily urine (~ 54%); feces (~ 2%) 
15.1.6 Potential Drug Interactions:   
Increased Effect/Toxicity: Nephrotoxic agents may increase oxaliplatin toxicity. When 
administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin, oxaliplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin. 
15.1.7 Known Potential Adverse Events:  
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list 
of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-
AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting 
Requirements' 
  for further clarification. Frequency is provided based on 1141 patients. Below is the 
CAEPR for oxaliplatin. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
 

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Version 2.3, November 1, 20111 
 
 Adverse Events with Possible  
 Relationship to Oxaliplatin 
 (CTCAE 4.0 Term) 
[n= 1141] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
(formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Disseminated intravascular 
coagulation 
 
 Disseminated intravascular 
coagulation (Gr 2) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
 
  Hemolysis 
 
 Hemolysis (Gr 2) 
 
 
Thrombotic 
thrombocytopenic purpura   
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
 Atrial fibrillation (Gr 2) 
 
Atrial flutter 
 
 Atrial flutter (Gr 2) 
 
Paroxysmal atrial tachycardia  
 Paroxysmal atrial tachycardia    
(Gr 2) 
 
Sinus bradycardia 
 
 Sinus bradycardia (Gr 2) 
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 2) 
 
Supraventricular tachycardia 
 
 Supraventricular tachycardia     
(Gr 2) 
 
Ventricular arrhythmia 
 
 Ventricular arrhythmia (Gr 2) 
 
Ventricular fibrillation 
 
 Ventricular fibrillation (Gr 2) 
 
Ventricular tachycardia 
 
 Ventricular tachycardia (Gr 2) 
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
 Hearing impaired (Gr 2) 
 
Middle ear inflammation 
 
 Middle ear inflammation (Gr 2) 
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
Eye disorders - Other 
(amaurosis fugax) 
 
 Eye disorders - Other 
(amaurosis fugax) (Gr 2) 
 
Eye disorders - Other (cold-
induced transient visual 
abnormalities) 
 
 Eye disorders - Other (cold-
induced transient visual 
abnormalities) (Gr 2) 
 
Eyelid function disorder 
 
 Eyelid function disorder (Gr 2) 
 
Papilledema 
 
 Papilledema (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Ascites 
 
 Ascites (Gr 2) 
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
Enterocolitis 
 
 Enterocolitis (Gr 3) 

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Esophagitis 
 
 Esophagitis (Gr 3) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastritis 
 
 Gastritis (Gr 2) 
 
 
 Gastrointestinal disorders –  
 Other (pneumatosis  
 intestinalis) 
  
 
Gastrointestinal hemorrhage2 
 
 Gastrointestinal hemorrhage2 
(Gr 3)   
 
Gastrointestinal necrosis3 
 
 Gastrointestinal necrosis3 (Gr 2) 
 
 Gastrointestinal ulcer4 
 
 Gastrointestinal ulcer4(Gr 2) 
 
Ileus 
 
 Ileus (Gr 3) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis 
 
 Pancreatitis (Gr 2) 
 
Small intestinal obstruction 
 
 Small intestinal obstruction (Gr 
3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
 Edema face (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Gait disturbance 
 
 Gait disturbance (Gr 2) 
 
General disorders and 
administration site conditions - 
Other (Hepato-renal syndrome) 
 
 General disorders and 
administration site conditions - 
Other (Hepato-renal syndrome) 
(Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Cholecystitis 
  
 
Hepatic failure 
 
 Hepatic failure (Gr 2) 
 
Hepatobiliary disorders - Other 
(hepatic enlargement) 
 
 Hepatobiliary disorders - Other 
(hepatic enlargement) (Gr 2) 
 
Hepatobiliary disorders - Other 
(veno-occlusive liver disease) 
 
 Hepatobiliary disorders - Other 
(veno-occlusive liver disease)    
(Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 3) 
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time prolonged 
 
 Activated partial thromboplastin 
time prolonged (Gr 2) 
Alanine 
aminotransferase 
increased 
 
 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased  
(Gr 2) 
Aspartate 
aminotransferase 
 
 
 Aspartate aminotransferase 
increased (Gr 3) 

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increased 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
INR increased 
 
 INR increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased  
(Gr 3) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count 
decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight gain 
 
 Weight gain (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 
4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 4) 
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hyperuricemia 
 
 Hyperuricemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 3) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 4) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
 Bone pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Trismus 
 
 Trismus (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Ataxia 
 
 Ataxia (Gr 3) 
 
Depressed level of 
consciousness 
 
 Depressed level of 
consciousness   (Gr 2) 
 
Dizziness 
 
 Dizziness (Gr 3) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Dysphasia 
 
 Dysphasia (Gr 2) 
 
Extrapyramidal disorder 
 
 Extrapyramidal disorder (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Intracranial hemorrhage 
 
 Intracranial hemorrhage (Gr 2) 
 
Ischemia cerebrovascular 
 
 Ischemia cerebrovascular (Gr 
2) 
 
Nerve disorder6 
 
 Nerve disorder6 (Gr 2) 
 
Nervous system disorders - 
Other (multiple cranial nerve 
palsies) 
 
 Nervous system disorders - 
Other (multiple cranial nerve 
palsies)  
(Gr 2) 

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Peripheral motor neuropathy 
 
 Peripheral motor neuropathy 
(Gr 3) 
Peripheral sensory 
neuropathy 
 
 
 Peripheral sensory neuropathy 
(Gr 3) 
 
Seizure 
 
 Seizure (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
 Anxiety (Gr 2) 
 
Confusion 
 
 Confusion (Gr 3) 
 
Depression 
 
 Depression (Gr 2) 
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
 Acute kidney injury (Gr 3) 
 
Hematuria 
 
 Hematuria (Gr 2) 
 
Renal hemorrhage 
 
 Renal hemorrhage (Gr 2) 
 
Urinary frequency 
 
 Urinary frequency (Gr 2) 
 
Urinary retention 
 
 Urinary retention (Gr 2) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Hematosalpinx 
 
 Hematosalpinx (Gr 2) 
 
Ovarian hemorrhage 
 
 Ovarian hemorrhage (Gr 2) 
 
Prostatic hemorrhage 
 
 Prostatic hemorrhage (Gr 2) 
 
Spermatic cord hemorrhage 
 
 Spermatic cord hemorrhage (Gr 
2) 
 
Testicular hemorrhage 
 
 Testicular hemorrhage (Gr 2) 
 
Uterine hemorrhage 
 
 Uterine hemorrhage (Gr 2) 
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Adult respiratory distress 
syndrome 
 Adult respiratory distress 
syndrome (Gr 2) 
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 2) 
 
Bronchopulmonary 
hemorrhage 
 
 Bronchopulmonary 
hemorrhage    (Gr 2) 
 
Bronchospasm 
 
 Bronchospasm (Gr 2) 
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 4) 
 
Hiccups 
 
 Hiccups (Gr 2) 
 
Pneumonitis 
 
 Pneumonitis (Gr 3) 
 
Pulmonary fibrosis 
 
 Pulmonary fibrosis (Gr 4) 
 
Sinus disorder 
 
 Sinus disorder (Gr 2) 
 
Voice alteration 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 

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Hot flashes 
 
 Hot flashes (Gr 2) 
 
Hypertension 
 
 Hypertension (Gr 2) 
 
Hypotension 
 
 Hypotension (Gr 3) 
 
Phlebitis 
 
 Phlebitis (Gr 2) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage with 
thrombocytopenia) 
 
 Vascular disorders - Other 
(hemorrhage with 
thrombocytopenia) (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail. 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Doudenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, 
Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under 
the GASTROINTESTINAL DISORDERS SOC. 
3Gastrointestinal necrosis includes Anal necrosis, Esophageal necrosis, Gastric necrosis, 
Pancreatic necrosis, Peritoneal necrosis, and Rectal necrosis under the GASTROINTESTINAL 
DISORDERS SOC. 
4Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, 
Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the 
GASTROINTESTINAL DISORDERS SOC. 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
6Nerve disorder includes Abducens nerve disorder, Accessory nerve disorder, Acoustic nerve 
disorder NOS, Facial nerve disorder, Glossopharyngeal nerve disorder, Hypoglossal nerve 
disorder, IVth nerve disorder, Oculomotor nerve disorder, Olfactory nerve disorder, Trigeminal 
nerve disorder, and Vagus nerve disorder under the NERVOUS SYSTEM DISORDERS SOC. 
7Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
Also reported on oxaliplatin trials but with the relationship to oxaliplatin still 
undetermined: 
CARDIAC DISORDERS - Heart failure; Left ventricular systolic dysfunction; Myocardial 
infarction; Pericardial effusion 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS – Gastrointestinal perforation7 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury to superior vena 
cava; Vascular access complication 
INVESTIGATIONS - Cardiac troponin I increased; Lipase increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness 
NERVOUS SYSTEM DISORDERS - Syncope 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia 
VASCULAR DISORDERS - Visceral arterial ischemia 
Note: Oxaliplatin in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 

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Addendum 10 
15.1.8 Drug Procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
15.1.9 Nursing Guidelines:  
15.1.9.1 
GI adverse events similar to cisplatin occurs with doses above 30 mg/m2. It can be 
almost constant and frequently severe, but not always dose limiting. Monitor for 
nausea and vomiting and treat accordingly. 
15.1.9.2 
Dose-limiting side effects can be paresthesias of hands, fingers, toes, pharynx, and 
occasionally cramps which develops with a dose-related frequency (>90 mg/m2). 
Duration of symptoms  tend to be brief (less than a week) with the first course, 
but longer with subsequent courses. Phase I patients have reported exacerbation of 
paresthesias by touching cold surfaces or exposure to cold. Advise patient of these 
possibilities and instruct patient to report these symptoms to the health care team. 
 
 Also advise patient to refrain from operating dangerous machinery that 
requires fine sensory-motor coordination, if symptoms appear. 
15.1.9.3 
These sensory neuropathies developed after subsequent courses with increasing 
intensity (Grade 3 toxicity after the fourth course) and with increasing duration. In 
63% of the patients tested in Phase I at high doses (135-200 mg/m2), neuropathies 
became long-term with slow reversal over several months. Disabling walking and 
handwriting difficulties, as well as mouth and throat dysesthesias and 
laryngospasms were seen. Instruct patient to report any swallowing difficulties or 
gait changes. 
15.1.9.4 
Oxaliplatin is incompatible with NS. Flush lines with D5W prior to and following 
oxaliplatin infusion. 
15.1.9.5 
Low back pain is a common side effect, perhaps a form of hypersensitivity 
reaction. Instruct patient in good body mechanics, advise light massage, heat, etc. 
15.1.9.6 
Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients and is 
acute, sporadic, and self-limited. It usually occurs within hours of infusion, is 
induced or exacerbated by exposure to cold, and presents with dyspnea and 
dysphagia. The incidence and severity appear to be reduced by prolonging infusion 
time. Instruct patient to avoid ice and cold drinks the day of infusion. If   Grade 
2 laryngopharyngeal dysesthesia occurs during the administration of oxaliplatin, 
do the following: 
• 
Stop oxaliplatin infusion 
• 
Administer benzodiazepine and give patient reassurance 
• 
Test oxygen saturation via a pulse oximeter 
• 
At the discretion of the investigator, the infusion can be restarted 
at 1/3 the original rate of infusion. 
• 
Rapid resolution is typical within minutes to a few hours. Can 
recur with retreatment.   
 
 
 
 
 
 
 
 

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Addendum 10 
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias and 
Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Laryngopharyngeal Dysesthesias 
Platinum Hypersensitivity 
Dyspnea 
Present 
Present 
Bronchospasm 
Absent 
Present 
Laryngospasm 
Absent 
Present 
Anxiety 
Present 
Present 
Oxygen saturation 
Normal 
Decreased 
Difficulty swallowing 
Present 
Absent 
Pruritus 
Absent 
Present 
Urticaria/rash 
Absent 
Present 
Cold-induced symptoms 
Yes 
No 
Blood pressure 
Normal or increased 
Normal or decreased 
 
 
Treatment 
Anxiolytics, observation in a 
controlled clinical setting until 
symptoms abate or at the physicians’ 
discretion 
Oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
15.1.9.7 
Alopecia is rare with oxaliplatin alone, but is seen with 5-FU and oxaliplatin 
combination. Advise patient.  
15.1.9.8 
Mild-to-moderate diarrhea has been seen -- usually of short duration. Treat 
accordingly with loperamide and according to standard practice.  
15.1.9.9a 
Respiratory problems (i.e., pulmonary fibrosis, cough, dyspnea, rales, pulmonary 
infiltrates, hypoxia, air hunger and tachypnea) have been observed in patients 
administered oxaliplatin. In rare cases, death has occurred due to pulmonary 
fibrosis. Please monitor and instruct the patient to report any respiratory 
difficulties and hold oxaliplatin until interstitial lung disease is ruled out for cases 
of Grade  3. If patient is experiencing shortness of breath, a chest x-ray and 
assessment of oxygenation via either finger oximetry or arterial blood gas 
evaluation are required to confirm the absence or presence of pulmonary infiltrates 
and/or hypoxia (treat accordingly:  no intervention, steroids, diuretics, oxygen, or 
assisted ventilation). 
15.19.9b 
Veno-occlusive disease (VOD) is a rare but serious complication that has been 
reported in patients receiving oxaliplatin in combination with 5-FU. This condition 
can lead to hepatomegaly, splenomegaly, portal hypertension and/or esophageal 
varices. Instruct patients to report any jaundice, ascites, or hematemesis to the MD 
immediately as these could be a sign of VOD or other serious condition. 
15.1.9.9c 
Acute vein irritation can occur with infusion. Apply heat to arm of infusion if you 
are using a peripheral line. However, extravasation of drug can cause severe pain, 
redness, soreness, and exfoliation of the skin in the affected area with loss of 
affected vein for a long period. If a patient has a problem with pain or sclerosis 
when chemotherapy is given by a peripheral line, then placement of a central line 
should be considered. 
15.1.9.9d 
Hemolytic Uremic Syndrome (HUS) may result in kidney damage. Oxaliplatin is 
to be discontinued in cases where hematocrit is < 25%, thrombocytopenia < 
100,000, and creatinine  1.6 mg/dL. 
15.1.9.9e 
Patients may experience sleep disturbances, specifically insomnia. Encourage 
good sleep hygiene and instruct patient to report any problems with sleep to the 
MD, to assess for the potential use of sleeping aids. 

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Addendum 10 
15.1.9.9f 
Cold-induced transient visual abnormalities can be experienced by patients while 
receiving oxaliplatin, although the relationship to oxaliplatin has not been 
completely determined. Instruct patient to report any problems with vision to the 
MD. 
15.1.9.9g 
Extrapyramidal side effects and/or involuntary limb movement has been seen with 
oxaliplatin administration. Patients may also experience restlessness. Instruct 
patient to report any of these side effects to the MD. 
Use the following if a bolus infusion is being used: 
15.1.9.9h 
A bolus infusion of oxaliplatin/capecitabine may increase the risk of developing 
life-threatening enteric sepsis secondary to neutropenia and diarrhea. Patients with 
Grade 4 ANC and Grade 3 diarrhea should be closely monitored and condition 
reported to MD for possible hospitalization for appropriate hydration and 
treatment with antibiotics, appropriate for gram negative or anaerobic sepsis.  
Patients should be monitored closely and provided with aggressive supportive care 
until neutropenia and diarrhea resolve. 
15.2 
Leucovorin Calcium (CF) 
15.2.1 Background: A reduced form of folic acid, leucovorin supplies the necessary cofactor 
blocked by methotrexate, enters the cells via the same active transport system as 
methotrexate. Stabilizes the binding of 5-dUMP and thymidylate synthetase, enhancing the 
activity of fluorouracil. 
15.2.2 Formulation: Commercially available as powder for reconstitution: 50 mg, 100 mg, 200 
mg, 350 mg. Injection, solution: 10 mg/mL (50 mL) 
15.2.3 Preparation, Storage, and Stability:  
Powder for injection: Store at room temperature, protect from light. Reconstitute with 
sterile water for injection or bacteriostatic water for injection; dilute in 100-1000 mL 0.9% 
NaCl or D5W. When doses > 10 mg/m2 are required, reconstitute using sterile water for 
injection, not a solution containing benzyl alcohol. Solutions reconstituted with 
bacteriostatic water for injection must be used within 7 days. Solutions reconstituted with 
sterile water for injection must be used immediately. Parenteral admixture is stable for 24 
hours stored at room temperature and for 4 days when stored under refrigeration. Solution 
for injection: Prior to dilution, store vials under refrigeration, protect from light. 
15.2.4 Administration: 
Due to calcium content, do not administer I.V. solutions at a rate > 160 mg/minute. Refer 
to individual protocols for specific administration instructions. Leucovorin should be 
administered I.V. push or I.V. infusion (15 minutes to 2 hours).  
In combination with fluorouracil: The fluorouracil is usually given after the leucovorin 
infusion. Leucovorin is usually administered by I.V. bolus injection or short (10-120 
minutes) I.V. infusion. Other administration schedules have been used; refer to the 
treatment section of the protocol for specific directions. In combination with oxaliplatin: 
Leucovorin is compatible with oxaliplatin and may be administered concurrently via Y-
connector at normal doses. Oxaliplatin is incompatible with 0.9% NaCl. Leucovorin must 
be diluted in D5W when administered with oxaliplatin. In combination with irinotecan: 
Leucovorin is compatible with irinotecan via Y-site injection. 
 
 

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Addendum 10 
15.2.5 Pharmacokinetic Information: 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate 
(5MTHF; active) 
Half-life Elimination: ~4-8 hours 
Time to Peak: I.V.: Total folates: 10 minutes; 5MTHF: ~1 hour 
Excretion: Urine (primarily); feces 
15.2.6 Potential Drug Interactions:   
Decreased Effect: May decrease efficacy of trimethoprim/sulfamethoxazole against 
Pneumocystis carinii pneumonia.  
15.2.7 Known Potential Adverse Events: Consult the package insert for the most current and 
complete information.  
Common known potential toxicities, > 10%:  None  
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Rash, pruritus, erythema, urticaria 
Gastrointestinal: Nausea, vomiting 
Rare known potential toxicities, <1% (Limited to important or life-threatening): 
allergic reactions, anaphylactoid reactions, dyspnea, thrombocytosis 
15.2.8 Drug Procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
15.2.9 Nursing Guidelines:  
15.2.9.1 
Headache may occur. Advise patient analgesics such as Tylenol may help. Instruct 
patient to report any headache that is unrelieved. 
15.2.9.2 
Observe for sensitization reaction (rash, hives, pruritus, facial flushing and 
wheezing). 
15.2.9.3 
May potentiate the toxic effects of fluoropyrimidine (5-FU) therapy, resulting in 
increased hematologic and gastrointestinal side effects (diarrhea, stomatitis). 
Monitor closely. 
15.2.9.4 
May cause mild nausea or upset stomach. Administer antiemetics if necessary and 
evaluate for their effectiveness. 
15.3 
Fluorouracil (Adrucil, Efudex, [5FU]) 
15.3.1 Background: Antineoplastic Agent, Antimetabolite (Pyrimidine Analog). Fluorouracil is 
a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the 
methylation of  deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a 
lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S 
phases of the cell cycle. 
15.3.2 Formulation: Commercially available for injection 50 mg/mL (10 mL, 20 mL, 50 mL, 
and 100 mL). 
15.3.3 Preparation, Storage, and Stability: Store intact vials at room temperature and protect 
from light. A slight discoloration may occur with storage but usually does not denote 
decomposition. Dilute in 50 – 1000 mL of 0.9% NaCl or D5W. If exposed to cold, a 
precipitate may form; gentle heating to 60ºC will dissolve the precipitate without impairing 
the potency. Solutions in 50 – 1000 mL 0.9% NaCl or D5W or undiluted solutions in 
syringes are stable for 72 hours at room temperature. Fluorouracil should not be co-

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administered with diazepam, doxorubicin, daunorubicin, idarubicin, cisplatin, or 
cytarabine. However, fluorouracil and leucovorin are compatible for 14 days at room 
temperature. 
Fluorouracil 
is 
compatible 
with 
vincristine, 
methotrexate, 
and 
cyclophosphamide. 
15.3.4 Administration:  Fluorouracil may be given IV push, IV infusion. Refer to Section 7.0 
(treatment) administration instructions specific to the protocol.  
15.3.5 Pharmacokinetic Information: 
Distribution: Vd ~ 22% of total body water; penetrates  extracellular fluid, CSF 
and third space fluids (e.g., pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil must be 
metabolized to be active. 
Half-life Elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP 
and FUTP, have prolonged half-lives depending on the type of tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 
hours. 
15.3.6 Potential Drug Interactions: Fluorouracil may increase effects of warfarin. Avoid ethanol 
(due to GI irritation).  
15.3.7 Known Potential Adverse Events: Consult the package insert for the most current and 
complete information. Counsel patients to use protective wear and avoid excessive sun 
exposure as direct sun exposure during 5FU or capecitabine therapy may be associated 
with severe sunburn. 
Common Known Potential Toxicities, >10%:  
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, 
anorexia, stomatitis, esophagitis, anorexia, diarrhea. GI toxicity (anorexia, nausea, 
and vomiting) is generally more severe with continuous-infusion schedules. 
Emetic potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: 
Hematologic: Leukopenia; Myelosuppressive (tends to be more pronounced in 
patients receiving bolus dosing of FU). Decreased white blood cell count with 
increased risk of infection; decreased platelet count with increased risk of bleeding. 
Local: Irritant chemotherapy.  
Less Common Known Potential Toxicities, 1% - 10%:  
Dermatologic: Dry skin. 
Gastrointestinal: GI ulceration 
Rare Known Potential Toxicities, <1% (Limited to Important or Life-
threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG changes 
similar to ischemic changes, hepatotoxicity; hyperpigmentation of nail beds, face, 
hands, and veins used in infusion; hypotension, palmar-plantar syndrome (hand-
foot syndrome), photosensitization. Cerebellar ataxia, headache, somnolence, 
ataxia are seen primarily in intracarotid arterial  infusions for head and neck 
tumors.  
15.3.8 Drug Procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
 
 

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15.3.9 Nursing Guidelines:  
15.3.9.1 Monitor complete blood count and platelet count. Instruct patient to report signs and 
symptoms of infection, unusual bruising or bleeding to the physician. 
15.3.9.2 Administer antiemetics as indicated. 
15.3.9.3 Diarrhea may be dose-limiting; encourage fluids and treat symptomatically. 
15.3.9.4 Assess for stomatitis; oral care measures as indicated.  
15.3.9.5 Monitor for neurological symptoms (headache, ataxia). 
15.3.9.6 Inform patient of potential alopecia. 
15.3.9.7 Those patients on continuous infusion may need instruction regarding central 
intravenous catheters and portable intravenous or IA infusion devices. 
15.3.9.8 5-FU-induced conjunctivitis is a common problem. Advise patient to report any eye 
soreness or redness to the healthcare team. 
15.3.9.9 Photosensitivity may occur. Instruct patients to wear sunblock when outdoors. 
15.4 
Capecitabine (Xeloda®)  
15.4.1 Background: Capecitabine is classified as an antineoplastic agent, antimetabolite 
(pyrimidine analog). Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in 
the liver and tissues to form fluorouracil which is the active moiety. Fluorouracil is a 
fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the 
methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser 
degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S phases 
of the cell cycle. 
15.4.2 Formulation: Commercially available in 150 mg and 500 mg tablets for oral 
administration. 
15.4.3 Preparation, Storage, and Stability: Store at room temperature of 25C with excursions 
between 15C and 30C permitted. 
15.4.4 Administration: Usually administered in 2 divided doses taken 12 hours apart. Doses 
should be taken with water within 30 minutes after a meal (Because current safety and 
efficacy data are based upon administration with food, it is recommended that capecitabine 
be administered with food. In all clinical trials, patients are instructed to take with water 
within 30 minutes after a meal). 
15.4.5 Pharmacokinetic Information: 
Absorption: Rapid and extensive 
Protein Binding: <60%; ~35% to albumin 
Metabolism:  
Hepatic: Inactive metabolites  
Tissue, Active metabolite, Fluorouracil 
Distribution: Vd: 46 mL/kg 
Half-life Elimination: 0.5-1 hour 
Time to Peak: 1.5 hours; Fluorouracil, 2 hours 
Excretion: Urine (96%), Feces (<3%) 
 
 

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15.4.6 Potential Drug Interactions:   
Increased Effect/Toxicity: Phenytoin and warfarin levels or effects may be increased. 
[U.S. Boxed Warning] Capecitabine may increase the anticoagulant effects of 
warfarin; monitor closely. 
Nutrition Interactions: Food reduced the rate and extent of absorption of capecitabine. 
15.4.7 Known Potential Adverse Events:  
Consult the package insert for the most current and complete information. Frequency 
listed derived from Monotherapy trials. 
Common Known Potential Toxicities, > 10%:   
Cardiovascular: Edema 
Central nervous system: Fatigue, fever, pain 
Dermatologic: Palmar-plantar erythrodysethesia (hand-and-foot syndrome), dermatitis. 
Gastrointestinal: Diarrhea may be dose limiting, nausea, vomiting, abdominal pain, 
stomatitis, appetite decreased, anorexia, constipation. 
Hematologic: Lymphopenia, anemia, neutropenia, thrombocytopenia. 
Hepatic: Bilirubin increased. 
Neuromuscular & skeletal: Paresthesia. 
Ocular: Eye irritation. 
Respiratory: Dyspnea. 
Less Common Known Potential Toxicities, 5% - 10%:  
Cardiovascular: Venous thrombosis, chest pain. 
Central Nervous System: Headache, lethargy, dizziness, insomnia, mood 
alteration, depression. 
Dermatologic: Nail disorder, rash, skin discoloration, alopecia, Erythema. 
Endocrine& metabolic: Dehydration. 
Gastrointestinal: Motility disorder, oral discomfort, dyspepsia, upper GI 
inflammatory disorders, hemorrhage, ileus, taste perversion. 
Neuromuscular & skeletal: Back pain, weakness, neuropathy, myalgia, arthralgia, 
limb pain 
Ocular: Abnormal vision, conjunctivitis. 
Respiratory: Cough. 
Miscellaneous: Viral infection. 
Rare Known Potential Toxicities, <5% (Limited to Important or Life-
threatening):  
Angina, 
ascites, 
asthma, 
atrial 
fibrillation, 
Bradycardia, 
bronchitis, 
bronchopneumonia, bronchospasm, cachexia, cardiac arrest, cardiac failure, 
cardiomyopathy, cerebral vascular accident, cholestasis, coagulation disorder, 
colitis, deep vein thrombosis, diaphoresis, duodenitis, dysphagia, dysrhythmia, ECG 
changes, encephalopathy, epistaxis, fungal infection, gastric ulcer, gastroenteritis, 
hematemesis, hemoptysis, hepatic failure, hepatic fibrosis, hepatitis, Hypokalemia, 
hypomagnesemia, 
hyper-/hypotension, 
hypersensitivity, 
hpertriglyceridemia, 
idiopathic thrombocytopenia purpura, ileus, infection, intestinal obstruction, 
keratoconjunctivitis, lacrimal duct stenosis, leukopenia, loss of consciousness, 
lymphedema, 
MI, 
multifocal 
leukoencephalopathy, 
myocardial 
ischemia, 
myocarditis, necrotizing enterocolitis (typhlitis), oral candidiasis, pericardial 
effusion, thrombocytopenic purpura, pancytopenia, photosensitivity reaction, 
pneumonia, pruritus, pulmonary embolism, radiation recall syndrome, renal 
impairment, respiratory distress, sedation, sepsis, skin ulceration, tachycardia, 
thrombophlebitis, toxic megacolon, tremor, ventricular extrasystoles. 

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Addendum 10 
15.4.7 Drug Procurement: Commercial supplies. Pharmacies or clinics shall obtain supplies 
from normal commercial supply chain or wholesaler. 
15.4.8 Nursing Guidelines: 
15.4.8.1 
Instruct patients to take the tablets within 30 minutes of a meal (breakfast and 
dinner). Tablets should be swallowed with 6-8 oz. of water. 
15.4.8.2 
Instruct patient to avoid taking a missed dose, to never double up on a dose, and 
to notify the health care team if a dose has been missed. 
15.4.8.3 
Diarrhea can be severe and dose limiting. Instruct patient to contact the health care 
team immediately if they experience > 4 BMs/day and/or nocturnal diarrhea above 
baseline. Monitor carefully for dehydration and need for fluid and electrolyte 
replacement. Standard anti-diarrheal treatment, e.g., loperamide is recommended. 
15.4.8.4 
Nausea and vomiting can be severe and dose-limiting. Instruct patient to report 
nausea and vomiting to the health care team if they experience > 2 episodes of 
emesis in a 24-hour period. Initiate symptomatic treatment. 
15.4.8.5 
Hand and Foot Syndrome is common and dose-limiting (redness, swelling, pain, 
numbness, tingling, blistering, and moist desquamation). Instruct patient to notify 
health care team immediately if symptoms appear. Chemotherapy may have to be 
discontinued until symptoms subside with future dose reduction initiated. The 
syndrome may recur with a rechallenge.  
• 
Advise patient to apply cool compress for comfort. 
• 
Advise patient to avoid harsh soaps and to use alcohol-free emollients. 
• 
Administer analgesics as prescribed. 
• 
Administer systemic steroids and pyridoxine as prescribed. 
15.4.8.6 
Treat stomatitis symptomatically -- may try dabbing vitamin E oil on lesions. Do 
not swallow oil. Advise frequent and careful oral hygiene. 
15.4.8.7 
Assess for warfarin use. Patients taking coumadin-derivative anticoagulants 
concomitantly with capecitabine should be monitored regularly for alterations in 
their coagulation parameters (PT or INR). 
15.4.8.8 
Carefully assess patient’s understanding and need of instruction in adequate birth 
control measures. Discuss importance of avoiding pregnancy. Periodically re-
assess. 
15.4.8.9a 
The use of Sorivudine or its analogue, Birivudine, is contraindicated for this study 
due to a possible, even fatal, drug reaction. Assess patient’s drug use. Impress on 
patients the importance of avoiding these drugs while on study. 
15.4.8.9b 
Cardiotoxicity (including MI, angina, dysrhythmias, and cardiac arrest) has been 
seen with capecitabine. Observe patients closely for signs of cardiac dysfunction. 
Instruct patient to report any chest pain or palpitations to the health care team 
immediately or seek emergency medical attention. 
15.4.8.9c 
Monitor patient closely who are taking concomitant phenytoin therapy. There have 
been reports of increased levels of phenytoin in patients who are also taking 
capecitabine. These patients may require more frequent monitoring of their 
phenytoin levels and dose adjustments as necessary. 
15.4.8.9d 
Cimetidine may alter the clearance of capecitabine and cause toxic levels. 
Cimetidine should be avoided while taking capecitabine. 

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Addendum 10 
16.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY  
16.1 
Study Overview 
This is a two-group randomized phase II/III trial of the selective use of radiation therapy in 
intermediate risk rectal cancer. Patients will be randomized to either neo-adjuvant combined 
modality therapy (treat all group, Group 2) or to initial pre-op chemotherapy with selected use 
of radiation depending on response to chemotherapy (selected use group, Group 1). Subject to 
passing all safety and initial efficacy stopping rules, accrual will continue uninterrupted between 
the phase II and phase III portions of the trial. This phase II/III design is highly efficient in that 
all patients are randomized and are able to be included in the phase III comparison. The main 
objective of the phase III component is to evaluate whether clinical outcomes for the selected 
use group are non-inferior to those of the treat all group based on a sequential decision strategy 
regarding co-primary endpoints of disease-free survival (DFS) and time to local recurrence 
(TLR). In the phase II component, the main objective is to closely monitor the safety and early 
evidence of inferiority of selected use group compared to treat all group based on the pelvic R0 
resection rate (RRR) and TLR. The study will not proceed to phase III component if there is 
evidence that either RRR in the selected use group is lower than in the treat all group, or TLR 
in the selected use group is shorter than in the treat all group. 
Addendum 10 of the N1048 protocol modified the phase III portion to evaluate a single primary 
endpoint of DFS (see Section 16.3.3). 
16.2 
Sample Size, Accrual Time, and Study Duration 
16.2.1 Sample Size: The study design to be utilized is fully described in Section 16.3. There will 
be total of 500 evaluable patients randomized to each group of this study (total of 1000 
evaluable patients) if the trial completes the full phase III accrual. The phase II portion is 
defined as the first 366 randomized patients. Current data shows the rate of patients who 
are not evaluable for primary endpoint to be about 15%. Therefore, we anticipate accruing 
an additional 90 patients in each group to account for cancellations, major violations, and 
ineligibility deemed by central imaging review. Thus the maximum accrual is 1180 patients 
in total.  
16.2.2 Accrual Time: Because this study does not involve novel agents, therapies or techniques, 
we anticipate this study to be straightforward to launch and conduct across sites. The 
observed accrual rate in the ongoing ACOSOG study (Z6051) in this patient population is 
about 100 patients per year. This study will be open to Alliance and CTSU sites. We 
estimate the accrual rate for this study is 200 patients per year. With this accrual rate we 
plan to accrual the required 1180 patients for the trial in 6 years, which includes the time 
period for achieving IRB approvals at treating sites after activation of the study. 
16.2.3 Primary Endpoint Completion Time Estimation: For the primary endpoint analysis, 3 
years of minimum follow-up is required. All patients will be followed for local recurrence, 
disease-free survival and overall survival for 8 years. Based on statistical design described 
in Section 16.3, we estimate the primary endpoint data will be mature 8.5 years after the 
activation of the study, and the results on primary endpoints will be reported 9 years after 
the activation of the study which includes time for quality control review of the case report 
forms and data analysis. 
16.3 
Statistical Design for Primary Endpoints 
16.3.1 Primary Endpoints 

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Addendum 10 
16.3.1.1 
Phase II Component 
16.3.1.1.1 The Pelvic R0 Resection Rate (RRR): A pelvic R0 resection is defined in Section 
11.0. The pelvic RRR is defined as the number of patients with pelvic R0 resection 
divided by total number of patients included in the analysis population (see 
definition in Section 16.3.3.1) in each group. A patient who undergoes a TME and 
has no tumor identified in the rectal cancer surgical specimen, but is found to have 
a focus of distant metastatic disease (must be outside the pelvis) such as a 
microscopic (R1) or macroscopic (R2) focus of liver metastasis would be 
considered to have a pelvic R0 resection. 
16.3.1.1.2 Time to Local Recurrence (TLR): TLR is defined as the time from randomization 
to the date of the first documentation of local recurrence. 
16.3.1.2 
Phase III Component 
16.3.1.2.1  Time to Local Recurrence (TLR): See Section 16.3.1.1.2. Removed per 
Addendum 10. 
16.3.1.2.2  Disease-free Survival (DFS): DFS is defined as the time from randomization to the 
date of local recurrence, distant recurrence or death due to all causes whichever 
comes first. Patients who fail to return for evaluation after beginning therapy will 
be censored for DFS on the last day of therapy. 
16.3.2 Decision Rules and Power Consideration (Original Design) 
16.3.2.1 
Phase II Component: 
The primary goal of the phase II component of this trial is to 1) assure that the 
selective use RT group achieves acceptable pelvic R0 resection rate compared to 
the treat all group and 2) assure that the selective use RT group does not result in 
inferior TLR. The testing for non-inferiority for the TLR endpoint in the phase II 
portion will be conducted as an interim analysis integrated into the phase III 
component at the time of the last pelvic R0 resection rate analysis. DFS will not 
be considered as an endpoint for testing in the phase II portion. Therefore, the 
power and sample size considerations are only presented for RRR.  
It is expected that the pelvic R0 resection rate will be approximately 90% on each 
group. A sample size of 366 patients will provide 82% power to detect that the 
RRR in the treat all group is higher than RRR in selective use group by at least 
0.06 (absolute percentage difference) assuming the RRR in selective use group is 
87%, based on one-sided test at significance level of 0.20. After the surgery data 
are available on all 366 patients, the final phase II analysis regarding RRR will be 
conducted. If the p-value is less than or equal to 0.114, then we will terminate the 
study and not proceed to phase III component, and conclude that the treat all group 
is preferred. Three interim analyses will be performed when surgery data are 
available on the first 92, 184 and 274 patients. The Pocock version of the Lan 
Demets stopping rules will be used to allow monitoring with a greater likelihood 
of early stopping for poor results on the selected use group for the RRR endpoint. 
If p-value is less than or equal to 0.072, 0.088, and 0.102 at three interim looks, 
respectively, accrual will be suspended and a determination will be made upon 
review of the data, whether to terminate the trial.  
For TLR, the phase II decision-making analysis will be conducted when at least 11 
events are observed (approximately 2.4 years after the first patient enrolled). If the 
HR (selective use vs. treat all) for TLR is less than or equal to 1.90, we will proceed 

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Addendum 10 
to phase III component if all RRR conditions are satisfied. Otherwise, we will 
terminate the study and conclude that treat all group is preferred.  
 
 

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Phase II Analytic Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*p-values adjusted at each look for multiple comparisons based on Pocock stopping 
boundaries (0.072, 0.088, 0.102, and 0.114) 
16.3.2.2 
Phase III Component: 
The primary goal of the phase III component of this trial is to compare combined 
modality neoadjuvant chemoradiation to the selective use of chemoradiation with 
respect to the co-primary endpoints of the Disease Free Survival (DFS) and time 
to local recurrence (TLR). Co-primary endpoints are chosen due to the particularly 
devastating nature of local recurrence in rectal cancer. 
The two co-primary endpoints will be considered jointly based on a sequential 
decision strategy in the final determination of which approach (selective use versus 
treat all) is preferred. The selective use group will be favored if either: 
1. The selective use group results in superior DFS compared to the 
treat-all group (regardless of the TLR results), or  
2. If the selective use group is at least non-inferior to the treat all group 
on both DFS and TLR.     
The final sequential hypothesis testing procedure for the phase III component will 
proceed as follows (outlined in Figure 1). First, DFS will be compared between the 
two groups for non-inferiority of the selective RT use group. If non-inferiority is 
supported, then the selective use group will be tested for superiority regarding to 
DFS based on a one-sided test. If non-inferiority is not demonstrated, the treat all 
group will be declared to be the preferred group. If superiority of the selective use 
Accrual total:  366 patients 
Every 92 patients: Compare 
R0 resection rate between 
groups 
 
Selective group R0 
rate < treat all R0 
rate at p < 0.20* – 
Stop trial 
Selective group R0 rate 
< treat all R0 rate at p 
> 0.20* – Continue 
trial 
After at least 11 total 
local recurrences 
observed: Compare 
TLR between groups  
Hazard Ratio > 
1.90 – Stop 
trial 
Hazard Ratio < 
1.90 – Continue 
trial 
If pelvicR0 resection rate passes all interim analyses and the phase II decision 
rule, and TLR passes the phase II decision rule, continue to phase III component 
f
i l

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Addendum 10 
group on the DFS endpoint is determined, further formal testing will stop for the 
primary aims and we will conclude that selective use group is preferred. If however 
non-inferiority but not formal superiority of the selective use group is found based 
on decision rules for the DFS endpoint, then the co-primary endpoint of TLR will 
be tested for non-inferiority. If non-inferiority in TLR is supported, the selective 
use group will be declared to be the preferred group. Otherwise, the treat all group 
will be declared to be the preferred group. The testing algorithm is outlined in 
Figure 1 below. 
Figure 1: Sequential Hypothesis Testing Plan for Phase III Component 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on preliminary data and literature review, the expected 3 year DFS rate in the treat-
all group is 74%, and the expected 3 year local recurrence rate in the treat all group is 4% 
(local recurrence-free rate of 96%). The sequential hypotheses testing are designed to test 
the null hypotheses: 
• 
DFS: the hazard ratio comparing the DFS in selective groups to the treat all 
group is ≥1.23. This is equivalent, based on design assumptions, to a 3 year DFS 
rate in the selective use group of 69% vs. 74% in the treat all group. 
• 
TLR: the hazard ratio comparing the time to local recurrence in the selective use 
group is to the treat all group is ≥1.775. This is equivalent to a 3 year recurrence 
free rate of 93% in the selective use group vs. 96% in the treat all group. 
 
Test non-inferiority of 
selective to treat all 
regarding DFS endpoint 
Test superiority of selective to 
treat all regarding DFS endpoint 
NI established on DFS 
NI NOT established on DFS 
Test non-inferiority of selective 
to treat all regarding TLR 
endpoint 
Conclude 
selective is 
preferred 
Conclude 
treat all is 
preferred 
Superiority 
established on 
DFS 
Superiority NOT 
established on DFS 
NI established on 
TLR 
NI NOT established on 
TLR 
Conclude 
selective is 
preferred 
Conclude 
treat all is 
preferred 

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This level of non-inferiority margin is necessary in order to justify the additional 
toxicity, long-term complications, and expense of the radiation component of 
therapy for all patients.  We note that rates are quoted here but that all statistical 
testing will use the full time to event variables of DFS and TLR.  
Assuming an accrual rate of 200 patients per year with 3 years of minimum follow-
up, 1000 total patients provides 85% power to detect non-inferiority of the DFS 
and TLR jointly at the overall alpha level of 0.05, if the true DFS in the selective 
use group is slightly superior (approximately 2% absolute percentage superior at 3 
years) to the treat all approach (equivalent to HR=0.91), and the true local 
recurrence-free in the selective use group is the same as in the treat all group 
(equivalent to HR = 1). These joint power and overall type I error rate calculations 
are based on simulation studies with 10,000 replicates, assuming an exponential 
survival function and a constant accrual rate, including 3 interim analyses for DFS 
and phase II decision-making (as outlined in Section 16.3.2.1) for TLR. The data 
generation process in the simulation studies also incorporates the correlation 
between DFS and TLR, as local recurrence is one component of the composite 
DFS endpoint. 
The final analysis will be conducted when there are at least 406 and 75 events 
observed for DFS and TLR, respectively. The final sequential decision rules are 
listed as following: 
1. If the HR comparing DFS in the selective use group to the treat all group 
is greater than 1.115 (in favor of the treat all group), then the treat all 
group is declared to be preferred, otherwise proceed to the following 
steps: 
2. If the HR comparing DFS in selective use group to treat all group is less 
than 0.8367, then selective use group is declared to be preferred, 
otherwise proceed to the following step: 
3. If the HR comparing TLR in selective use group to treat all group is less 
than or equal to 1.44, then the selective use group is declared to be 
preferred, otherwise the treat all group is declared to be preferred. 
EAST version 5 was used to set up the initial decision rules for DFS and TLR 
separately. For the TLR phase II decision rule, which is equivalent to one interim 
analysis in phase III portion, was determined using EAST version 5 based on 
O’Brien-Fleming version of the Lan-Demets stopping rules. Simulation studies 
were further performed to refine the decision rules according to the joint-testing 
nature of the final sequential hypothesis testing procedure, and incorporating all 
the interim analyses in phase II and III portion for DFS and TLR. 
Three interim analyses testing for superiority in DFS (selective use vs. treat all, 
two-sided log-rank test) will be conducted when 102, 230, and 305 have been 
events observed. The O’Brien-Fleming version of the Lan-Demets stopping rules 
will be implemented for the DFS interim analyses. If the p-value of the two-sided 
log-rank test is less than or equal to 0.001, 0.0077, 0.0246 at the three interim 
looks, respectively, the study will be stopped early and we will conclude that the 
selective use group is preferred if the HR is less than 1, or the treat all group is 
preferred if the HR is greater than 1. 
All patients enrolled in phase II and III component will be used in the phase III 
analysis and decision-making. In order to protect the phase III comparison, the 

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Addendum 10 
results of the phase II portion will not be released beyond the DMC until all phase 
III patients have been randomized and have undergone surgery. The independent 
Data Monitoring Committee will only report whether the criteria for continuation 
have been satisfied, not any of the actual results. 
16.3.2.3 
Study Operating Characteristics: 
The table below shows the study operating characteristics assuming the time-to-
event outcomes of DFS and TLR follow exponential survival functions. Table 1 
includes the operating characteristics according to the monitoring plan outlined in 
previous sections. The proportion of times that 1) the study would conclude that 
the selective use group is preferred at the final analysis of phase III portion, 2) the 
study would stop early at phase II analysis due to inferiority regarding TLR, 3) the 
study would stop early at interim analyses due to significant difference in hazard 
rates between two treatment groups regarding DFS if the study proceeds to phase 
III portion, are tabulated by true 3-year rates for TLR and DFS by treatment groups.  
Table 1: Study Operating Characteristics When Jointly Assessing DFS and TLR 
True 3-year rates† 
%‡ of times 
that SUA is 
preferred at 
the final 
analysis 
%‡ of times that the study will be stopped  early 
LR-free 
DFS 
Phase II  
TLR 
Phase III DFS interim analyses, 
if the study proceeds to phase III 
portion 
TAA 
SUA 
TAA 
SUA 
Due to SUA 
is inferior to 
TAA 
Due to SUA is 
inferior to 
TAA 
Due to SUA is 
superior to 
TAA 
0.96 
0.93 
0.74 
0.69 
0.045 
0.387 
0.183 
0.000 
0.96 
0.93 
0.74 
0.76 
0.209 
0.385 
0.000 
0.060 
0.96 
0.96 
0.74 
0.69 
0.129 
0.112 
0.289 
0.000 
0.96 
0.96 
0.74 
0.76 
0.846 
0.108 
0.001 
0.080 
Abbreviations:  LR, local recurrence; DFS, disease-free survival; TAA, treat all group; SUA, selective use 
group; † Although we use the 3-year rates to illustrate each scenario, the hypothesis testing is based on the 
entire survival curve.  ‡ Proportions are based on 10,000 replicates in the simulation study. 
From this table, we see when both LR-free and DFS 3-year rates are at the non-
inferiority margin (null hypotheses), there is a 4.5% chance of concluding the 
selective use group is preferred incorrectly. This is the overall alpha level. When 
the both true rates of LR-free and DFS are under the non-inferiority alternatives, 
i.e., the selective use group performs as well as the treat all group on both 
endpoints, we have 84.6% power to conclude that selective use group is preferred 
correctly. When either of two endpoints follows the null hypothesis but the other 
follows the alternative, there is a relatively small chance (12.9% to 20.9%) to 
conclude that the selective use group is preferred. There is a 57.0% chance that the 
study will stop early (either at phase II stage or phase III interim looks) due to 
inferiority of selective use group when both endpoints follow the null hypotheses. 
There is a 10.9% chance of stopping early due to inferiority of selective use group 
when both endpoints follow the alternative hypotheses. There is a 38.5% to 40.1% 
chance that the study will stop early due to inferiority of selective use group when 
either of the two endpoints follows the null but the other the alternative. 
 

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The marginal alpha and power for DFS following the same final non-inferiority 
testing decision rule with the same interim analyses decision rules, ignoring 
inference on TLR, are 15.9% and 98.1%, respectively. The marginal alpha and 
power for TLR following the same final non-inferiority test decision rule with the 
same phase II decision rule, ignoring inference on DFS, are 15.3% and 85.3%, 
respectively. We note that the marginal alpha level for each of the endpoints, DFS 
and TLR, is > 0.05. This is acceptable as for the selective use group to be 
considered the preferred approach; it must satisfy the non-inferiority bounds for 
both endpoints. The procedure outlined maintains the overall type I error rate of ≤ 
0.05 with acceptable joint power.  
16.3.3 Major Re-Design 
16.3.3.1 
Background:  
N1048 (PROSPECT) study was designed with disease-free survival (DFS) and 
time to local recurrence (TLR) as co-primary endpoints for the phase III portion of 
the study. The original design was based on the best available information from 
the literature, expert opinion, and historical data which were accessible prior to 
2012. The protocol specified that the primary analyses will be performed after 
observing at least 406 and 75 events observed for DFS and TLR, respectively to 
ensure 85% power.  
The first patient was randomized on June 11, 2012. Phase II analyses were 
completed in February 2018, and the study was open to phase III portion. The first 
Phase III DFS interim analysis per original design was completed in August 2018 
when 102 DFS events were observed, and the study continued accrual. The alpha 
spent was 0.001. The last patient was randomized on December 28, 2018 and the 
phase III full accrual was reached. The median follow-up time as of February 2021 
is 39 months for all evaluable patients (N = 1023, according to the definition in the 
protocol version 9.0 and prior versions). As of February 2021, the planned 406 
DFS events and 75 TLR events have not yet been reached likely due to the higher 
than expected 3-year DFS rates.  
A review of blinded N1048 data revealed that the 3-year DFS rate (combining two 
treatment arms) is much higher than what was expected in the original design 
(69%). Recent data reported in January 2021 by Schmoll et al from the PETACC 
trial also showed higher 3-year DFS rate in the similar disease population. In order 
to preserve the scientific goal of the trial, a major statistical redesign request was 
submitted to Group Statistician, 
 on Feb 11, 2021. An 
independent statistician, 
from NRG, was appointed to perform 
the major redesign in collaboration of CTEP statistician, 
 and 
the study chair. The study statistician, 
 was blinded to all redesign 
conversations. The proposed re-design was completed by 
 
 
 
16.3.3.2 
Updated Statisticial Design for Phase III Portion:  
To ensure the timely reporting of the trial results, the following simplifications are 
made to the statistical design of Phase III portion to reduce the number of DFS 
events needed while maintaining the overall type I error rate and power. 
1) 
Reduce the number of hypotheses to be tested: 

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• 
Remove TLR as one of the co-primary endpoints and include it as one 
of the secondary endpoints, so the alpha can be preserved solely for 
the DFS primary analysis.  
• 
Remove the 2nd and 3rd interim analyses in the original design, so the 
remaining alpha (0.049) can be preserved for the DFS primary 
analysis. 
2) 
Modify the relative effect sizes (hazard ratio) for the primary DFS non-
inferiority hypotheses, but keep the prior absolute effect size in terms of DFS: 
• 
Null hypothesis: The 5-year DFS rate in the selective use group is 75% 
vs. 80% in treat all group. Same 5% absolute delta as the original 
protocol but based on 5-year DFS instead of 3. This is equivalent to a 
non-inferiority margin of hazard ratio (HR) = 1.29, assuming 
exponential survival functions.   
• 
Alternative hypothesis: The 5-year DFS rate in the selective use group 
is 82% vs. 80% in treat all group. Same 2% absolute delta as the 
original protocol but based on 5-year DFS instead of 3. This is 
equivalent to HR = 0.89, assuming exponential survival functions.  
Assuming a lost-to-follow-up rate of 8% annually, a minimal of 210 DFS events 
are required to achieve 85% power to test the alternative hypothesis against the 
null hypothesis incidated above.  
16.3.3.3 
Updated Analysis Timing and Decision Rule for Phase III Portion:  
The primary analysis for the single endpoint of DFS will be conducted at the either 
occurrence of the following: 
• 
Observe at least total of 210 DFS events pooling two arms. 
• 
December 31, 2022 (i.e. 10.5 and 3.5 years after the first and last 
patient was randomized, respectively) using whatever events are 
available and possibly accepting reduced power.  
At the final analysis, the p-value of testing non-inferiority (against null hypothesis 
of HR = 1.29) will be calculated based on a stratified Cox model. If this p-value is 
< 0.049, then the selective use of chemoRT treatment will be considered non-
inferior to the treat all approach. 
16.3.4 General Analysis Plan 
16.3.4.1 
Definition of Analysis Population:  
16.3.4.1.1 Per-Protocol (PP) Population: All randomized patients who received any quantity 
of the initial chemotherapy FOLFOX or chemoradiation (5FUCMT) before 
surgery and did not have major treatment violation. Patients will be included in the 
analysis in the group closest in principle to the initial treatment they actually 
received. Because the primary testing procedure is non-inferiority testing, the 
primary analyses of phase II and III component will be conducted based on the PP 
population. 
16.3.4.1.2 Intention-to-treat (ITT) Population: All randomized patients regardless whether 
received any treatment. Patients will be included in the analysis in the group they 

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are randomized. ITT population will be used only for sensitivity analysis for 
primary and/or secondary endpoints when it is applicable.  
16.3.4.1.3 Safety Population: All randomized patients who received any quantity of study 
drug. Patients will be grouped according to treatment received. Safety population 
will be used for safety related analyses. 
16.3.4.2 
General Analysis Plan for Primary Endpoints: 
The analysis plans outlined in this section refer to marginal analysis, i.e., 
examining each primary endpoint individually.  
16.3.4.2.1 Pelvic R0 Resection Rate (RRR): Point estimate and confidence interval 
(according to approach of Duffy and Santner) will be calculated by treatment 
groups. The Chi-square test will be used to compare the RRR between groups. 
Logistic regression will be used for multivariate analysis.  
16.3.4.2.2 Disease-free Survival (DFS): The distribution of DFS by group will be estimated 
using the method of Kaplan-Meier. 3 and 5 year disease free rates by treatment 
group with confidence intervals based on Kaplan-Meier curves will be reported. 
Log-rank test will be used to compare DFS between two treatment groups. Hazard 
ratio with confidence interval will be estimated based on Cox proportional hazard 
model. The Cox proportional hazard model will be used for multivariate analysis. 
16.4 
Supplementary Analysis Plans 
16.4.1 Secondary Endpoints: 
All analyses on secondary endpoints will be conducted on PP population, except Safety 
population for safety endpoints. ITT population will be used for sensitivity analyses if it is 
applicable.  
16.4.1.1 
Time to Local Recurrence (TLR): The distribution of TLR by group will be 
estimated using the method of Kaplan-Meier. 3 and 5 year local recurrence free 
rates by treatment group with confidence intervals based on Kaplan-Meier curves 
will be reported. The comparison of the cumulative incidence of local recurrence 
between groups, treating distant recurrence and death as competing risks using the 
test of Gray (Annals of Statistics, 1988) will be conducted. 
16.4.1.2 
Pathologic Complete Response (pCR): The pCR rate is defined as number of 
patients who achieve pCR divided by total number of patients included in the 
analysis population (see definition in Section 16.3.3.1) in each group. Patients who 
didn’t undergo surgery will be classified as non-pCR. Point estimate and 
confidence interval (according to approach of Duffy and Santner) will be 
calculated by treatment groups. Chi-square test will be used to compare the pCR 
rates between groups.  
16.4.1.3 
Overall Survival (OS): OS is defined as time from randomization to the date of 
death due to all causes. The distribution of OS by group will be estimated using 
the method of Kaplan-Meier. Three and five year survival rates by treatment group 
with confidence intervals based on Kaplan-Meier curves will be reported. Log-
rank test will be used to compare OS between two treatment groups. Hazard ratio 
with confidence interval will be estimated based on Cox proportional hazard 
model. The Cox proportional hazard model will be used for multivariate analysis. 
16.4.1.4 
Adverse Event (AE) Profiles: The maximum grade for each type of adverse events 
during neoadjuvant chemotherapy and chemoradiation therapy, and surgical 

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complications will be recorded for each patient. The frequency tables will be 
reviewed to determine patterns. The overall AE rates for Grade3 or higher events, 
Grade 4 or higher events will be compared between two treatment groups using 
Chi-square test.  
16.4.1.5 
Rates of Receiving 5FUCMT: For selective group patients, the proportion of 
patients who received 1) pre-operative 5FUCMT, 2) post-operative 5FUCMT, 3) 
either pre or post-operative 5FUCMT, and confidence intervals (according to 
approach of Duffy and Santner) will be reported.  
16.4.1.6 
Neoadjuvant Response Score: The Neoadjuvant Response (NAR) score is defined 
based on the formula devised by George, Allegra, and Yothers (George et al., 
2015). The NAR scores between between the two treatment groups will be 
compared using the Wilcoxon Rank Sum test (continues version) and Chi-square 
test (categorical version). (The NAR is defined in Section 11.3.3.3). 
16.4.2 Clinical and Biological Correlative Studies 
The details of the statistical analysis plan for the QOL, PRO-CTCAE, genomic 
characterization, immunologic and pharmacogenomics studies are contained in 
Appendices VI, VII, XII, XIII, and XIV. 
16.5 
Adverse Event Stopping Rule 
The study PI, statistician and Research Base Adverse Event Coordinator review all Serious 
Adverse Events occurring on both groups of the trial on an ongoing basis. In addition, the 
independent Data Monitoring Committee (DMC) reviews all safety data every 6 months and 
may convene for a special session when necessary. In addition to this standard safety monitoring 
we have developed a formal monitoring plan for treatment-related toxicity. 
• 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the 
event of either (1) the study re-opening to accrual or (2) at any time during the conduct 
of the trial and in consideration of newly acquired information regarding the adverse 
event profile of the treatment(s) under investigation. The study team may choose to 
suspend accrual because of unexpected adverse event profiles that have not crossed the 
specified rule below. 
• 
Based on previous experience with this disease, we expect approximately 3% of patients 
to experience at least one Grade 4+ non-hematologic adverse event which is at least 
possibly related to the treatment. Therefore, accrual will be temporarily suspended to 
the study (both Groups) to allow for a full review of data, if any time, we observe events 
that satisfy either of the following: 
o After 10 patients are randomized to each group (total of 20 patients enrolled), 
if at any time, in patients who have completed all protocol-specified treatment, 
the rate of any Grade 4+ adverse events in either group is higher than 15%. All 
treatment includes preoperative treatment, surgery and postoperative 
chemotherapy. 
o OR if at any time the 80% two-sided confidence interval for the rate of on study 
death combining both groups excludes 5% to the right (i.e., includes only values 
greater than 5%). 
• 
After consideration by the study team (study chair[s], statistician[s], etc.) and DMC, a 
decision will be made as to whether accrual can be resumed or whether protocol 
modifications are necessary. 

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16.6 
Accrual Monitoring Stopping Rule 
Accrual will be monitored closely. The Investigators including study statisticians and the data 
monitoring committee will convene monthly conference calls. Input from NCI leadership, the 
Rectal Anal Task Force, GI Steering Committee, Cooperative Group leadership and Patient 
Advocates will be obtained on an ongoing basis. During the first 4 months, the team will 
carefully review the lists of sites that have activated the study and will engage in outreach to 
sites to understand potential obstacles to activation. After the trial has been open for 4 months, 
investigators will carefully review accrual based on feedback from sites and will consider 
whether any amendments need to be made. These amendments will be submitted no later than 
6 months from activation. Investigators will evaluate accrual within the 5th to 6th quarter from 
activation (months 12 to 18). If accrual during this time period is less than 20% of what was 
projected to meet accrual goals, the study will automatically be closed. If accrual is >20% but 
less than 50% of what was projected, working together with the Data Monitoring Committee 
and the National Cancer Institute, we will plan modifications including the potential for closure. 
16.7 
Study Monitoring 
16.7.1 This study will be monitored by the independent Data Monitoring Committee (DMC), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and 
administrative information will be provided to the DMC every six months as per NCI 
guidelines. 
16.7.2 This study will be monitored by the Clinical Data Update System (CDUS) version 3. 
Cumulative Abbreviated CDUS data will be submitted quarterly to CTEP by electronic 
means. Reports are due January 31, April 30, July 31 and October 31. 
16.8 
Women and Minorities Distributions  
16.8.1 This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin. 
16.8.2 There is no information currently available regarding differential effects of study regimens 
in subsets defined by race, gender, or ethnicity, and there is no reason to expect such 
differences to exist. Therefore, although the planned analysis will, as always, look for 
differences in treatment effect based on racial and gender groups, the sample size is not 
increased in order to provide additional power for subset analysis.  
16.8.3 Based on prior studies involving similar disease sites, we expect about 10% patients will 
be classified as minorities by race and about 45% patients to be women. Expected size of 
racial by gender subsets are shown in the following table: 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
2 
3 
0 
0 
5 
Asian 
5 
7 
0 
0 
12 
Native Hawaiian 
or Other Pacific 
Islander 
31 
42 
1 
1 
75 
Black or African 
American 
2 
3 
0 
0 
5 
White 
424 
529 
9 
9 
971 
More Than One 
0 
0 
0 
0 
0 

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Addendum 10 
Race 
Total 
464 
584 
10 
10 
1068 
 
 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian 
or Other Pacific 
Islander 
3 
5 
0 
0 
8 
Black or African 
American 
0 
0 
0 
0 
0 
White 
44 
56 
1 
1 
102 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
48 
62 
1 
1 
112 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0 RECORDS AND DATA COLLECTION PROCEDURES  
For SAKK sites, please refer to the Swiss Specific Appendix for information regarding 
documentation. 
17.1 
Data Submission Using RAVE 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 

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• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
 for registration types and 
documentation required.Site staff that have not previously activated their iMedidata/Rave 
account at the time of initial site registration approval for the study in RSS will receive a separate 
invitation from iMedidata to activate their account. Account activation instructions are located 
on the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section at 
 or by contacting the 
 
   
For questions regarding forms completion and submission, please contact the Data Manager 
listed on the Protocol Resources page of the protocol. 
17.2 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and 
review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. 
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms with 
current status and timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms, DQP Form Status, and DQP Reports modules. 
17.3  Submission Timetable 
Please refer to the forms packet found on the N1048 study page on the Alliance for Clinical 
Trials in Oncology and/or the CTSU web site for the most up to date data submission 
requirements. 
18.0 BUDGET 
18.1 
Costs Charged to Patient  
Routine clinical care, all study procedures but the tissue and blood biospecimens required for 
correlative studies. NOTE: all imaging scans, biopsies, and treatment regimens should be billed 

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to the patient’s insurance company. FOLFOX is standard of care and is incorporated into many 
practice guidelines for rectal cancer including those put forth by the NCCN. 
18.2 
Reimbursement 
The most up to date details regarding the per-case funding available for patients enrolled onto 
N1048 may be found on the study funding sheet available on the N1048 study page on the 
Alliance and CTSU web sites.  
18.3 
MRI Reimbursement 
Pelvic MRIs are standard of care and procedures should be reimbursed by the patients’ insurance 
companies. Every effort will be made to appeal to insurance companies on patient’s behalf.  
18.4 
Correlative Science Funding 
Study investigators will seek independent NIH funding to support the correlative science work 
as well as analyses of QOL assessments. The PRO-CTCAE component is funded under an 
existing NCI contract (HHS-N261201000063C; PI: Basch). 
For more information about per patient reimbursement to sites, please see the Funding Memo 
available on 
 under protocol N1048. 
For SAKK sites, please refer to the Swiss Specific Appendix for information regarding 
translational research costs. 

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19.0 REFERENCES 
American Cancer Society. (2009). “Cancer Facts and Figures.” Atlanta: American Cancer  
Society; posted to American Cancer Society website, 2009, from 
http://www.cancer.org/docroot/STT/STT_0.asp. 
 
 
Carlsen E., E.Schlichting et al. (1998). “Effect of the introduction of total mesorectal excision for 
the treatment of rectal cancer.”  Br J Surg  85(4): 526-9. Pub Med ID: 9607540. 
 
Carne, P.W. and H. Nelson. (2004). “Are we overtreating rectal cancer: time for another trial?” 
Ann Surg Oncol 11(2): 124-6. Pub Med ID: 14761913. 
 
Eisenhauer E.A., P. Therasse, et al. (2009). “New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1).”  Eur J Cancer 45(2): 228-247. 
 
Ender W.E., N. Merchant, et al., (1999). “Safety and efficacy of low anterior resection for rectal 
cancer: 681 consecutive cases from a specialty service.” Ann Surg  230(4): 544-52; discussion 
552-4. Pub Med ID: 10522724. 
 
Fisher B., N. Wolmark, et al. (1988). “Postoperative adjuvant chemotherapy or radiation therapy 
for rectal cancer: results from NSABP protocol R-01.” J Natl Cancer Inst  80(1): 21-9. Pub Med 
ID: 3276900. 
 
Gastrointestinal Tumor Study Group. (1985). “Prolongation of the disease-free interval in 
surgically treated rectal carcinoma.” N Engl J Med 312(23): 1465-72. Pub Med ID: 2859523. 
 
George T.J., C.J. Allegra, et al. (2015). “Neoadjuvant Rectal (NAR) Score: a New Surrogate 
Endpoint in Rectal Cancer Clinical Trials.” Curr Colorectal Cancer Rep 11(5): 275-280. Pub 
Med ID: 26321890. 
 
Glimelius B., H. Grönberg, et al. (2003). “A systematic overview of radiation therapy effects in 
rectal cancer.” Acta Oncol 42(5-6): 476-92. Pub Med ID: 14596508. 
 
Goldberg R.M., D.J. Sargent, et al. (2004). “A randomized controlled trial of fluorouracil plus 
leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated 
metastatic colorectal cancer.” J Clin Oncol  22(1): 23-30. Pub Med ID: 14665611. 
 
Grothey A., D. Sargent, et al. (2004). “Survival of patients with advanced colorectal cancer 
improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course 
of treatment.” J Clin Oncol  22(7): 1209-14. Pub Med ID: 15051767. 
 
Imam I., K. Hammarström, et al. (2021). “Neoadjuvant rectal (NAR) score: Value evaluating the 
efficacy of neoadjuvant therapy and prognostic significance after surgery?” Radiother Oncol 
(157): 70-77. Pub Med ID: 33453311. 
 
Kapiteijn E., C.A. Marijnen, et al. (2001). “Preoperative radiotherapy combined with total 
mesorectal excision for resectable rectal cancer.” N Engl J Med  345(9): 638-46. Pub Med ID: 
11547717. 
 
Krook J.E., C.G. Moertel, et al. (1991). “Effective surgical adjuvant therapy for high-risk rectal 
carcinoma.” N Engl J Med  324(11): 709-15. Pub Med ID:1997835. 
 

N1048 
Version Date:08/25/2022 
 115 
Addendum 10 
MacFarlane, J.K. , R.D. Ryall et al. (1993). “Mesorectal excision for rectal cancer.” Lancet 
341(8843): 457-60. Pub Med ID: 8094488. 
 
Matzel K.E., B. Bittorf, et al. (2003). “Rectal resection with low anastomosis: functional 
outcome.” Colorectal Dis  5(5): 458-64. Pub Med ID: 12925081. 
 
 
 
Merchant, N.B., J.G. Guillem et al. (1999). “T3N0 rectal cancer: results following sharp 
mesorectal excision and no adjuvant therapy.” J Gastrointest Surg  3(6): 642-7. Pub Med ID: 
10554372 
 
Minsky B.D., J.A. Conti, et al. (1995). “Relationship of acute gastrointestinal toxicity and the 
volume of irradiated small bowel in patients receiving combined modality therapy for rectal 
cancer.” J Clin Oncol 13(6): 1409-16. Pub Med ID: 7751886. 
 
NIH consensus conference. (1990). “Adjuvant therapy for patients with colon and rectal cancer.” 
Jama 264(11): 1444-50. Pub Med ID: 2202842. 
 
Paty P.B., W.E. Enker, et al. (1994). “Long-term functional results of coloanal anastomosis for 
rectal cancer.” Am J Surg 167(1):90-4; discussion 94-5. Pub Med ID: 8311145. 
 
Roh M.S., L.H. Colangelo , et al. (2009). “Preoperative multimodality therapy improves disease-
free survival in patients with carcinoma of the rectum.” J Clin Oncol 27(31): 5124-30.  
 
Rosen, R.C. et al. (1997). “The international index of erectile function (IIEF): a multidimensional 
scale for assessment of erectile dysfunction.” Urology.  49(6): 822-30. 
 
 
Rosen, R. et al. (2000) “The Female Sexual Function Index (FSFI): a multidimensional self-report 
instrument for the assessment of female sexual function.” Journal of Sex & Marital Therapy.  26(2): 
191-208. 
 
 
Saltz L.N., J.V. Cox,, et al. (2000). “Irinotecan plus fluorouracil and leucovorin for metastatic 
colorectal cancer.” N Engl J Med  343(13): 905-14. Pub Med ID: 11006366. 
 
Sauer R., H. Becker, et al. (2004). “Preoperative versus postoperative chemoradiotherapy for 
rectal cancer.” N Engl J Med  351(17): 1731-40. Pub Med ID: 15496622. 
 
Shibata D., J.G. Guillem, et al. (2000). “Functional and quality-of-life outcomes in patients with 
rectal cancer after combined modality therapy, intraoperative radiation therapy, and sphincter 
preservation.” Dis Colon Rectum 43(6): 752-8. Pub Med ID: 10859073. 
 
Smith, T.J. et al. (2006). “2006 Update of recommendation for the use of white blood cell growth 
factors: an evidence-based clinical practice guideline.” J Clin Oncol  24(19): 3187-205. Pub Med 
ID: 16682719. 
 
 
Temple L.K., W.D. Wong, et al. (2003). “The impact of radiation on functional outcomes in 
patients with rectal cancer and sphincter preservation.”  Semin Radiat Oncol  13(4): 469-77. Pub 
Med ID: 14586835. 
 
Tepper J.E., M.J.  O'Connell, et al. (1997). “Adjuvant postoperative fluorouracil-modulated 
chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of 
intergroup 0114.” J Clin Oncol. 15(5): 2030-9. Pub Med ID: 9164215. 
 

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Version Date:08/25/2022 
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Addendum 10 
van der Valk M.J.M., F.A. Vuijik, et al. (2019). “Disqualification of Neoadjuvant Rectal Score 
Based on Data of 6596 Patients From the Netherlands Cancer Registry.” Clin Colorectal Cancer. 
18(2): e231-e236. Pub Med ID: 30772135. 
 
 
Wolmark N., H. Rockette, et al. (1993). “The benefit of leucovorin-modulated fluorouracil as 
postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant 
Breast and Bowel Project protocol C-03.” J Clin Oncol  11(10): 1879-87. Pub Med ID: 8410113. 

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APPENDIX I: PATIENT INFORMED CONSENT VISUAL PRESENTATION  
 
The Patient Informed Consent Visual Presentation can be found as a separate document on the N1048 
study-specific webpage on the Alliance and CTSU websites. 
 
 
 

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APPENDIX II: PATIENT FAQ- PROSPECT RECTAL CANCER STUDY 
 
The Patient Guide for the PROSPECT Rectal Cancer Study can be found as a separate document on 
the N1048 study-specific webpage on the Alliance and CTSU websites. 

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APPENDIX III: OPTIONAL PATIENT CAPECITABINE MEDICATION DIARY 
Optional Patient Capecitabine Medication Diary (Optional; does not need to 
be submitted to the Alliance) 
 
Patient Capecitabine Medication Diary 
PROSPECT (N1048) 
 
Study ID#:                      __________________________ 
 
Patients Initials:            __________________________ 
 
Starting Dose:               __________________________ 
 
 
INSTRUCTIONS TO PATIENT: 
 
1. Complete on form for the entire period during which you receive radiation therapy and 
capecitabine. The duration of treatment is usually 5.5 weeks but may be a bit longer if 
treatment is interrupted for any reasons. 
2. Please follow the dosing instructions carefully. 
3. Please record the date and approximate times you take the capecitabine tablets. Your 
physician or nurse will write down your dose and explain to you how many tablets are in your 
dose. 
4. Start taking capecitabine on day 1 and take Monday through Friday while you are receiving 
radiation treatment. 
5. You should take the capecitabine dose prescribed for you by mouth twice a day on Days 1-5, 
8-12, 15-19, 22-26, 29-33, and 36-38. Take a dose every morning and a dose every evening, 
about 12 hours apart. Take the dose with 8 ounces of water each time. It is best to take the 
dose within 30 minutes after eating food. 
6. If you vomit after taking a dose, or if you forget to take a dose, please note it on this diary, 
and do not take capecitabine again until your next scheduled dose. 
7. The use of a daily moisturizer to hands, feet and face are commended. Please use sunscreen if 
you are going outdoors. 
8. Please contact your health care team with any questions or for help understanding exactly 
how to take your medicine. 
9. Bring this Medication diary with you when you meet with your doctor each week. 
 
PLEASE CONTINUE TO PAGE 2 
 
 
Day 
Date 
Approximate times tablets taken 
a.m. 
p.m. 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
Do not take capecitabine tablets today 
-- 
-- 
7 
Do not take capecitabine tablets today 
-- 
-- 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 

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12 
 
 
 
13 
Do not take capecitabine tablets today 
-- 
-- 
14 
Do not take capecitabine tablets today 
-- 
-- 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
Do not take capecitabine tablets today 
-- 
-- 
21 
Do not take capecitabine tablets today 
-- 
-- 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
Do not take capecitabine tablets today 
-- 
-- 
28 
Do not take capecitabine tablets today 
-- 
-- 
29 
 
 
 
30 
 
 
 
31 
 
 
 
32 
 
 
 
33 
 
 
 
34 
Do not take capecitabine tablets today 
 
 
35 
Do not take capecitabine tablets today 
 
 
36 
 
 
 
37 
 
 
 
38 
 
 
 
39 
Do not take capecitabine tablets today 
 
 
 
 
___________________________________                 ______________________________ 
      Patient signature                                                                  Date 
Physician’s office will complete this section: 
 
1.  Date patient started radiation therapy:         ____________________ 
2.  Date patient completed radiation therapy:   ____________________ 
3.  Date patient started capecitabine:                ____________________ 
4.  Date patient finished capecitabine:              ____________________ 
 
Physician/Nurse/Data Manager’s signature ______________________________Date___________________ 
 
 

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APPENDIX IV: SUGGESTED DOSE MODIFICATION OF CAPECITABINE  
Dose Modification of Capecitabine During 5FUCMT 
Capecitabine tablets are available as 150mg and 500mg sizes and doses therefore need to be rounded since 
splitting tablets is difficult and imprecise. The following tables are provided for the convenience of treating 
clinicians in order to provide patients with clear dosing instructions based on BSA and total daily dose. The 
need to provide patients with clear written instructions and of monitoring adherence is an essential 
component of dispensing oral chemotherapy such as capecitabine. 
 
 
 
 
Adapted from RTOG study 0247 “A Randomized Phase II Trial of Neoadjuvant Combined Modality 
Therapy for Locally Advanced Rectal Cancer” 
 

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APPENDIX V: PATIENT-REPORTED OUTCOMES  
Patient-Reported Outcomes: Evaluation of the Clinical Value and Feasibility 
of the Patient-reported Outcomes Version of the Common Terminology 
Criteria (PRO-CTCAE) 
 
1. Correlative Study Background 
 
The PRO-CTCAE is a group of items currently being developed by the NCI for direct electronic patient-
reporting of adverse symptoms via the Web or automated telephone system, in order to complement the 
CTCAE (Basch, 2010). Development and testing of the PRO-CTCAE is funded under an NCI contract 
(HHS-N261201000063C). This contract includes assessment of the feasibility of implementing the PRO-
CTCAE in cooperative group treatment trials, which is the primary aim of the PRO-CTCAE correlate in 
this trial. To date, 78 symptoms in the CTCAE have been developed for patient self-reporting via the 
PRO-CTCAE, and have undergone refinement in a cognitive testing study (Hay, 2010).  A validation 
study of the PRO-CTCAE is near completion, with interim descriptive statistics supporting validity of the 
items, and a final analysis planned for December 2011. The items are now ready for assessment of 
feasibility of electronic implementation in a cooperative group trial, in order to assess the ability and 
effort at sites to use the system, and the extent to which study participants are willing and able to use the 
system throughout treatment.       
 
In this correlative study, all patients enrolling in the phase II and phase III portions of the clinical trial will 
be required to self-report selected PRO-CTCAE symptoms at baseline, once every week during active 
treatment, and once every 6 months for three years following surgery, via an automated electronic system.  
 
Patients will be given a choice to report either via an automated telephone system (interactive voice 
response system [IVRS]), or via Web. The electronic system for administering the PRO-CTCAE items 
has previously been developed, is hosted and maintained on servers at the NCI, and has undergone 
rigorous safety and privacy assessment per NCI requirements. This reporting will be completed by 
patients from home. It will be made clear in the training and software that the PRO-CTCAE information 
being collected is for research purposes only, and is not being monitored by a clinician. Therefore, 
patients will be advised to directly contact their doctor’s office for any symptoms of concern.  
 
The work for site personnel will consist of training patients to use the system; registering patients into the 
system; printing PRO-CTCAE patient symptom reports at preoperative visits for reference when 
documenting study AEs (Sites will be randomly assigned at the time of training by the PRO-CTCAE 
Coordinator to report adverse events either by: a) using the Solicited AE Form from the paper forms 
packet posted on the CTSU website or: b) using a Solicited AE Form generated from the PRO-CTCAE 
system which contains the patient’s PRO-CTCAE scores); and completing a feasibility survey/discussion 
about experiences using the system. 
 
2. Specific Hypotheses 
The primary hypothesis of this correlative study is that study sites will be willing and able to register 
patients to use the PRO-CTCAE; that this activity will incur a minimal incremental effort; and that 
patients will be willing and able to self-report via the PRO-CTCAE throughout treatment. 
The secondary hypothesis of this correlative study is that patient-reported PRO-CTCAE data will be able 
to detect differences in symptoms between study groups.   
The exploratory hypothesis of this correlative study is that exposure to printed patient-reported symptoms 

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will increase the severity of symptom reporting by research staff for symptoms known to be associated 
with the trial’s neoadjuvant treatments. 
3. PRO-CTCAE Training and Reporting for Site Study Staff and Patients 
Note: At least one staff personnel from the site study team should be credentialed to perform patient 
PRO-CTCAE training and registration before the first study participant’s baseline visit. 
 
For further information about site credentialing for PRO-CTCAE, site training and reporting and patient 
training and reporting, please refer to protocol Section 4.4. 
 
4. Statistics 
 
For the primary hypothesis, descriptive statistics will be used to characterize the proportion of sites where 
patients are enrolled onto this correlative study and the proportion of participating patients adhering to 
scheduled self reports at each time point during the trial. Qualitative information about the feasibility of 
implementing the PRO-CTCAE at sites will be collected via a survey of study personnel and clinical 
research staff at participating sites. Moreover, site personnel will be asked in the survey if they are willing 
to participate in a brief semi-structured discussion by telephone or in person regarding their experiences 
with this new system (including effort/cost, technical issues, and administrative burden). These 
discussions will be conducted with staff members of the PRO-CTCAE project. In addition, the frequency 
of backup reminders and success of backup reminders for questionnaire completion will be evaluated. 
 
For the secondary hypothesis, the patient-reported maximum score (post baseline) for each 
frequency/severity/interference item for each patient will be computed and compared between groups 
using a two-sample independent samples t-test. Present/absent items will be analyzed similarly, however, 
using a chi-squared test. Multiple testing will be handled using Hochberg’s step-up method.   
 
Power (gender-neutral t-tests): Assuming that 70% patients are eligible to participate in this correlative 
study and provide data (i.e., N= 700 with reported scores for a given gender-neutral 
frequency/severity/interference question), we will have 80 % power to detect a 0.30 standard deviation 
difference between groups using a t-test. With this sample size, we will have 90 % power to detect a 0.34 
standard deviation difference between groups using a t-test. Estimates are based on a two-sided 
α=0.05/30=0.00167 two-sample t-test using a Bonferonni correction. We base calculations on the more 
conservative Bonferonni correction but plan to handle multiple testing using Hochberg’s step-up method. 
With 70 % participation, this study will be able to detect small (0.2 standard deviations) to moderate (0.5 
standard deviations) effect size differences between groups (Cohen, 1988).   
 
Power (gender-neutral chi-squared tests): With N=700, we have 80 % and 90 % power to detect a 
Cohen’s w of 0.15 or 0.17, respectively, using a chi-squared test in testing for association between 
“present” vs. “not present” and group. Cohen’s w of 0.3 is considered a moderate effect size (Cohen, 
1988).  If the number of responders is somewhat less than N=700, a sample size of N=500 provides 80 % 
and 90% power to detect a Cohen’s w of 0.18 and 0.20, respectively.  
 
Power (gender-specific t-tests):  For gender-specific t-tests, we assume that approximately 65% of 
patients will be male.  With N=455 males agreeing to participate in this correlative study and providing 
data, we will have 80 % and 90 % power to detect a 0.38 and 0.42 standard deviation difference between 
groups using a t-test, respectively. With N=245 females agreeing to participate in this correlative study 
and providing data, we will have 80 % and 90 % power to detect a 0.52 and 0.57 standard deviation 
difference between groups using a t-test, respectively. If the number of responders is somewhat less (e.g., 
for sexual functioning questions), a sample size of N=325 males provides 80 % and 90 % power to detect 

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a 0.45 and 0.50 standard deviation difference between groups using a t-test, respectively; and N=175 
females provides 80 % and 90 % power to detect a 0.61 and 0.68 standard deviation difference between 
groups using a t-test, respectively.   
 
Power (gender-specific chi-squared tests):  Present/absent gender-specific questions are only assessed 
for females so power is provided for N=245 females. A sample size of N=245 females provides 80% and 
90% power to detect a Cohen’s w of 0.25 and 0.28, respectively. If the number of responders is somewhat 
less, a sample size of N=175 females provides 80 % and 90 % power to detect a Cohen’s w of 0.30 and 
0.33, respectively. 
 
Additional analyses will include a comparison of the incidence of patient-reported maximum score ≥3 
(i.e., severity reported as “severe” or “very severe”; frequency reported as “frequently” or “almost 
constantly”; or interference reported as “quite a bit” or “very much”) between groups using chi-squared 
testing for each item; and a comparison of the time to patient-reported score ≥3 between groups using 
Kaplan-Meier and log-rank analyses. Further, these three endpoints (maximum score/grade, incidence of 
score/grade ≥3, and time to score/grade ≥3) will be compared between patient- and clinician-report 
overall and within groups using appropriate paired analyses. The PRO-CTCAE items related to bowel and 
genitourinary function will be further validated by computing Pearson correlations between each of these 
items and associated patient-reported outcomes (bowel, bladder, and sexual function, pain, and health-
related quality of life) collected as part of the Quality of Life study at the 12-month and 24-month post-
surgery assessment time points. 
 
Anticipated differences in toxicities between arms which we hypothesize the PRO-CTCAE system will 
detect include: 1) In the control arm, toxicities related to chemoradiation during the first 6 weeks will 
include increasing perineal pain, diarrhea, and fatigue which should improve by week 9; no peripheral 
neuropathy is anticipated due to lack of oxaliplatin. 2) In the intervention arm including FOLFOX, more 
of a steady state pattern is expected with relatively less diarrhea and less pain, but more nausea and more 
peripheral neuropathy. 
 
For the exploratory analysis involving a comparison of symptom severities between patients at sites 
randomized to (1) printing of PRO-CTCAE responses vs. (2) no printing of PRO-CTCAE responses, the 
clinician-reported maximum grade (post baseline) for each AE for each patient will be computed and 
compared between groups using a generalized linear mixed model including a fixed effect for randomized 
group (print vs. no print) and a random effect for site-specific mean intercepts (sites are nested within the 
randomized arm). Similar models will also be developed to compare AE severity over time between the 
randomized groups. Assuming that 70 % of patients agree to participate in this correlative study and have 
reported data (i.e., N=700 with reported clinician grades for a given AE), we have 80% power to detect a 
0.42 standard deviation difference between groups without adjustment for multiple AE comparisons.  
This power calculation assumes that 5 patients will be accrued at each site and conservatively that the 
intracluster correlation coefficient is strong (= 0.7).  
 
5.  PRO-CTCAE Question Bank  
 
1. 
In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR 
HANDS OR FEET at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
2. 
In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 

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3. 
In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA): 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
4. 
In the last 7 days, did you have any RASH: 
• 
Yes / No 
 
5. 
In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
6. 
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their 
WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
1. In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual 
or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
2. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF 
ENERGY at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
3. In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
4. In the last 7 days, how OFTEN did you have PAIN: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
5. In the last 7 days, what was the SEVERITY of your PAIN at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
6. In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
7. In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
8. In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or 
daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
9. In the last 7 days, how OFTEN did you have NAUSEA: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
10. In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
11. In the last 7 days, how OFTEN did you have VOMITING: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 

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12. In the last 7 days, what was the SEVERITY of your VOMITING at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
13. In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its 
WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
14. In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its 
WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
15. In the last 7 days, how much did SHORTNESS OF BREATH INTERFERE with your usual or 
daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
16. In the last 7 days, how OFTEN did you FEEL ANXIETY: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
17. In the last 7 days, what was the SEVERITY of your ANXIETY at its WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
18. In the last 7 days, how much did ANXIETY INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
19. In the last 7 days, how OFTEN did you FEEL THAT NOTHING COULD CHEER YOU UP: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
20. In the last 7 days, what was the SEVERITY of your FEELINGS THAT NOTHING COULD 
CHEER YOU UP at their WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
21. In the last 7 days, how much did FEELING THAT NOTHING COULD CHEER YOU UP 
INTERFERE with your usual or daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
22. In the last 7 days, how OFTEN did you have ARM OR LEG SWELLING: 
• 
Never / Rarely / Occasionally / Frequently / Almost constantly 
 
23. In the last 7 days, what was the SEVERITY of your ARM OR LEG SWELLING at its 
WORST: 
• 
None / Mild / Moderate / Severe / Very severe 
 
24. In the last 7 days, how much did ARM OR LEG SWELLING INTERFERE with your usual or 
daily activities: 
• 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
 
 

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6.  References 
Basch E.M., Reeve B.B., Cleeland C.S., Sloan J.A., Mendoza T.R., Abernethy A.P., Bruner 
D., Minasian L.M., Burke L.B., Schrag D. Development of the Patient-Reported Outcomes Version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Clin Oncol 2010;28:15s 
(suppl; abstr 19605).  
 
Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, New Jersey: Lawrence 
Erlbaum Associates; 1988 
 
Hay J., Atkinson T.M., Mendoza T.R., Reeve B.B., Willis G., Gagne J.J., Abernethy A.P., Cleeland 
C.S., Schrag D., Basch E. Refinement of the -Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) via cognitive interviewing. J Clin Oncol 2010;28:15s 
(suppl; abstr 9060).  

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APPENDIX VI: FUNCTIONAL OUTCOMES AND QUALITY OF LIFE  
Functional Outcomes and Quality of Life after Rectal Cancer Therapy: A 
Comparison Between Patients Randomized to Selective Pre-operative 
Radiation vs. Traditional Pre-operative Chemoradiation 
 
Background   
Significant long term sequelae of rectal cancer therapy exist and alterations in bowel, bladder and sexual 
function are prevalent. Many factors (i.e., age, gender, level of tumor, level of anastomosis, reconstructive 
techniques, timing of radiation, temporary diversion) are frequently reported to affect long term outcomes. 
The data almost uniformly suggest that radiation significantly impacts function (Temple et al., 2003; Thong 
et al., 2011). In a recent prospective longitudinal study of 168 patients treated for rectal cancer, there was 
significant bowel and sexual dysfunction at 12 months, particularly amongst patients treated with pre-
operative radiation (Lee et al., 2010; Temple et al.., 2010). While measurement has varied, RCTs and 
population based studies comparing pre-operative short course radiation results in worse bowel, bladder 
and sexual function (Bruheim et al., 2010b; Bruheim et al., 2010a; Murata et al., 2008; Stephens et al., 
2010; Lange and van de Velde et al., 2008; Lange et al., 2008).when compared to surgery alone.  Although 
no comparisons have been made between short and long course RT, function is also significantly affected 
by standard long course radiation (Sauer et al., 2004; Pucciarelli et al., 2011; Parc et al., 2009; Wilson and 
Alexander, 2008; Hoerske et al., 2010). 
 
While it is clear that radiation impacts long term outcomes, there are many unanswered questions.  To date, 
there has been no single institution, cohort or randomized trial that has evaluated the functional outcomes 
of a selective approach to chemoradiation. Most studies report bowel function symptoms (i.e., incontinence) 
rather than a global score so that it is difficult to determine the actual overall effect of radiation. When 
studies report global bowel function, they typically use an EORTC-CRC38 subscale which may not be a 
sensitive enough measure to assess issues faced in patients with sphincter preserving surgery (Neuman et 
al., 2007). Some studies did not require TME (Sebag-Montefiore et al., 2009) and as such surgical injury 
to the nerves may have confounded the results, particularly with respect to sexual function.  Sexual function 
has been infrequently studied, particularly in women. When studied, response rates in women are often so 
low that data were not meaningful (Ho et al., 2011). There are several studies that have demonstrated that 
global QOL is high after treatment for rectal cancer (Thoneg et al. 2011; Wilson et al., 2008; Engel et al., 
2003; Camilleri-Brennan and Steele, 2001; Savatta and Teple, 2005; Jess et al., 2002). However, there has 
been little work done to evaluate the relationship between QOL and function. While there are some data 
that suggest that QOL can be affected by function (Bruheim et al., 2010; Stephens et al., 2010; Wilson and 
Alexander, 2008;  Hoerske et al., 2010), it has never been studied in a systematic manner and the studies 
have been small. Systematic collection of rectal cancer related QOL data will permit comparison of the 
neoadjuvant combined modality therapy approach and the selective approach. This will permit evaluation 
of the impact of pelvic radiation on long term QOL. 
 
The functional and quality of life outcomes in this trial would influence the preferred treatment group, 
particularly if survival and recurrence outcomes are similar. If oncologic non-inferiority is established between 
selective vs. standard 5FUCMT, then the rationale supporting selective use of 5FUCMT may be that long term 
disease specific quality of life is better. While we hypothesize that the patients in the selective radiation group 
will have better function than patients with upfront chemoradiation, there will be patients in the selective 
5FUCMT who will require post-operative radiation. The European trial which compared pre and postoperative 
chemoradiation included a QOL component and the QOL results influenced the overall interpretation that 
favors preoperative treatment approach (Sauer et al., 2004). Thus, the benefit of selective radiation may be 
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of patients and the actual detrimental effect of post operative radiation, the overall function in the selective pre-
operative radiation group could be worse. Thus, in establishing a new paradigm for the treatment of rectal 
cancer, it is very important to compare the functional outcomes and quality of life outcomes using these 
treatment strategies. The QOL companion to this study will use validated instruments to compare overall health 
related quality of life (HRQOL) as well as disease specific quality of life with emphasis on the specific domains 
of interest in rectal cancer, bowel, bladder and sexual function.    
 
Objectives 
 
Primary Objective:  
To compare bowel function in patients randomized to selective pre-operative radiation vs. traditional pre-
operative radiation at 12 and 24 months post-operatively. We hypothesize that patients randomized to the 
selective RT group will have superior bowel function at each of these time points compared to patients 
randomized to the traditional pre-operative radiation.   
 
Secondary Objective:  
1. To compare sexual function separately within men and within women between groups at 12 and 24 
months post-operatively. We hypothesize that men and women randomized to the selective RT group 
will have superior sexual function at each of the post-operative time points compared to patients 
randomized to the traditional CMT group.   
2. To compare bladder function between groups at 12 and 24 months post-operatively. We hypothesize 
that bladder function will be superior in patients randomized to the selective RT compared to patients 
randomized to the traditional CMT group at each of the post operative time points.   
3. To compare health-related quality of life between groups at 12 and 24 months post-operatively. We 
hypothesize that patients randomized to the selective RT group will not have inferior health-related 
quality of life at each of these time points compared to patients randomized to the traditional CMT 
group. 
 
Exploratory Objectives:  
To assess the correlation between bladder, bowel, and sexual function and quality of life; to investigate factors 
associated with bladder, bowel, and sexual dysfunction; to compare bladder and bowel function over time 
between genders; and to perform subgroup analysis by language. 
 
Methods 
 
All patients randomized in the phase II or phase III component of the study who are fluent (reading/speaking) in 
English will be asked to participate in this correlative study until the target number of patients has been accrued. 
Patients will complete a booklet on paper during a clinic visit at designated time points.  Patients must use pre-printed 
questionnaire booklets ordered from the CTSU website. (Note: There are 2 versions of the QOL booklet. One for 
males and one for females. Be sure to order both male and female QOL booklets from CTSU.) Study booklets will 
be completed in clinic at the time of study consent prior to neoadjuvant therapy, 1-2 weeks prior to surgery (after neo-
adjuvant therapy is completed, ideally, at time of surgical consent) and post-operatively at approximately 12 months 
+/- 6 weeks and 24 months +/- 6 weeks after rectal resection. The post-operative time points will be anchored to rectal 
resection and in general, correspond to approximately 15-18 and 27-30 months after randomization depending on the 
neoadjuvant therapy and rectal resection. In the event that the patient has a stoma at the 12 and/or 24 month intervals, 
given the nature of the bowel function items, they will be deemed ineligible to complete the survey for that time point. 
The booklets will be administered by the site research staff. For sites using RAVE, enter the patient responses from 
the QOL booklet into RAVE and keep the original QOL booklet that contains patient responses at your site. If a 
patient does not have an appointment, misses a clinic visit and/or is missed by the study staff at the designated time 
points, the study center research coordinator will contact the patient via telephone and will ask the patient to complete 
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questions (items #20-34 MEN, #20-38 WOMEN) will not be asked. In the event that the patient chooses to complete 
the survey via mail, a stamped self addressed return envelope should be included with the booklet. In the event that 
the patient cannot be contacted by telephone, a booklet and stamped self addressed envelope should be mailed to the 
patient’s home. If the coordinator is still not able to have the patient complete the booklet, a noncompliance form will 
be completed stating the reason for the missing assessment. 
 
QOL Forms Employed 
 
Patients will receive one survey packet that will include 42 (men) or 46 (women) items depending on the patient’s 
gender.  To assess bowel function, the19 item Bowel Function Index (Temple et al., 2005) will be used. To assess 
sexual function, we will use gender specific questionnaires: the International Index of Erectile Function (Rosen et al., 
1997) and the Female Sexual Functioning Index (Rosen et al., 2000). Bladder function will be assessed using two 
items from validated questionnaires. We will assess global HRQL using the EuroQOL5D-5L which evaluates 
domains of pain, anxiety, physical function, ambulation and activities of daily living as well as the linear analogue 
scale. These instruments have been embedded in many prior NCCTG and CALGB clinical trials and reproducibly 
assess health related quality of life in a succinct manner. The entire functional assessment can be completed in less 
than 30 minutes with an average of 15-20 minutes per patient.   
 
Bowel function will be measured using the 19 item Bowel Function Index (BFI). The BFI was developed to 
specifically assess bowel function after sphincter preserving surgery in patients treated for rectal cancer [25] and has 
recently been further validated in Europe (Zotti et al., 2011). It includes 18 items with three subscales and a total score 
and is written at an eighth-grade level. In addition, we will include an additional item in the BFI (question #19) that 
will ask patients about their global assessment of how much their bowel function changed in the last month using a 5 
point Likert scale. This instrument takes no more than 5 minutes to complete. 
 
Sexual function will be assessed with gender specific surveys. For men, the IIEF (Rosen et al., 1997) will be used.  It 
consists of 15 questions with 5 domains (erectile function, orgasmic function, sexual desire, intercourse satisfaction, 
overall satisfaction), has good internal consistency (0.71-0.91) and test-retest reliability (0.71-0.84), and has been 
widely used. It takes about 10 minutes to complete. For women, the FSFI (Rosen et al., 2000) consists of 19 questions 
with 6 domains (desire, subjective arousal, lubrication, orgasm, satisfaction and pain). This instrument has 
demonstrated good internal consistency (0.89-0.96, 0.97), and high test-retest reliability for the 6 domains (0.79-0.86, 
0.88) and global score, as well as good validity. It takes about 10 minutes to complete. 
 
Bladder function will be assessed using 2 items from 2 well validated instruments, the Prostate Health Related QOL 
questionnaire (Befort et al., 2005) and the International Prostate Symptom Score (IPSS) (Barry et al., 1992). 
Given the problems associated with rectal cancer patients typically are urinary retention and continence, we have 
included questions about incomplete evacuation and leakage. The questions are specifically directed at bladder 
dysfunction, and are gender neutral. This takes less than 1 minute to complete. 
 
Health-related quality of life will be assessed using the EuroQOL5D-5L (EQ5D) (euroqol website; Herdman et al., 
2011). This is a widely used descriptive system of health-related quality of life states. It consists of five dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take one of five 
responses. The responses record five levels of severity (no problems/slight problems/moderate problems/severe 
problems/extreme problems or unable to function) within a particular EQ5D dimension. The EQ5D is almost 
always combined with a simple linear analogue scale that asks respondents to rate their overall health on a vertical 
scale of 0 to 100.  
 
Statistical Considerations  
 
All items/questionnaires will be scored according to published scoring guidelines. Descriptive statistics will include 
means, standard deviations, medians, and ranges for each continuous or ordinal scale/subscale/item by group at each 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
124
time point. Descriptive graphical techniques will include mean plots by group for each continuous or ordinal 
scale/subscale/item. Relative frequencies of responses for each ordinal item will also be generated at each time point 
by group.   
 
Analyses 
 
The primary analysis will compare bowel function between groups at 12 and 24 months. Specifically, the primary 
analysis will consist of two hypothesis tests and adjustment for multiple testing will employ the Bonferonni method. 
The hypothesis tests will use two-sided alpha=0.05/2=0.025 two-sample t-tests to compare the BFI overall score 
between groups at the 12-month and 24-month time points.   
 
Supplement analyses to the primary analyses will include (1) analyses of covariance to compare means between 
groups or estimate confidence intervals for the mean difference between groups at the 12-month and 24-month time 
points while adjusting for the baseline value of the given score; (2) repeated measures analyses to compare scores 
over time; and (3) similar analyses as described for the primary analyses however applied to the other subscales/items 
of the BFI. 
 
For the secondary objective, the total IIEF and FSFI score will be compared between groups (within males and within 
females, respectively) at 12 and 24 months using two-sample t-tests followed by analysis of covariance adjusting for 
the baseline value at each time point. Each ordinal score on the two bladder function items will be compared between 
groups at 12 and 24 months using two-sample t-tests followed by analysis of covariance adjusting for the baseline 
value at each time point. Health related quality of life comparisons will employ confidence intervals for the difference 
between groups (mean for the selective RT group minus the mean for the traditional CMT group) in mean EQ5D 
summary index at the 12-month and 24-month time points. If the lower limit of the two-sided 95% confidence limit 
falls above -0.05, then we will deem health related quality of life of patients in the selective RT group noninferior to 
that of patients in the traditional CMT group at the given time point. A difference of 0.05 is felt to be a conservative 
estimate of the minimally important difference in the EQ5D summary index based on a 0.33 standard deviation 
difference in N=534 US and English-speaking Canadian cancer patients when using ECOG performance status as an 
anchor (Pickard et al., 2007). If non-inferiority of health related quality of life in the selective RT group is concluded 
at a given time point, we will additionally test for superiority using a two-sample t-test followed by analysis of 
covariance adjusting for the baseline health related quality of life. 
 
For the exploratory objective, Pearson correlations will be computed among each continuous or ordinal bowel, 
bladder, and sexual function scale/subscale/item, the EQ5D summary index, and EQ-VAS and at each time point.  
Correlations with sexual function scales/subscales/items will only be computed within gender subgroups.  Regression 
models will be used to model each bowel, bladder, and sexual function scale/subscale/item at the 12-month and 24-
month time points using baseline patient/disease characteristics and patient-reported outcomes at baseline. Repeated 
measures analyses will be used to compare bladder and bowel function over time between genders. Such analyses 
will be adjusted for group and will be supplemented with appropriate two-sample comparisons at each time point. 
Lastly, primary and secondary analyses will be repeated within subgroups according to language. 
 
Missing data will be handled in a number of ways. Baseline patient/disease characteristics will be compared between 
responders and nonresponders for each endpoint. We will also graphically explore patterns of missing data. All 
analyses will be completed using all available data, followed by analyses completed using imputed data using the last 
observation carried forward. Lastly, we will employ pattern mixture models for longitudinal analyses. Output from 
all analyses will be compared to assess the degree to which missing data impacts study results. 
 
For all statistical analyses other than the primary analyses, p-values <0.05 will be considered statistically significant. 
For interpreting the clinical significance of effects, 0.2, 0.5, and 0.8 SD effects will be considered as small, moderate, 
and large based on Cohen (Cohen, 1988) throughout. 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
125
Power: We will use Bonferonni adjustment for handling two primary hypothesis tests. We plan to accrue 460 
patients to allow for missing data (25%) for reasons including patient refusal, administrative error (e.g., 
coordinator failed to give a booklet to a patient), missing items due to lack of applicability (e.g., if a patient 
does not have the temporary ileostomy reversed some bowel items may not be applicable), patient drop-out or 
death due to metastatic disease, and other reasons.  Based on data from the validation of the BFI, patients not 
receiving pre-operative RT had a mean score of 54.8 (SD=9, n=45) and patients receiving pre-operative RT 
had a mean score of 48.6 (SD=10.2, n=67). In the current study, we do not expect as large a difference between 
groups but reasonably expect a mean score of about 48.6 in the traditional CMT group (similar to the pre-
operative RT in the validation study) and a 60%/40% weighted average or a mean score of about 52.3 in the 
selective RT group with a pooled standard deviation of 9.7. With data for 344 patients (assuming a 25% missing 
data rate), we have 90% power to detect this 3.7 point difference between groups at a given time point using a 
two-sided alpha=0.025 two-sample t-test.  
 
This sample size also gives reasonable power for the secondary comparison of sexual function between groups 
within men and non-inferiority assessment of health related quality of life between groups. Power for the 
secondary comparison of sexual function between groups within women is marginal and no power is computed 
for bladder function items due to lack of availability of preliminary data. 
 
For comparison of sexual function between groups within gender subsets, we assume that 65% of patients will 
be men. Based on previous IIEF data in this population (also from the BFI validation study), men not receiving 
pre-operative RT had a mean score of 58.3 (SD=19.6, n=21) and men receiving pre-operative RT had a mean 
score of 34.8 (SD=22.4, n=46). In the current study, we do not expect as large a difference between groups but 
reasonably expect a mean score of about 34.8 in the traditional CMT group (similar to the pre-operative RT in 
the validation study) and a 60%/40% weighted average or a mean score of about 48.9 in the selective RT group 
with a pooled standard deviation of 21.5. With data for 224 men, we have >90% power to detect this 14.1 point 
difference between groups at a given time point using a two-sided alpha=0.05 two-sample t-test. 
 
Based on previous FSFI data in this population (also from the BFI validation study), women not receiving pre-
operative RT had a mean score of 21.4 (SD=10.8, n=15) and women receiving pre-operative RT had a mean 
score of 13.8 (SD=11.1, n=23). In the current study, we do not expect as large a difference between groups but 
reasonably expect a mean score of about 13.8 in the traditional CMT group (similar to the pre-operative RT in 
the validation study) and a 60%/40% weighted average or a mean score of about 18.4 in the selective RT group 
with a pooled standard deviation of 11.0. With data for 120 women, we have 62% power to detect this 4.6 point 
difference between groups at a given time point using a two-sided alpha=0.05 two-sample t-test.   
 
Finally, for comparison of health related quality of life between groups, with data for 344 patients, the lower 
limit of the two-sided 95% confidence interval for the mean difference between groups in the EQ5D summary 
index has >90% likelihood of falling above -0.05 (i.e., above a 0.33 standard deviation difference) if the true 
difference between groups is 0. 
 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
126
PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet FOR MEN 
____________________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some questions about 
your ‘quality of life’ as a patient receiving treatment for cancer. Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
1. The booklet contains 4 sets of questions: 
a. Bowel Function Index (19 questions) 
b. Bladder Function Questions (2 questions) 
c. EuroQOL5D-5L (6 questions) 
d.   International Index of Erectile Function (15 questions) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. If you were given this booklet during a clinical visit, please complete the booklet during your 
clinical visit and return it to your nurse or your physician. 
 
4. If you received this booklet in the mail, please return the completed booklet in the provided 
envelope. 
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
If any questions make you feel uncomfortable, you may skip those questions and not give an answer. 
 
Thank you for taking the time to help us. 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
127
PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet FOR WOMEN 
____________________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer. Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. The booklet contains 4 sets of questions: 
a. Bowel Function Index (19 questions) 
b. Bladder Function Questions (2 questions) 
c. EuroQOL5D-5L (6 questions) 
d. Female Sexual Functioning Index (19 questions) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. If you were given this booklet during a clinical visit, please complete the booklet during your 
clinical visit and return it to your nurse or your physician. 
 
4. If you received this booklet in the mail, please return the completed booklet in the provided 
envelope. 
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
If any questions make you feel uncomfortable, you may skip those questions and not give an answer. 
 
Thank you for taking the time to help us. 
 
 
 

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N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
130
For male patients ONLY 
 
We would like to ask you questions about your sexual function. 
 
International Index of Erectile Function 
  
 
Directions: Circle the number that best describes your erectile function for the past 4 weeks. 
20. Over the past 4 weeks, how often were you able to get an erection during sexual activity? 
No sexual 
activity 
Almost never 
or never 
A few times 
(much less 
than half the 
time 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
21. Over the past 4 weeks, when you had erections with sexual stimulation, how often were your 
erections hard enough for penetration? 
No sexual 
activity 
Almost never 
or never 
A few times 
(much less 
than half the 
time 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
22.  Over the past 4 weeks, when you attempted sexual intercourse, how often were you able to 
penetrate (enter) your partner? 
Did not 
attempt 
Almost never 
or never 
A few times 
(much less 
than half the 
time 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
23.  Over the past 4 weeks, during sexual intercourse how often were you able to maintain your 
erection after you had penetrated (entered) your partner? 
Did not 
attempt 
Almost never 
or never 
A few times 
(much less 
than half the 
time 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
 
 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
131
24. Over the past 4 weeks, during sexual intercourse, how difficult was it to maintain your 
erection to completion of intercourse? 
Did not 
attempt 
Extremely 
difficult 
Very difficult 
Difficult 
Slightly 
difficult 
Not difficult 
1 
2 
3 
4 
5 
6 
25.  Over the past 4 weeks, how many times have you attempted sexual intercourse? 
No attempts 
One to two 
attempts 
Three to four 
attempts 
Five to six 
attempts 
Seven to ten 
attempts 
More than 11 
attempts 
1 
2 
3 
4 
5 
6 
26. Over the past 4 weeks, when you attempted sexual intercourse, how often was it satisfactory 
to you? 
Did not 
attempt 
Almost never 
or never 
A few times 
(much less 
than half the 
time) 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
27.  Over the past 4 weeks, how much have you enjoyed sexual intercourse?  
No 
intercourse 
No enjoyment 
Not very 
enjoyable 
Fairly 
enjoyable 
Highly 
enjoyable 
Very highly 
enjoyable 
1 
2 
3 
4 
5 
6 
28.  Over the past 4 weeks, when you had sexual stimulation or intercourse, how often did you 
ejaculate? 
No sexual 
stimulation/ 
intercourse 
Almost never 
or never 
A few times 
(much less 
than half the 
time) 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
29. Over the past 4 weeks, when you had sexual stimulation or intercourse, how often did you 
have the feeling of orgasm or climax? 
No sexual 
stimulation/ 
intercourse 
Almost never 
or never 
A few times 
(much less 
than half the 
time) 
Sometimes 
(about half 
the time) 
Most times 
(much more 
than half the 
time) 
Almost 
always or 
always 
1 
2 
3 
4 
5 
6 
 
 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
132
30. Over the past 4 weeks, how often have you felt sexual desire? 
Almost never or 
never 
A few times 
(much less than 
half the time) 
Sometimes 
(about half the 
time) 
Most times 
(much more than 
half the time) 
Almost always or 
always 
1 
2 
3 
4 
5 
31. Over the past 4 weeks, how would you rate your level of sexual desire? 
Very low/none at 
all 
Low 
Moderate 
High 
Very high 
1 
2 
3 
4 
5 
32. Over the past 4 weeks, how satisfied have you been with your overall sex life? 
Very dissatisfied 
Moderately 
dissatisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
satisfied 
Very satisfied 
1 
2 
3 
4 
5 
33. Over the past 4 weeks, how satisfied have you been with your sexual relationship with your 
partner? 
Very dissatisfied 
Moderately 
dissatisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
satisfied 
Very satisfied 
1 
2 
3 
4 
5 
34. Over the past 4 weeks, how do you rate your confidence that you could get and keep an 
erection? 
Very low 
Low 
Moderate 
High 
Very high 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 

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N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
135
42. We would like to know how good or bad your health is TODAY.   
 
• 
This scale is numbered from 0 to 100. 
 
• 
100 means the best health you can imagine. 
 
• 
0 means the worst health you can imagine. 
 
• 
Mark an X on the scale to indicate how your health is TODAY.  
 
• 
Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For male QOL, questions  1-19 are from Temple et al., 2005; question 20 from Sparngers 
et al., 1999; questions 21-23 from Basch et al., 2006; questions 25 and 26 are from Barry 
et al., 1992 and Befort et al., 2005; questions 27-32 are from the euroqol website and 
Herdman et al., 2011. 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
136
 
For female patients ONLY  
 
 
 
We would like to ask you questions about your sexual function. 
 
Female Sexual Function Index Questionnaire 
  
 
Instructions: These questions ask you about your sexual feelings and responses during the past 4 
weeks. Please answer the following questions as honestly and clearly as possible. Your responses 
will be kept completely confidential. In answering these questions the following definitions apply:   
Sexual activity can include caressing, foreplay, masturbation and vaginal intercourse  
Sexual intercourse is identified as penetration (entry) of the vagina.  
Sexual stimulation includes situations like foreplay with a partner, self-stimulation (masturbation), or 
sexual fantasy.  
Sexual desire or interest is a feeling that includes wanting to have a sexual experience, feeling receptive to 
a partner’s sexual initiation, and thinking or fantasizing about having sex.  
CIRCLE ONLY ONE NUMBER PER QUESTION. 
 
20. Over the past 4 weeks, how often did you feel sexual desire or interest? 
Almost always or 
always 
Most times 
(more than half 
the time) 
Sometimes 
(about half the 
time) 
A few times (less 
than half the 
time) 
Almost never or 
never 
1 
2 
3 
4 
5 
21. Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest? 
Very high 
High 
Moderate 
Low 
Very low or none 
at all 
1 
2 
3 
4 
5 
 
Sexual arousal is a feeling that includes both physical and mental aspects of sexual excitement. It may 
include feelings of warmth or tingling in the genitals, lubrication (wetness) or muscle contractions. 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
137
22.  Over the past 4 weeks, how often did you feel sexually aroused (“turned on”) during sexual 
activity or intercourse? 
No sexual 
activity 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
23.  Over the past 4 weeks, how would you rate your level of sexual arousal (“turn on”) during 
sexual activity or intercourse? 
No sexual 
activity 
Very high 
High 
Moderate 
Low 
Very low or 
none at all 
1 
2 
3 
4 
5 
6 
24. Over the past 4 weeks, how confident were you about becoming sexually aroused during 
sexual activity or intercourse? 
 
No sexual 
activity 
Very high 
confidence 
High 
confidence 
Moderate 
confidence 
Low 
confidence 
Very low or 
no confidence 
1 
2 
3 
4 
5 
6 
25.  Over the past 4 weeks, how often have you been satisfied with your arousal (excitement) 
during sexual activity or intercourse? 
No sexual 
activity 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
26. Over the past 4 weeks, how often did you become lubricated (“wet”) during sexual activity or 
intercourse? 
No sexual 
activity 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
27.  Over the past 4 weeks, how difficult was it to become lubricated (“wet”) during sexual 
activity or intercourse?  
No sexual 
activity 
Extremely 
difficult or 
impossible 
Very difficult 
Difficult 
Slightly 
difficult 
Not difficult 
1 
2 
3 
4 
5 
6 
 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
138
28.  Over the past 4 weeks, how often did you maintain your lubrication (“wetness”) until 
completion of sexual activity or intercourse? 
No sexual 
activity 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
29. Over the past 4 weeks, how difficult was it to maintain your lubrication (“wetness”) until 
completion of sexual activity or intercourse? 
No sexual 
activity 
Extremely 
difficult or 
impossible 
Very difficult 
Difficult 
Slightly 
difficult 
Not difficult 
1 
2 
3 
4 
5 
6 
30. Over the past 4 weeks, when you had sexual stimulation or intercourse, how often did you 
reach orgasm (climax)? 
No sexual 
activity 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
31. Over the past 4 weeks, when you have had sexual stimulation or intercourse, how difficult 
was it for you to reach orgasm (climax)? 
No sexual 
activity 
Extremely 
difficult or 
impossible 
Very difficult 
Difficult 
Slightly 
difficult 
Not difficult 
1 
2 
3 
4 
5 
6 
32. Over the past 4 weeks, how satisfied were you with your ability to reach orgasm (climax) 
during sexual activity or intercourse? 
No sexual 
activity 
Very satisfied 
Moderately 
satisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
dissatisfied 
Very 
dissatisfied 
1 
2 
3 
4 
5 
6 
33. Over the past 4 weeks, how satisfied have you been with the amount of emotional closeness 
during sexual activity between you and your partner? 
No sexual 
activity 
Very satisfied 
Moderately 
satisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
dissatisfied 
Very 
dissatisfied 
1 
2 
3 
4 
5 
6 
 
 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
139
34. Over the past 4 weeks, how satisfied have you been with your sexual relationship with your 
partner? 
No sexual 
activity 
Very satisfied 
Moderately 
satisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
dissatisfied 
Very 
dissatisfied 
1 
2 
3 
4 
5 
6 
35. Over the past 4 weeks, how satisfied have you been with your overall sexual life? 
No sexual 
activity 
Very satisfied 
Moderately 
satisfied 
About equally 
satisfied and 
dissatisfied 
Moderately 
dissatisfied 
Very 
dissatisfied 
1 
2 
3 
4 
5 
6 
36. Over the past 4 weeks, how often did you experience discomfort or pain during vaginal 
penetration? 
Did not 
attempt 
intercourse 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
37. Over the past 4 weeks, how often did you experience discomfort or pain following vaginal 
penetration? 
Did not 
attempt 
intercourse 
Almost 
always or 
always 
Most times 
(more than 
half the time) 
Sometimes 
(about half 
the time) 
A few times 
(less than half 
the time) 
Almost never 
or never 
1 
2 
3 
4 
5 
6 
38. Over the past 4 weeks, how would you rate your level (degree) of discomfort or pain during 
or following vaginal penetration? 
Did not 
attempt 
intercourse 
Very high 
High 
Moderate 
Low 
Very low or 
none at all 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
 
 

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N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
142
46. We would like to know how good or bad your health is TODAY.   
 
• 
This scale is numbered from 0 to 100. 
 
• 
100 means the best health you can imagine. 
 
• 
0 means the worst health you can imagine. 
 
• 
Mark an X on the scale to indicate how your health is TODAY.  
 
• 
Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For female QOL, questions  1-19 are from Temple et al., 2005; question 20 from Sparngers 
et al., 1999; questions 21-23 from Basch et al., 2006; questions 25 and 26 are from Barry et 
al., 1992 and Befort et al., 2005; questions 27-32 are from the euroqol website and Herdman 
et al., 2011. 
 

N1048 
Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
143
References 
 
Barry, M., F. Fowler, and M. O'Leary.  (1992). “The Measurement Committee of the American Urological 
Association.  The American Urological Association symptom index for benign prostatic hyperplasia.” 
Journal of Urology. 148: 1549-57. 
 
Basch, E. et al.  (2006). “Patient versus clinician symptom reporting using the National Cancer  
Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. 
Lancet Oncol. 7(11): 903-9. 
 
Befort, C.A.. et al.. (2005). “ A measure of health-related quality of life among patients with localized 
prostate cancer: results from ongoing scale development.” Clin Prostate Cancer.  4(2):100-8. 
 
Bruheim, K. et al.. (2010) “Late side effects and quality of life after radiotherapy for rectal cancer”. 
Int J Radiat Oncol Biol Phys. 76(4):1005-11. 
 
Bruheim, K. et al. (2010). “.Sexual function in males after radiotherapy for rectal cancer.” Int J Radiat 
OncolBio Phy. 76(4): 1012-7. 
 
Camilleri-Brennan, J. and R.J. Steele,. (2001) “Prospective analysis of quality of life and survival following  
mesorectal excision for rectal cancer.” Br J Surg. 88(12): 1617-22. 
 
Cohen, J., Statistical Power Analysis for the Behavioral Sciences. 1988, Hillsdale, New Jersey: Lawrence  
Erlbaum Associates. 
 
Engel, J. et al. (2003) “Quality of life in rectal cancer patients: a four-year prospective study.” Annals of  
Surgery.  238: 203-213 
 
Euroqol website at http://www.euroqol.org/home.html 
 
Herdman, M. et al.. (2011) “Development and preliminary testing of the new five-level version of EQ-5D  
(EQ-5D-5L)”. Qual Life Res. 
 
Ho, V.P. et al.. (2011) “Sexual function after treatment for rectal cancer: a review”. Dis Colon Rectum, 
54(1): 113-25. 
 
Hoerske, C. et al.. (2010). “Long-term outcomes and quality of life after rectal carcinoma surgery.” Br J  
Surg. 97(8): 1295-303. 
 
Jess, P., J. Christiansen, and P. Bech. (2002). “Quality of life after anterior resection versus  
Abdominoperineal extirpation for rectal cancer.” Scand J Gastroenterol. 37(10): 1201-4. 
 

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Lee, Y. et al.  Sexual Dysfunction After Surgery for Rectal Cancer. ASCRS Annual Meeting, 2010. 
 
Lange, M.M. and C.J. van de Velde. (2008). “Faecal and urinary incontinence after multimodality treatment  
of rectal cancer.”  PLoS Med.  5(10): e202. 
 
Lange, M.M., et al., (2008). “Urinary dysfunction after rectal cancer treatment is mainly caused by surgery.” 
Br J Surg.  95(8): 1020-8. 
 
Murata, A. et al. (2008) “Impact of short-course radiotherapy and low anterior resection on quality of life 
and bowel function in primary rectal cancer.” Am J Surg. 195(5): 611-5; discussion 615. 
 
Neuman, H.B. et al. (2007). “Can differences in bowel function after surgery for rectal cancer be identified 
 by the European Organization for Research and Treatment of Cancer quality of life instrument?” Ann Surg 
Oncol. 14(5): 1727-34. 
 
Parc, Y. et al.. (2009). “Preoperative radiotherapy is associated with worse functional results after coloanal  
anastomosis for rectal cancer.” Dis Colon Rectum. 52(12): 2004-14. 
 
Pickard, AS, et al. (2007) “Estimation of minimally important differences in EQ-5D utility and VAS scores 
in cancer.” Health Quality Life Outcomes 5:70 Erratum in: Health Qual Life Outcomes. 2010; 8:4., 2007. 
5(Dec21): p. 70. 
 
Pucciarelli, S. et al.. (2011) “Patient-reported outcomes after neoadjuvant chemoradiotherapy for rectal  
cancer: a multicenter prospective observational study.” Ann Surg. 253(1):  71-7. 
 
Rauch, P. et al. (2004). “Quality of life among disease-free survivors of rectal cancer.” J Clin Oncol. 22(2):  
354-60. 
 
Rosen, R.C. et al. (1997). “The international index of erectile function (IIEF): a multidimensional scale 
for assessment of erectile dysfunction.” Urology.  49(6): 822-30. 
 
Rosen, R. et al. (2000) “The Female Sexual Function Index (FSFI): a multidimensional self-report 
instrument for the assessment of female sexual function.” Journal of Sex & Marital Therapy.  26(2): 191- 
208. 
 
Sauer, R.. et al.. (2004). “Preoperative versus postoperative chemoradiotherapy for rectal cancer.”  N Engl J  
Med. 351(17): 1731-40. 
 
Savatta, S. and L. Temple. (2005) “Quality of Life in Patients with Stage I-III Rectal Cancer.”  Seminars in  
Colon and Rectal Surgery. 16: 170-180. 
 
Sebag-Montefiore, D. et al. (2009). “Preoperative radiotherapy versus selective postoperative  
chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, 
 randomised trial.” Lancet.  373(9666):  811-20. 
 
Sprangers, M.A. et al. (1999). “The construction and testing of the EORTC colorectal cancer 
specific quality of life questionnaire module (QLQ-CR38). European Organization for Research and  
treatment of Cancer Study Group on Quality of Life”. Eur J Cancer. 35(2):  238-47. 
 
Stephens, R.J. et al.. (2010) “Impact of short-course preoperative radiotherapy for rectal cancer on patients'  
quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical 

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Trials Group C016 randomized clinical trial.” J Clin Oncol. 28(27): 4233-9. 
 
Temple L. et al.  Bowel Dysfunction after Rectal Cancer. ASCO, June 2010. 
 
Temple, L.K. et al.. (2005) “The development of a validated instrument to evaluate bowel function after  
sphincter-preserving surgery for rectal cancer.” Dis Colon Rectum. 48(7): 1353-65. 
 
Temple, L.K. et al. (2003). "The impact of radiation on functional outcomes in patients with  
rectal cancer and sphincter preservation." Semin Radiat Oncol. 13(4): 469-77. 
 
Thong M.S. et al. (2011) "Impact of Preoperative Radiotherapy on General and Disease-Specific Health 
 Status of Rectal Cancer Survivors: A  Population-Based Study." International Journal of Radiation  
Oncology and Biologic Physics.. 
 
Wilson, T.R. and D.J. Alexander. (2008). "Clinical and non-clinical factors influencing postoperative  
health-related quality of life in patients with colorectal cancer." Br J Surg. 95(11): 1408-15. 
 
Zotti, P. et al. (2011). "Validity and reliability of the MSKCC Bowel Function instrument in a sample of 
Italian rectal cancer patients." Eur J Surg Oncol. epub. 
 

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Addendum 10 
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APPENDIX VII: SURGICAL CONSIDERATIONS AND QUALITY ASSURANCE 
 
Operative Technique 
Treatment on this protocol must commence by the accruing membership under the supervision of a surgeon 
experienced in TME. Note: To ensure proper stratification and consistency, the registering surgeon, 
assessing the inclusions parameters MUST be the surgeon intended to perform the assigned 
procedure. 
 
Operative procedures will include either laparascopic or open anterior/low anterior resection with a hand 
sewn or stapled anastomosis with or without temporary fecal diversion. The pelvic dissection must include 
the division of the inferior mesenteric pedicle, the transection of the specimen and the construction of the 
anastomosis. The mobilization of the proximal colon and splenic flexure may be performed by laparoscopic, 
laparoscopic-assisted, robotic-assisted or hand-assisted techniques to limit the incision to the lower 
abdomen. Although variation in technical approaches can be anticipated based on variation in patient's body 
habitus and surgical incision, the following technical descriptions will serve as guidelines.  
 
Upon entering the abdominal cavity the abdomen will be explored for evidence of advanced disease 
including inspection of the liver, retroperitoneum, paraaortic nodes, ovaries and peritoneal surface. The site 
and location of the tumor relative to the peritoneal cavity and adjacent structures will be noted.  Minimal 
tumor handling will be adhered to and contact of the tumor to the wound will be minimized.  Mobilization 
of the left colon +/- splenic flexure, identification and protection of the left ureter, identification and 
ligation/division of inferior mesenteric vein and artery or superior hemorrhoidal vessels after bifurcation of 
the inferior mesenteric artery are essential features. Dissection of the rectum from the sacrum should occur 
in the avascular plane behind the fascia propria of the rectum and anterior to the presacral fascia in order to 
maintain intact the envelope containing the mesorectum. The pelvic nerves (right and left) at the pelvic 
brim should be identified and freed from the dissection plane unless dictated otherwise by tumor 
involvement. The dissection posteriorly is performed sharply (not blunt dissection)  in the avascular areolar 
tissue plane and carried out through the rectosacral fascia to a level well below the tumor or all the way to 
the pelvic floor depending on tumor level in the rectum. The lateral peritoneal and anterior cul-de-sac 
incision should be made outside the area of the tumor and, if possible, within the pelvic confines to avoid 
the ureters, nerves, prostate, seminal vesicles, vagina, pelvic floor and side wall muscles. Retraction of the 
sigmoid and rectum should be accomplished in such a way that injury to that area is avoided and 
contamination limited. 
 
The posterior mesorectum should be transected ideally 5 cm below the level of the tumor for upper rectal 
lesions or completely removed for mid to low rectal cancers (total mesorectal excision). Cautery, RF 
energy, clips, bipolar sealing devices or harmonic scalpel are all acceptable means of vascular control.  
 
Transection of the distal rectum should be performed using the appropriate stapling instrument. For the 
anastomosis, the proximal bowel will be prepared for suturing or stapling. The anastomosis should be 
performed using standard techniques. 
 
Minimal acceptable margins should be obtained at the time of transection and evaluated on the fresh, 
unstretched specimen. A proximal margin of greater than 5 cm and a clear 1 cm margin distally will be 
considered adequate for low rectal lesions in order to achieve sphincter preservation. The use of diverting 
loop ileostomy will be left to the surgeon’s discretion and recorded. 
 
At the completion of the procedure photos of the anterior and posterior mesorectum on the fresh, 
unstretched specimen must be taken. Photographs of the open specimen are not required. 

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Extent and Technique of Resection 
Extent of resection, including assessment of the margins and of completeness of TME will be documented 
for all procedures in the operative report and on data forms. Case report forms note the use of laparascopic 
assisted techniques as well as robotic assisted techniques. 
 
Intraoperative Pathology and Pathologic Examination of Surgical Specimen 
Pathologists will measure fresh, unstretched proximal and distal margins. The completeness of the TME 
resection will be assessed by the surgeon in the operating room and evaluated by the pathologist and 
categorized as defined in the Surgical QA Plan section. Prior to opening the specimen, it should be prepared 
by the pathologist to evaluate radial margins by applying ink to the mesorectal surface in the area of the 
tumor. Note: The mesorectal specimen must be photographed with a digital camera with minimum 
of 2 megapixels to verify the quality of the dissection. Photos taken with an iPhone are accceptable. 
The anterior and posterior mesorectum should be photographed fresh. A photo of the open specimen 
is not required. The photo should be centered on the extraperitoneal mesorectal surphace and not 
the entire specimen (see figures at the end of this Appendix). The image files should not be 
compressed. These photographs should be retained in patient’s research records and sent 
electronically within 2 weeks. These photos should be sent to 
 
 
Morbidity and Mortality 
Early, in hospital and late (within 30 days) morbidity and mortality will be closely monitored and recorded 
using the study data forms with the following definitions: 
 
Pulmonary, urinary tract, and intraabdominal infections will be defined by the need for antibiotic treatment 
and/or interventional radiology drainage. 
 
Abdominal wound infections will be defined by the location, extent and severity (i.e. superficial vs. deep 
space infection) and the need for wound opening and/or surgical intervention. Urinary retention will be 
defined as the condition of urinary dysfunction that occurs for greater than 5 days following surgery or that 
requires intervention, including replacement of Foley catheter, surgery, etc 
 
Perioperative hemorrhage requiring blood transfusion(s) or reoperation will be considered as a 
complication. Correction of preoperative anemia will not be included as a complication. The decision to 
transfuse will be made at the surgeon's discretion. 
 
Any documented medical or anesthetic complications that result in patient disability or that requires 
intervention will be recorded. 
 
Problems with healing, function or management of the ostomy that requires intervention or additional 
hospital stay will be considered complication and recorded. 
 
Surgical Complications 
Perioperative and postoperative complications will be collected and submitted via CTEP-AERS; see 
Section 10.0, Adverse Event Reporting and Monitoring, for further instructions.  
 
Perioperative Complications 
Complications after rectal resections include: 
Death after rectal resection (0-7.4%) 
Anastomotic leak after recta1 resection (1-17%) 
Abdominal wound infection (3-24%) 
Stoma complications (4-10%) 
 
 
 

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Late or Delayed Complications 
Late or delayed complications such as bowel obstruction will be monitored and reported on data forms. 
Details of hospital admissions will be recorded in the patient’s records, including dates, location, and 
admitting physician’s name. The “reason for admission” will provide guidance as to whether the 
hospitalization was related to the cancer diagnosis and surgery or for other reasons. See Section 10.0, 
Adverse Event Reporting and Monitoring, for reporting guidelines for complications occurring > 30 days 
after surgery. 
 
Surgical QA Plan 
Evaluation at the Time of Surgery 
• Intact TME resection as assessed by the surgeon, evaluated by the pathologists, documented on surgery 
and pathology intake forms and on the photo of the fresh specimen  
• Circumferential margin positivity (< 1mm). 
• Distal margin status (< 1cm). 
• Lymph node harvest and number of positive lymph nodes 
• Evaluation of surgical complications 
 
Performance Monitoring 
Surgery PI Review 
The Study Chairs will review each enrolled case for patient eligibility and intervention compliance. If an 
investigator has a possible performance issue, the Study Chairs will review the issue(s) and make 
recommendations to the investigator. It is expected that in most cases, the Study Chairs or designee will 
work with the investigator to improve performance. However, the Study Chairs are empowered to suspend 
protocol participation, if necessary. 
 
Monitoring of Surgical Performance 
Photo documentation of every TME specimen is required and will be reviewed by the Surgical Quality 
Committee. These photos should be sent to 
  
 
 

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Please Note: Including a ruler in the photographs is preferred but NOT mandatory.  

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APPENDIX VIII: SUGGESTED MRI TECHNICAL AND QUALITY REQUIREMENTS  
Suggested Technical and Quality Requirements for Rectal MRI Scans  
 
MRI Field Strength: 1.0 T to 3.0 T, closed bore 
Coil: Phased array: minimum 4 channels 
IV Contrast: Optimal (preferred: 0.1mmol/kg Gadolinium), noncontrast acceptable 
Spasmolytic: Glucagon optional: 1.0 mg IM, immediately before exam, no glucagon acceptable 
Rectal Preparation: 1 Bisacodyl (Dulcolax) suppository inserted three hours prior to exam optimal, no 
prep acceptable. 
Rectal Filling: 80-100 mL ultrasound transmission gel optimal (Kim et al., Eur Radiol 2011;21: 987-
995). 
Non-filling is acceptable as long as rectum is not collapsed, i.e. natural air or fluid distension [but not 
stool-distension] without gel insertion is acceptable. 
 
1.5 Tesla Recommended Parameters 
Plane:      
Axial T1 
   Axial T2 
      Coronal T2             Sagittal T2     Oblique Axial T2* 
Sequence:   
2DF(R)SE/TSE for all planes  
Options: 
no phase wrap    no phase wrap        no phase wrap 
no phase wrap no phase wrap 
TE: 
 
minimum/full    80-120 
        80-120 
 
80-120  
80-120 
TR: 
 
400-650 
   4000-6000 
        4000-6000  
4000-6000 
4000-6000 
ETL: 
 
4 
 
   18-26  
        18-26 
 
18-26  
18-26 
Flip Angle: 
90 
 
   90 
 
        90  
 
90 
 
90 
Bandwidth: 
32kHz  
   32kHz 
        32kHz 
 
32kHz  
32kHz 
Sat. Pulse:  
S/I/A 
 
   S/I/A  
        none 
 
none 
 
S/I/A 
Field of View: 28-36  
   18-26  
        18-26 
 
18-26  
18-26 
Slice Thick.: 
5mm 
 
   2-4 mm 
        2-4mm 
 
2-4 mm  
2-4 mm  
Gap: 
 
1-2mm  
   1-2mm 
        1-2mm 
 
1-2mm  
1-2mm  
Phase Enc.: 
160 
 
   180-220 
        180-220 
 
180-220 
180-220 
Frequency: 
256 
 
   300-340 
        300-340 
 
300-340 
300-340 
NEX:  
2 
 
   3-4 
 
        3-4 
 
3-4 
 
3-4 
Freq. Direction: A/P 
 
   A/P  
        S/I  
 
R/L 
 
R/L 
Comment: 
no-breathhold    breathhold 
        no-breathhold 
no-breathhold no breathhold 
 
 
Notes: *Oblique Axial is required. Angle is perpendicular to tumor. If tumor is long and follows curvature 
of rectum, re-angling is recommended, but rarely necessary. 
 
Gadolinium-enhanced sequences (FSPGR, any plane) are optional and welcome 
 
FAT SATURATION IS NOT ACCEPTABLE EXCEPT FOR GADOLINIUM SEQUENCES. 
 
 
 
 
 

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3.0 Tesla Recommended Parameters 
Plane:  
Axial T1 
   Axial T2 
        Coronal T2 
Sagittal T2    Oblique Axial T2* 
Sequence: 
2DF(R)SE/TSE  for all phases 
Options : 
no phase wrap    no phase wrap        no phase wrap 
no phase wrap no phase wrap 
TE: 
 
minimum/full    80-120 
        80-120 
 
80-120  
80-120 
TR: 
 
400-650 
   4000-6000 
        4000-6000  
4000-6000 
4000-6000 
ETL: 
 
3 
 
   18-26  
        18-26 
 
18-26  
18-26 
Flip Angle: 
90 
 
   90 
 
        90  
 
90 
 
90 
Bandwidth: 
32kHz  
   32kHz 
        32kHz 
 
32kHz  
32kHz 
Sat. Pulse:  
S/I/A 
 
   S/I/A  
        none 
 
none 
 
S/I/A 
Field of View: 28-36  
   18-26  
        18-26 
 
18-26  
18-26 
Slice Thick.: 
5mm 
 
   2-4 mm 
        2-4mm 
 
2-4 mm  
2-4 mm  
Gap: 
 
1-2mm  
   1-2mm 
        1-2mm 
 
1-2mm  
1-2mm  
Phase Enc.: 
160 
 
   200-256 
        200-256 
 
200-256 
200-256 
Frequency: 
256 
 
   300-340 
        300-340 
 
300-340 
300-340 
NEX:  
2 
 
   4 
 
        4  
             4 
 
4 
Freq. Direction: A/P 
 
   A/P  
        S/I  
 
R/L 
 
R/L 
Comment: 
no-breathhold    breathhold 
        no-breathhold 
no-breathhold no-breathhold 
 
 
Notes: *Oblique Axial is required. Angle is perpendicular to tumor. If tumor is long and follows curvature 
of rectum, re-angling is recommended, but rarely necessary. 
 
Gadolinium-enhanced sequences (FSPGR, any plane) are optional and welcome 
 
FAT SATURATION IS NOT ACCEPTABLE EXCEPT FOR GADOLINIUM SEQUENCES. 
 
 
 
 

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APPENDIX IX: SCHEDULE AND PROCEDURE FOR IMAGING SUBMISSION  
Schedule and Procedure for Image Submission to Central Review (Quality 
Assurance) 
 
Procedure for Submitting Images to the Alliance Imaging Core Lab: 
Imaging data shall be submitted to the Imaging Core Lab as promptly as is feasible.  
 
Imaging studies listed in the following table must be electronically submitted to the Alliance Imaging Core 
Laboratory in digital DICOM format only; any other formats such as bitmap, JPG or hardcopies (scanned 
films) are unacceptable. The source data of the entire study should be saved until the images are accepted 
by the Imaging Core Lab. Remove all identifiers such as patient name and medical record number; the date 
of procurement should be kept. Be certain to include the patient study ID number and study protocol 
number. 
 
Images may be securely transferred to the Imaging Core Laboratory by: 
1. Secure web transfer; 
2. Secure FTP transfer; 
 
For web and FTP transfers, please contact the Imaging Core Lab at the e-mail address 
 to request a site-specific username and password that the site will use to 
log in at 
In addition to the login credentials, detailed instructions how to 
upload the images will be sent. Once logged into the website (
), a tutorial folder 
will contain the upload instructions. A video demonstration of the transfer process is available for viewing 
or downloading. A live demonstration of the transfer process is available upon request.  
 
Web Transfer 
Any PC or workstation with Internet access and a web browser (such as Internet Explorer, Mozilla Firefox, 
etc.) can be used to securely upload/transfer DICOM images and other required files to the Imaging Core 
Lab. Enter “
 into the address bar of the web browser and the PC will establish 
an encrypted connection (via Secure Sockets Layer – SSL) to the login page of the website. Once logged 
in, entire folders and subfolders can be securely transferred from a hard disk drive or from a CD/DVD. The 
scans are stored on the server using 256-bit AES encryption. 
 
File Transfer 
Any FTP software (such as WS_FTP, FileZilla, etc.) that is installed on a local PC or workstation can be 
used to securely connect to the FTP server. Start the program, enter the login credentials, and the PC can 
establish an encrypted connection via Secure Sockets Layer (SSL) or SSH. Once logged in, entire folders 
and subfolders can be securely transferred from a hard disk drive or from a CD/DVD. The scans are stored 
on the server using 256-bit AES encryption. 
 
Important: Once the electronic imaging data submission is done, send an email to the Imaging Core Lab 
at 
 listing what images have been sent electronically. Please include the 
basic information of submitted data sets as follows: 
1) N1048 Patient Study ID 
2) Scan Time Point (Baseline, Restaging or Surveillance) 
3) Type of Scans  
4)   Date of Scans 
5) Date of First Day of Protocol Treatment 
6) Institution Name 

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Shipment/Mail Transfer 
If electronic transfer of data is not possible, the de-identified images in digital DICOM format should 
be burned to a CD/DVD then snail-mailed to the Imaging Core Lab at te address listed directly below. 
Please submit only one patient’s imaging study per CD with the basic information listed above (#s 1-
6). Multiple CDs can be sent together. Please note that the Imaging Core Lab does not accept deliveries 
on weekends and legal holidays. 
 
For Questions or Concerns, Contact: 
 
 
 
 
 
 
 
 
 
The Imaging Core Lab will acknowledge by email the receipt of the imaging data from the submitting site 
within 1 business day of receipt. 
 
Schedule of Submission of Imaging Scans for Central Radiologic Review 
 
Submit electronically at 
 
For help, email 
 
Study Type 
Group 1: FOLFOX 
Group 2: 5FUCMT 
If the patient receives an MRI and a 
CT at baseline, submit the Baseline 
MRI to Central Radiology for 
review 
Submit as soon as feasible. 
Submit as soon as feasible. 
If the patient receives an ERUS and 
a CT at baseline, submit the 
Baseline CT to Central Radiology 
for review 
Submit as soon as feasible. 
Submit as soon as feasible. 
If the patient receives an MRI at 
restaging*, submit the Restaging 
MRI to Central Radiology for 
review 
Submit as soon as feasible. 
Scan not required. If scan was 
performed, submit 
If the patient receives an ERUS and 
a CT at restaging*, submit the 
Restaging CT to Central 
Radiology for review 
Submit as soon as feasible. 
Scan not required. If scan was 
performed, submit 
Surveillance Imaging: 
MRI, CT, PET-CT to identify 
recurrent disease  
Submit as soon as feasible. 
Submit as soon as feasible. 
*Note: At restaging, use the same imaging modality that was used at baseline for a given patient. ERUS studies 
do not need to be submitted. 
 
NOTE: Central Radiology Review is for quality assurance purposes and is not done in "real-time"; Decisions 
about clinical management based on interpretation of images rest with the accruing site and primary clinical team 
based on the best clinical interests of the patient. 
 

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APPENDIX X: GENOMIC CHARACTERIZATION  
Genomic Characterization of Rectal Tumors using Molecular Inversion Probe 
(MIP) Arrays and MALDI-TOF Mass Spectrometry. 
 
Summary 
Ongoing research is directed at developing patient-specific therapies by learning more about the molecular 
features of a tumor within an individual patient. Unlike normal cells, cancer cells are characterized by 
alterations in their molecular machinery related to damage or changes to their genetic material or DNA. 
Damage to the DNA can result in cancer-causing mutations; however, an alternative way for cancer cells 
to develop and grow is related to gains (amplifications) or losses (deletions) of genetic material referred to 
as copy number alterations. These mutations or copy number alterations can lead to uncontrolled cell 
growth, an inability to undergo normal cell death, and a propensity for cancerous cells to travel to other 
sites in the body, referred to as metastases.  
 
We and others have previously demonstrated that colorectal cancer is more than one disease, as illustrated 
by the different somatic mutations that can occur in an individual’s tumor involving genes such as KRAS, 
NRAS, BRAF, PIK3CA, AKT, PTEN, and TP53, as well as others. We hypothesize that pre-treatment 
determination of the molecular alterations that occur in an individual’s rectal tumor will allow for patient- 
or tumor-specific therapies with a greater likelihood of a successful outcome.  
 
A major challenge of a targeted approach to cancer therapy is the need for fresh-frozen tumor tissue for 
analysis in order to determine the genetic variants in a specific patient’s tumor. Historically, most tumor 
tissue has been preserved by stabilizing it with formalin, a formaldehyde solution, and embedding it in 
paraffin. The result is known as formalin-fixed, paraffin-embedded (FFPE) tumor tissue. During this 
process, the DNA is degraded, limiting the ability to perform genetic analyses using currently available 
technologies. The objective of the current proposal is to prospectively determine mutations and copy 
number alterations in rectal tumors from patients participating in the current NCI cooperative group rectal 
cancer trial, using a novel technology called molecular inversion probe (MIP) arrays, which can be used on 
FFPE tumor tissue. The MIP technology allows for simultaneous assessment of copy number alterations 
and mutations at commonly altered locations using significantly less DNA than older technologies. We 
anticipate that this technology will greatly facilitate our ability to maximize the information we can obtain 
from the relatively small tissue samples anticipated from the pre-treatment rectal biopsies. The ability to 
obtain all of this information in a single assay using FFPE tumor tissue will allow us to identify genetic 
events that represent targets for current and novel therapeutics. We hypothesize that together, these data 
will act as an integrated biomarker that will be able to predict which patients are most likely to respond to 
which agents and treatment modalities. The knowledge obtained from this project is anticipated to be used 
to design prospective clinical trials of therapies for rectal cancer patients whose tumors posses the genetic 
profile predicted to be most likely to respond. By potentially individualizing treatment strategies to the 
patients who are most likely to respond, this approach is anticipated to accelerate the development of 
promising therapies. 
 
Specific Aims 
Aim 1: To prospectively use molecular inversion probe (MIP) array technology and mass spectrometry-
based genotyping to identify copy number aberrations and somatic mutations that mediate tumor formation 
using formalin-fixed, paraffin-embedded (FFPE) tumor tissue from patients participating in the Alliance 
cooperative group rectal cancer neoadjuvant trial. 
 
 
 

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Aim 2: To correlate the MIP array copy number and mutational data collected from patients with locally 
advanced rectal cancer with clinical outcomes in each treatment cohort (pathologic complete response, 
recurrence-free, pelvic recurrence-free, and overall survival). 
 
Background and Significance 
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of 
cancer death in the United States. CRC is not a single disease entity arising as a result of a single 
pathognomonic genetic alteration, but rather a collection of diseases with a common tissue of origin.  
Clinically this is demonstrated both by the heterogeneity of outcomes following surgical resection and by 
the heterogeneity of response of CRC patients to systemic agents. Given this clinical heterogeneity, 
strategies to increase the cure rate must focus on accurately predicting the likelihood of recurrence after 
resection.  In an attempt to improve the likelihood of cure following complete resection of CRC, adjuvant 
systemic therapy is administered to those patients who are at a perceived high risk of recurrence. Current 
models employing clinicopathologic features, however, are imperfect in predicting cancer recurrence, 
which leads to potential overtreatment in a subset of patients, and under-treatment in others. A classification 
of colorectal cancer that incorporates both clinical and tumor genetic variables thus holds promise for 
improvement in prognostication and the development of more individualized treatment plans.  For example, 
a reported 18 gene assay of tumor DNA has the ability to classify one clinicopathological subgroup, stage 
II disease, into higher and lower risk categories (Salazar et al., 2011). However, to really provide benefit, a 
classification scheme must be able to both accurately assign patients to low versus high risk cohorts, but 
also identify which if any systemic agents will significantly lower the risk of recurrence. 
 
Although most cases of CRC seem to be sporadic, age-related cancers with a mean age at diagnosis of 64 
years, approximately 10% of patients with colorectal cancer are diagnosed under the age of 50. In such 
early-onset cases, genetic over environmental risk factors are presumed to be implicated, and evaluation for 
underlying cancer predisposition syndromes is appropriate. In fact, according to the revised Bethesda 
guidelines, all patients with a diagnosis of colorectal cancer under the age of 50 should be evaluated for 
Lynch syndrome (Hereditary Non-polyposis Colorectal Cancer) regardless of family history (Umar,  2004). 
However, despite extensive genetic evaluation, a germline mutation in one of the known colon cancer 
susceptibility genes is identified in only about 10-20% of early-onset CRC patients, thereby leaving the 
etiology of the majority of early-onset CRC cases unexplained. While accounting for only a small fraction 
of CRCs, investigation of the genetic and/or epigenetic alterations that lead to tumor initiation in these early 
onset CRC patients may provide insight into pathways of carcinogenesis in common to all colorectal cancer 
patients.   
 
Approximately 70% of CRC tumors have identifiable somatic mutations within the RAS/RAF and 
PIK3CA/AKT pathways. In CRC models harboring RAS and BRAF mutations, RAS-pathway mutations 
are required for tumor maintenance, suggesting that therapies that target RAS or its downstream effectors 
may represent a useful therapeutic strategy in this disease. Further, RAS pathway mutations are highly 
predictive of resistance to anti-EGFR targeted therapies such as cetuximab and panitumumab. Although 
typically assumed to confer overlapping downstream dependencies, our preliminary data suggest that 
individual RAS pathway mutations confer variable prognostic effects. Definitive elucidation of the 
prognostic value of individual mutant alleles has been hampered by an exclusive focus on only the most 
frequent “hot spot” mutations and the use of small datasets inadequate for analysis of low frequency 
mutations. Furthermore, little is known about the relative frequency of RAS pathway mutations in patients 
with early-onset CRC, and in minority populations, both of which exhibit a relatively poor outcome. A 
comprehensive effort to prospectively profile rectal tumors for both tumor-initiating alterations and those 
required for tumor maintenance may thus help explain the disparity in outcome seen in early-onset and in 
minority populations. 
 
 

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Significance 
We strongly believe that stratification of patients with advanced rectal cancer by genotype, as compared to 
histological pathology, will lead to improved outcomes for our patients. This approach has demonstrated 
some positive results in non-small cell lung cancer with the use of epidermal growth factor receptor 
(EGFR)-targeted therapy and, more recently, ALK-targeted therapy in patients with genomic ALK 
alterations such as the EML4-ALK fusion. This proposal seeks to use the novel MIP array technology to 
characterize copy number alterations and mutations in FFPE tumor specimens to develop individualized 
treatment strategies for patients with locally advanced rectal cancer. The ability to obtain all of this 
information from a single assay that can be performed on FFPE tumor tissue represents a significant 
technological advance over currently available methods. Furthermore, the multiplexed nature of the MIP 
array will allow for the identification of actionable genetic alterations in the majority of patients with locally 
advanced rectal cancer. We believe that the current approach will rapidly improve outcomes in patients as 
many of the alterations that will be identified (BRAF mutation, etc.) have been validated as targets in other 
cancer types. FDA-approved drugs for such patients are available but not yet deployed in an individualized 
manner in locally advanced rectal cancer. 
 
Preliminary Data 
At MSKCC, we have embarked on a Colorectal Cancer Oncogenome Project (CCOP) with two main goals: 
1) to identify known driver alterations for use in guiding treatment/trial selection; and 2) to identify genetic 
drivers in patients in whom no known driver alteration has yet been identified. The CCOP uses three 
complementary genomic approaches to characterize tumors for mutations (targeted sequencing), 
identification of structural variations (translocations, amplifications and deletions) and methylation events. 
These efforts have been closely coordinated with those of the Tumor Cancer Genome Atlas project of which 
we are an active participant.  
 
In order to complement the TCGA efforts, we have compared the genomic profiles of primary and 
metastatic colorectal cancers (CRC). To date, we have analyzed 736 frozen CRC tumors samples from 613 
patients.  Annotated clinical data was available for all patients. The median age of the cohort was 62 years 
(mean 60 years, range 17-88 years); 23% of patients were less than 50 years old. Approximately half of the 
patients presented with metastatic disease. These patients had a 5-year disease specific survival of 24%. 
The mean follow-up time for all study patients was 4.5 years. Primary invasive carcinomas comprised 57% 
(n=406) of the specimens, while 291 were collected from metastatic foci and 39 were adenomas with or 
without high grade dysplasia/intramucosal carcinoma. The site of metastases included liver (n=227, 78%), 
lung (n=34), soft tissue (n=14), brain (n=7), ovary (n=5) and distant lymph nodes (n=4).  
 
For all 613 patients, tumors were profiled for KRAS, NRAS, BRAF and TP53 mutations. To identify 
hotspot alterations in the KRAS, NRAS and BRAF genes, we used a mass spectrometry based (Sequenom) 
assay. As TP53 mutations are found scattered throughout the coding sequencing, to determine the 
mutational status of this gene, we performed Sanger sequencing of all TP53 coding exons.  Mutations in 
KRAS were identified in 277 (45.1%) patients. 219 (35.7%) of the KRAS mutations were located at codons 
12 or 13 whereas 58 (9.4%) patients had either NRAS (2.9%) mutation or mutations within exons 3 or 4 of 
KRAS (exon 3: 2%: exon 4: 4.6%). BRAF mutations were detected in 40 (6.5%) patients, PIK3CA 
mutations in 72 (11.7%) patients and TP53 mutations were identified in 247 (40.3%) patients. Consistent 
with prior series, mutations in KRAS, NRAS and BRAF were non-overlapping in distribution. PIK3CA 
and TP53 mutations were found to co-occurred with both RAS and BRAF mutations, although PIK3CA 
mutations were significantly more common in the KRAS mutant tumors (16.2% vs. 8.1%, p=0.001), while 
TP53 mutations were significantly more common in BRAF wild type cases (9% vs. 2.6%, p=0.002). In 
stages I-III disease, KRAS exon 2 and TP53 mutations were associated with a worse prognosis, while in 
metastatic (stage IV) disease all RAS and BRAF mutations were associated with significantly worse disease 
specific survival. In ongoing work, we are comparing the frequency of novel mutational events identified 
in the TCGA dataset by whole exome sequencing in our matched set of primary and metastatic samples. 

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The goal of these efforts will be to identify additional molecular events that correlate with clinical outcome.   
 
On the basis of these preliminary findings, the current proposal seeks to use MIP array technology to 
identify prognostic and/or predictive, potentially druggable mutations involving MEK, AKT, PIK3CA, and 
BRAF, as well as others, and copy number alterations, such as ERBB2 amplification, using FFPE material. 
As only FFPE material is typically available for patients with locally advanced rectal cancer, the validation 
of this approach should pave the way for a biomarker-driven approach to individualized cancer treatment 
in patients with locally advanced rectal cancer. Molecular inversion probe technology has been successful 
in obtaining high-quality copy number and genotype data from both frozen and FFPE-derived DNA. Since 
the MIP probe requires only a small (~40 base pairs) target-binding site, it was hypothesized that it could 
be applied effectively to degraded FFPE DNA as well (Wang et al., 2009). As an example of the use of this 
technology, a MIP panel of 50,000 markers was performed on DNA derived from 93 FFPE tumor samples 
from patients with breast, colon, kidney, and liver cancers. A major advantage of this technology is that an 
input of only 37 ng of genomic DNA was required. High-quality copy number data was generated in 88% 
of the FFPE samples. In 38 samples with matched fresh-frozen tissue, the genotype concordance averaged 
99.9%, with only a modest loss in performance in FFPE. In collaboration with Affymetrix, the laboratory 
of 
at MSKCC has enhanced the platform by adding additional coverage to ~200 well-characterized 
cancer-associated genes, including those identified in our CCOG project and the TCGA. Furthermore, 
coverage of over 700 recurrent hotspot mutations, such as those in PIK3CA, and BRAF, were added to the 
revised cancer-specific assay. 
 
Methods 
 
Molecular Inversion Probe (MIP) Array Technology  
Molecular inversion probe technology may offer a solution to the challenge of acquiring copy number and 
genotype data from limited quantities of FFPE-derived tumor samples (Wang et al., 2009). FFPE specimens 
represent a vast, underutilized resource for genomic characterization. Such samples suffer from a number 
of limitations, including DNA fragmentation and crosslinking (which are a consequence of the fixation 
process), low DNA yield, and age-related degradation, all of which impair their utility for use with array-
based technologies, such as copy number and mutation profiling. The MIP array selectively amplifies a 
locus of interest using unique padlock primers that significantly enhance the specificity and sensitivity of 
single nucleotide polymorphism (SNP) and mutation detection. This technology requires only 40 base pairs 
of intact target DNA and 75 ng of input material, thereby overcoming the most common limitations of 
FFPE samples. Briefly, each padlock probe consists of two terminal regions complementary to the target 
sequence of interest, two universal polymerase chain reaction (PCR) primer regions, a DNA cleavage site, 
and a tag sequence used for identification on an array. Linear MIP probes hybridize and anneal to the target 
genomic DNA sequence, resulting in probe circularization (molecular inversion) with a single-nucleotide 
gap between the hybridized ends.  Polymerization and ligation of the gap occurs in an allele-specific 
manner, resulting in a covalently closed circular probe hybridized to the genomic DNA region of interest. 
Exonucleolysis of excess linear probes and genomic DNA is followed by probe release through site-specific 
enzymatic cleavage. The common primer regions within the probe are then utilized to amplify the region 
of interest; fluorescent labels are additionally attached. Amplified products are subsequently hybridized 
onto DNA microarrays and the relative fluorescence signaling intensity discriminates between mutations 
and can also be used to detect copy number alterations. We have been involved in the design of a custom 
array that utilizes the multiplexing capabilities of MIP probes to detect 744 mutations across 72 genes 
within a single sample. The array was designed to have extremely high probe densities within known cancer 
associated genes, allowing for highly sensitive detection of oncogene amplification and intragenic deletions 
within tumor suppressor genes.  
 
 
 

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if the mutation is represented within our Sequenom assay, by mass spectrometry-based genotyping. Only 
those mutations that can be confirmed by an orthogonal method will be considered true positives. As the 
MIP array and the Sequenom assay may have greater sensitivity than the Sanger method, mutations that 
fail to be confirmed will be further assayed using next-generation sequencing methods on a case-by-case 
basis. 
 
We will use hierarchical clustering to determine whether patients can be divided into subgroups defined by 
similar copy number profiles. These data will guide the formation of distinct subclasses of patients that are 
likely to respond to different treatments as described in Aim 3.  
 
Aim 2: To correlate the MIP array copy number and mutational data collected from patients with locally 
advanced rectal cancer with clinical outcomes. For patients with locally advanced disease, the outcomes of 
interest will be complete pathologic response, pelvic recurrence-free, extra-pelvic recurrence-free, and 
overall survival. Patients will be followed for a minimum of 3 years in order to ensure that the majority of 
events have occurred before performing the initial test for association between mutational and copy number 
alteration status and outcome. Estimates of these endpoints will be calculated using the methods of Kaplan 
and Meier and comparisons between those with and without each mutation/copy number alteration will be 
examined using the log rank test. We will also correlate survival with the genomic subclasses discovered 
in Aim 1. The biomarker groups selected for the clinical trial should have similar clinical characteristics for 
all patients within this group; otherwise, subgroups will be redefined. 
 
References 
 
Barker, A.D. et al.. (2009). " I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant 
 chemotherapy". Clin Pharmacol Ther. 86(1): 97-100. 
 
Berry, D.A.. (2011) "Adaptive clinical trials: the promise and the caution."  J Clin Oncol. 29(6): 606-9. 
 
Janakiraman, M et al. (2010). "Genomic and biological characterization of of exon 4 KRAS mutation in  
human cancer." Cancer Res. 70(14): 5901-11.  PMID 20570890.  
 
Salazar, R. et al. (2011). "Gene expression signature to improve prognosis prediction of stage II and III 
 colorectal cancer." J Clin Oncol. 29(1): 17-24. PMID 21098318. 
 
Umar, A. (2004) "Lynch syndrome (HNPCC) and microsatellite instability." Dis Markers  20(4-5): 179- 
80. PMID 15528783.  
 
Wang, Y. et al. (2009) "High quality copy number and genotype data from FFPE samples using 
Molecular Inversion Probe (MIP) microarrays."  BMC Med Genomics 2: 8. 
 
Zhou, X. et al.. (2008) "Bayesian adaptive design for targeted therapy development in lung cancer--a step  
toward personalized medicine."  Clin Trials 5(3):  181-93. 

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APPENDIX XI: INDICATORS OF IMMUNOLOGIC ACTIVATION 
Indicators of Immunologic Activation in Locally Advanced Rectal Cancer 
 
Objectives:  
(1) To identify immune markers for response to neoadjuvant chemotherapy or chemoradiation using 
very well established, validated immunologic assays.  
(2) To investigate the ability of neoadjuvant FOLFOX or chemoradiation to augment anti-tumor 
immunity against rectal cancer. 
(3) To identify novel immune targets in rectal cancer. 
 
Specific Aims: 
(1) To measure serum cytokine profiles before and after therapy. 
(2) To determine the impact of chemotherapy or chemoradiation on antibody responses to cancer-testes 
antigens. 
(3) To utilize recently developed protein array technology to simultaneously assay for induction of 
antibody responses to >8000 recombinant proteins as a tool for both correlation with clinical 
response as well as novel antigen discovery.  
 
Significance and Background:  
The rationale for immune recognition of colorectal cancer is based on several observations that 
effector/memory T cells infiltrate colorectal tumors, have prognostic value, and correlate with earlier 
disease stage and prolonged survival. This was furthermore shown in a retrospective analysis to be superior 
to and independent of the current TNM staging classification. Of particular relevance here, was the 
observation that the density of CD3+ and CD45RO+ T-cell density has prognostic value (Galon et al., 2006; 
Pages et al., 2005). 
 
The core hypothesis that chemotherapy and radiation can both augment immunity is based on observations 
that genetic instability in cancer leads to a diverse number of mutations (Sjoblom et al.., 2006), and that 
such mutational diversity can provide novel targets that could be perceived by the immune system as non-
self. As presented by 
at the 2009 ASCO Plenary Session, we have confirmed that many 
candidate tumor antigens, that can bind to MHC class I, arise due to such mutational diversity (Segal et al., 
2008). The important point is that each antigen recognized by the immune system is a potential target for a 
tumor-specific immune response. Therefore tumor cell destruction in situ by neoadjuvant FOLFOX or 
chemoradiation can provide a polyvalent tumor vaccine by causing cell death and liberating tumor antigens 
(Peggs et al., 2007)  
 
This hypothesis has led to several studies combining standard chemotherapy with immune augmentation. 
At Memorial Sloan-Kettering Cancer, we are currently leading two multicenter immunotherapy clinical 
trials, studying (1) cetuximab plus Imprime-PGG; and, (2) FOLFOX with or without Programmed Death-
1 (PD-1) blockade in patients with metastatic colorectal cancer, under the leadership of 
 
 
 
Similar studies have been done in melanoma with ipilimumab and dacarbazine (Hersh et al., 2011) and 
prostate cancer with radiation and ipilimumab (ASCO 2008). The success of immune augmentation using 
ipilimumab has led to its recent FDA approval in melanoma. Further studies toward immune therapy in 
colorectal cancer are warranted. 
 
Recently the Immune Monitoring Facility (IMF) and the Ludwig Center for Cancer Immunotherapy at 
MSKCC has recently advanced the field of immune therapy and immune monitoring, under the leadership 

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of 
 in collaboration with the Cancer Vaccine Consortium, an international network of 
investigators who are focused on the conduct of clinical trials of novel immunotherapies for cancer. Our 
recent experience in tumor immunology with anti-PD-1 in colorectal cancer and melanoma, and CTLA-4 
(Cytotoxic T-Lymphocyte Antigen 4) in melanoma has provided invaluable experience toward studying 
the immune response in cancer. 
 
Specimens Required: 
Mandatory research blood draws will be collected at baseline (≤ 28 days of start of FOLFOX or 5FUCMT) 
and ≤ 28 days before surgery. Specimens should be collected prior to drug administration or radiation on 
relevant days. See Section 14.0 for instructions regarding acquiring, processing, and shipping mandatory 
research blood specimens.  
 
Specific Aim #1. To measure serum cytokine profiles before and after therapy. 
  
Rationale and Design: Cytokine profiles provide insight in to the status of immune activation and whether 
there is predominance of a Th1 or Th2 tumor response. Th1 type immune responses are associated with 
cellular cytotoxicity and effective anti-tumor immunity. It has previously been shown that chemotherapy 
and radiation result in altered cytokine profiles in patients with colorectal cancer (Gremy et al., 2008; 
Tsavaris et al., 2010). Baseline and changes in cytokine profiles may be measured in patients treated with 
FOLFOX or chemoradiation. Matched Pre- and post-treatment patient sera may be assayed using the 
Human Th1/Th2 Cytokine Cytometric Bead Array Kit (BD Biosciences, San Jose, CA, USA) to measure 
serum levels of IFN- γ, IL-2, IL-4, IL-5, IL-10, and tumor necrosis factor-α according to the 
recommendations of the manufacturer. Serum may also be tested for VEGF, basic fibroblast growth factor 
(bFGF), and IL-8 using ELISA kits (R&D Systems, Minneapolis, MN, USA) according to the 
recommendations of the manufacturer.  
 
Specific Aim #2. To determine the impact of chemotherapy or chemoradiation on antibody responses 
to the class of cancer-testes antigens. 
  
Rationale and Design:  Cancer-testis antigens are expressed in male germ cells, absent from adult somatic 
tissues, and are re-expressed in cancer due to disrupted gene regulation. Due to their restricted expression 
profile, these tumor antigens are ideal candidate tumor vaccines. More than 20 cancer-testes antigen 
families have been identified, including NY-ESO-1 and MAGE-A. Our previous studies in melanoma used 
ELISA to detect antibody responses to a panel of cancer-testis antigens. There is no clear consensus on the 
implication of these tumor antigens in patients with colorectal cancer and further work in this regard is 
warranted. We plan to study LAGE-1, MAGE, CT-7, CT-47, Sox-2, XAGE-1 or others.  
 
Specific Aim #3: To utilize recently developed protein array technology to simultaneously assay for 
induction of antibody responses to >8000 recombinant proteins as a tool for both correlation with 
clinical response as well as novel antigen discovery. 
  
Rationale and Design: Protein microarrays from Invitrogen allow for concurrent serological screening of 
>8000 full-length antigens with a single serum, on an unprecedented scale (termed seromics).  We have 
performed a pilot study using serum from patients with colorectal cancer treated with chemotherapy and 
demonstrated seroreactivity against tumor antigens. In a study of melanoma before and after anti-cancer 
therapy, we demonstrated a relative increase in overall antibodies titers in patients with clinical response 
compared with patients that did not respond. While these numbers are small, we feel that these preliminary 
data justify further use of the seromics approach as an extremely powerful platform to study anti-tumor 
responses in colorectal cancer. We plan to apply seromics in patients treated with FOLFOX or 
chemoradiation. Matched Pre- and post-treatment patient sera will be assayed on one array each at an 
appropriate dilution to reveal specifically bound serum IgG.  

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The primary location of research will be within the Immune Monitoring Facility and the Ludwig Center for 
Cancer Immunotherapy, MSKCC. 
 from the department of epidemiology and 
biostatistics will perform statistical analysis on the data. 
 
Interpretation of Data: Data analysis of resulting assays is expected to yield: (1) differences in immune 
activation after neoadjuvant chemotherapy or chemoradiation; (2) a limited number of antigens with 
significant changes in seroreactivity after each treatment, indicating potential targets “hit” as a result of 
treatment; and, (3) a profile of baseline immunoreactivity in these sera. Together, these studies will help 
identify prognostic and predictive markers of response to FOLFOX or chemoradiation, and identify 
antigens with that may be targets of future immune therapies in combination with chemotherapy or 
chemoradiation. 
 
References 
Galon, J., et al. (2006) “Type, denisty and location of immune cells within human colorectal tumors 
predict clinical outcome.” Science 313(5795) 1960-4. 
 
Gremy, O., M. Benderitter, et al. (2008).  “Acute and persisting Th2-like immune response after 
fractionated colorectal gamma-irradiation.” World J Gastroenterol. 14(46):  7075-85. 
 
Hersh, E.M., et al. (2011). “A phase II multicenter study of ipilimumab with or without dacarbazine in 
chemotherapy-naive patients with advanced melanoma.” Invest New Drugs 29(3): 489-98. 
 
Pages, F. et al. (2005). “ Effector memory T cells, early metatasis and survival in colorectal cancer.” N 
Eng J Med  353(25): 2654-66. 
 
Peggs, K.S., N.H Segal et al. (2007). “Targeting immunosupportive cancer therapies: accentuate the 
positive, eliminate the negative.” Cancer Cell 12(3): 192-9. 
 
Segal, N.H. et al. (2008) “Epitope landscape in breast and colorectal cancer “Cancer Res 68(3): 889-92. 
 
Sjoblom, T. et al. (2006). “The consensus coding sequences of human breast and colorectal cancers.” 
Science 314(5797): 268-74. 
 
Tsavaris, N., et al.. (2010) Combined treatment with Bevacizumab and standard chemotherapy restores 
abnormal immune parameters in advanced colorectal cancer patients. Invest New Drugs, DOI 
10.1007/s10637-010-9533-0 
 
 

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APPENDIX XII: ASSESSMENT OF GERMLINE VARIATION 
Assessment of Germline Variation as a Predictor of Response and Toxicity to 
Platinum-based Chemotherapy and to Radiation Therapy in Patients with 
Rectal Cancer  
 
A major challenge in rectal cancer is that response, as well as treatment-related toxicity, is highly variable 
between patients. Pharmacogenomics has the potential to optimize, and personalize, the management of 
cancer patients by helping clinicians predict which individuals may be at increased risk of toxicity or 
resistance to a specific treatment modality. While response to chemotherapy and radiation therapy may be 
a function of an intrinsic biologic characteristic of the tumor itself (i.e., colorectal tumors with KRAS 
mutations are resistant to EGFR-inhibitors), host factors, as assessed through germline genetics, may 
influence pharmacokinetics of therapies and may thereby alter treatment efficacy and side effects. A small 
number of pharmacogenomic studies have already been performed in colorectal cancer but have largely 
been limited to single-institutions studies with small sample sizes, heterogeneous treatment groups, and/or 
consisted of the assessment of patients with metastatic, as opposed to early-stage, colorectal cancer. 
Furthermore, to our knowledge, the assessment of potential germline predictors of radiation response and 
toxicity in rectal cancer patients receiving radiation therapy has not been performed. The objective of this 
study is to identify germline genetic variants that may predict for chemotherapy and radiation 
sensitivity/toxicity which could potentially help tailor therapy according to individual host genetic factors.  
 
Specific Aims:  
1.  To determine whether germline genetic variants in candidate genes of interest (Table1) are associated 
with response and/or toxicity to platinum and 5FU-based chemotherapy; 
2.  To determine whether germline genetic variants in candidate genes of interest (Table 2) are associated 
with response and/or toxicity to radiation therapy; 
3.  To assess whether genetic risk variants identified in genome-wide association studies of colorectal 
cancer susceptibility (Table 3) are associated with rectal cancer clinical outcome and response to therapy.  
Aim 1 
 
Rationale: Resistance to platinum agents has been attributed to enhanced tolerance to DNA adducts, 
decreased drug accumulation, and enhanced DNA repair. As such, the genes involved in some of these 
pathways have served as potential candidate genes for assessment in pharmacogenomic studies. In a number 
of small studies, functional polymorphisms in DNA-repair genes such as XPD(ERCC2), ERCC1, XRCC1, 
and metabolizing genes, glutathione S-transferase GSTP1, GSTM1, and GSTT1 have been assessed for their 
ability to predict resistance/toxicity to oxaliplatin (Ruzzo et al., 2007; Pare et al., 2008a; Stoehlmacher et 
al., 2004; Lamas et al., 2011) In addition to these genes, for the combination of 5FU and oxaliplatin, 
germline genetic variants relevant to genes implicated in 5FU related function such as thymidylate synthase 
(TS), methylenetetrahydrofolate reductase (MTHFR), dihydropyrimidine dehydrogenase (DYPD) have 
also been assessed (Marsh et al., 2001; Etienne-Grimaldi et al., 2010 ; Pare et al., 2008b; Deenen et al., 
2011; Salonga et al., 2000; Villafranca et al., 2001). Although results of such studies have identified a 
number of potential genetic variants predictive of outcome and toxicity, data have not been consistently 
replicable, due probably in part to cancer and treatment heterogeneity within the study group, and a limited 
sample size. 
 
 
To date, there have been two large metastatic colorectal studies that have evaluated pharmacogenomic 

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associations with clinical outcomes and toxicity. In the NCI Intergroup N9741 trial, in which metastatic 
colorectal cancer patients were randomized to IFL, FOLFOX or IROX, a subgroup of patients were assessed 
for genetic predictors of chemotherapy response and adverse events (McLeod et al., 2010) Using a 
candidate gene approach, 34 germline genetic variants were assessed in 15 candidate genes, with the five 
genes of primary interest including TYMS, DPYD, CYP3A4, UGT1A1 and GSTM1, for associations with 
adverse events or outcomes. The homozygous UGT1A1*28 allele, observed in 9% of patients, was 
associated with a 55% risk of grade 4 neutropenia in the patients receiving IROX, while a deletion variant 
in GSTM1 was associated with a 28% risk of grade 4 neutropenia in the FOLFOX group.  For outcome, 
presence of the CYP3A5 variant was significantly associated with response rate to IFL (29% versus 60%).   
 
In the French FFCD 2000-05 randomized phase III trial, a subgroup of patients with metastatic colorectal 
cancer receiving either first-line LV5FU2 followed by second-line FOLFOX6, followed by third-line 
FOLFIRI (Group A) or first-line FOLFOX6 followed by second-line FOLFIRI (Group B) also underwent 
pharmacogenomic assessment (Boige et al., 2010) Genotyping for 20 polymorphisms from nine genes 
involved in the FU (DPD, TS, and MTHFR), oxaliplatin (ERCC1, ERCC2, GSTT1, GSTM1 and GSTP1) 
and irinotecan (UGT1A1) pathways was performed. In this study, the ERCC2-K751QC allele was 
independently associated with risk of grade 3/4 hematologic toxicity to FOLFOX, while 3 genetic variants 
were associated with response to FOLFOX (MTHFR-1298C; TS5-’ UTR3RG, and GSTT1 alleles). 
Moreover, progression free survival from first-line FOLFOX was limited to patients with 2R/2R or the 
2R/3R TS-5’UTR genotypes. It is notable that only a subgroup of patients in each of these studies underwent 
pharmacogenomic assessment limiting study results (for example, in N9741, informed consent for 
pharmacogenetic studies and blood sampling was added as an amendment midway through study accrual). 
On the other hand, these large metastatic colorectal studies clearly established that pharmacogenomic 
studies can be successfully conducted in large, multicenter research studies (Goldberg et al., 2010)  
 
Our Genetics and GU oncology groups at MSKCC recently assessed whether germline variation in 
candidate genes predicted response to platinum-based chemotherapy in patients with urothelial carcinoma 
(ASCO Genitourinary Cancer Symposium, February, 2011 Oral Presentation). Our results showed that 4 
SNPs retained associations with response. A greater number of “at-risk” alleles in an individual correlated 
with decreased response to platinum. In a multivariate model, that included a previously established 
MSKCC clinical risk score, each additional “at-risk” allele of the SNP score was associated with nearly 
50% decrease in odds of response. The bootstrap-adjusted c-index (equivalent to AUC) of this model was 
0.78, a marked improvement over 0.65 seen with the MSKCC clinical risk score alone. SNPs assessed, 
genotyping methods, and subsequent statistical analysis used in this prior study of platinum-sensitivity in 
urothelial carcinoma will be used as a source of reference for this study of platinum-based response/toxicity 
in rectal cancer.  
 
In addition to hematologic toxicity, a major, often dose-limiting, side effect of oxaliplatin is the 
development of chronic sensory neuropathy, which appears to be cumulative, and in some cases results in 
permanent residual toxicity despite drug cessation. Studies aimed at preventing this life-altering side effect 
have been largely unsuccessful and the mechanism of neurotoxicity has not been clearly elucidated 
(McWhinney et al., 2009). The incidence of clinical neurotoxicity is not directly associated with tumor 
response. Pharmacogenomic studies assessing for predictors of neurotoxicity are limited. In smaller studies 
of colorectal cancer patients receiving oxaliplatin-based treatment, genetic variants in ERCC1 and GSTP1 
predicted for earlier development of neurotoxicity.(Ruzzo et al., 2007; Inada et al., 2010]) In the 
aforementioned N9741 trial, patients with a homozygous variant genotype of GSTP1 were more likely to 
discontinue FOLFOX due to neurotoxicity (24% versus 10%) (McLeod et al., 2010). Given the importance 
of this potentially irreversible toxicity, further pharmacogenomic studies to identify markers that predict 
for this toxicity are clearly needed.  
 
Design: To determine whether germline genetic variants in candidate genes of interest are associated with 

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response and/or toxicity to platinum and 5FU-based chemotherapy.   
 
Using the genetic variants within the listed candidate genes in Table 1 (other possible genetic 
variants/candidate genes may be added), we will perform genotyping (see Methods) using genomic DNA 
on all patients randomized to receive neoadjuvant chemotherapy with FOLFOX. Clinical outcome, as 
assessed by pathologic response to chemotherapy at time of surgical resection will be correlated with 
genotype for each SNP/genetic alteration. In addition, toxicity, using NCI-CTCAE, including but not 
limited to hematologic toxicity and neurotoxicity, will also be assessed and correlated with genotype.  
 
Table 1. Genetic Variants Associated with Platinum and 5FU-based Chemotherapy Response or 
Toxicity  
Candidate Genes  
Polymorphism 
5FU 
 
TS 5'-untranslated region (5'UTR) 
VNTR 
TS 3'-untranslated region (3'UTR) 
6bp ins/del 
TS 5’UTR  
G/C 
MTHFR 
677 C>T 
MTHFR 
1298 A>C 
MTHFR 
1793 G>A 
DPYD 
1627 A>G 
DPYD 
2194 G>A 
DPYD 
85 T>C 
DPYD 
IVS14+1 G>A 
Platinum 
 
ERCC1 
IVS5+33 C>A 
ERCC1 
IVS3+74C>G 
ERCC1 
IVS4+86T>C 
ERCC1 
354 C>T 
ERCC2 
IVS19-70G>A 
ERCC2 
-1989A>G 
ERCC2 
2133 C>T 
ERCC2 
2251 A>G 
GSTM1 
del poly 
GSTP1 
2293 C>T 
GSTP1 
1578 A>G 
XRCC1 
1196 G>A 
GSTT1 
del poly 
Table 1 candidate gene references: Wang et al., 2009; Berry et al., 2011; Zhou et al., 2008; Barker et al., 
2009; Galon et al., 2006; Pages et al., 2005 ; Sjoblom et al., 2006; Segal et al., 2008; Peggs et al., 2007; 
Hersh et al., 2011; Gremy et al., 2008; Tsavaris et al., 2007. 

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Aim 2 
 
Rationale: Response to radiation therapy varies widely, ranging from a complete response to virtually no 
response in the tumor, and from little toxicity to severe short- and/or long-term treatment related adverse 
reactions in normal tissue. Although clinical factors such as radiation dose, volume, and fraction certainly 
have an important impact on response and toxicity, it has been estimated that nearly 80% of inter-individual 
variation in normal tissue response to radiation may be due to genetic factors (Barnett et al., 2009). Given 
the relatively narrow therapeutic index for radiation therapy, understanding the underlying variation in 
response to radiation might help us maximize radiation efficacy in the tumor, while minimizing side effects 
in normal tissue. Genetic variants in a number of candidate genes in pathways that include endogenous 
oxidation stress defense, inflammatory response, cytokine activity related to fibrosis, DNA damage 
signaling, cell cycle control, and DNA repair have been associated with radiation response (Andreassen et 
al., 2009; Chistiakov et al., 2008; Popanda et al., 2009; Pugh et al., 2009) More recently, genome-wide 
basal gene expression profiles and genome-wide SNPs for 277 lymphoblastoid cell lines were used to 
identify SNPs/genes that might contribute to variation in radiation response (Niu et al., 2010). Using an 
integrated analysis that included genome-wide SNP data, basal expression and radiation AUC, 50 unique 
SNPs were identified with the most significant regions containing the LRRN2, IL19, KCNK1, LDB2, 
NCRNA00290, DEPDC1B, PPIGP1 and PLEKHF2 genes. Pharmacogenomic studies in radiation response 
and toxicity in rectal cancer have not been performed and, as such, this large adjuvant trial, will provide the 
platform for this novel study.  
 
Design: Using the genetic variants within the listed candidate genes in Table 2 (other possible genetic 
variants/candidate genes may be added), we will perform genotyping (see Methods) using genomic DNA 
on all patients randomized to receive neoadjuvant radiation therapy. Clinical outcome, as assessed by 
pathologic response to radiation at time of surgical resection will be correlated with genotype for each 
SNP/genetic alteration. In addition, short-term radiation toxicity, using NCI-CTCAE, will also be assessed 
and correlated with genotype. Given that the radiation treatment will be receiving 5FU for 
radiosensitization, a subgroup of the SNPs listed in Aim1 that have been implicated in 5FU 
response/toxicity will also be assessed in this group.  
 
 

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Table 2. Genetic Variants Associated with Radiation Response or Toxicity  
Candidate Genes  
Polymorphism 
Implications in Other Cancers  
GSTP1 
1578A>G 
Skin Toxicity  
TGFB1d 
869 T>C 
Subcutaneous fibrosis 
ATM 
5557G>A; 
IVS22-77 T>C; 
IVS48+238C>G 
Late adverse normal tissue reaction; rectal bleeding 
(prostate cancer) 
XRCC1c 
rs25489 
Late rectal bleeding; erectile dysfunction (prostate cancer)  
LIG4 
26C>T 
Rectal and bladder toxicity (prostate cancer)  
XRCC3a 
5’UTR; 
4541A>G; -
1843A>G 
Rectal and bladder toxicity (prostate cancer)  
MLH1 
rs1799977 
Rectal and bladder toxicity (prostate cancer)  
CYP2D6 4a 
rs1800716 
Rectal and bladder toxicity (prostate cancer)  
XRCC3b 
IVS5-14G 
Gastrointestinal toxicity  
IL12RB2a 
rs3790566 
Radiation dermatitis 
 
RAD 21 
rs1050838 
Radiosensitivity 
SMAD4 
Multiple 
Chemo and radioresistance 
Candidate Genes from 
GWAS 
Polymorphism 
Implication 
PLEKHF2 
rs7000734 
Radiosensitivity 
TINAG 
rs1685294 
Radiosensitivity 
PLEKHF2 
rs1561715 
Radiosensitivity 
PLEKHF2 
rs1610110 
Radiosensitivity 
Table 2 candidate genes from Andreassen et al., 2009; candidate genes from GWAS from Niu et al., 2010. 
 
Aim 3 
 
Rationale: Genome-wide association studies (GWAS) have identified at least 10 independent susceptibility 
loci associated with colorectal cancer risk (Table 3) (Stadler et al., 2010). The effect size for each of the 
identified risk SNPs is modest resulting in a 10-30% increase in the relative risk of CRC. While some of 
the risk SNPs map to genes of interest in colorectal cancer (SMAD7, BMP4, CDH1), several SNPs map to 
areas devoid of known genes. For the majority of risk SNPs, the causal variant(s) have not been identified 
and functional studies to determine how these risk variants may exert their effect are currently on-going. 
Also unknown are the possible gene-gene and gene-environment interactions that may further modify the 
effect of these risk alleles.  
 
Our Genetics and GI Oncology groups at MSKCC recently completed a study to determine whether 
germline colorectal cancer risk variants (SNPs) discovered in recent GWAS are associated with cancer 
phenotype and outcome. Using an incident cohort of 891 colorectal cancer cases, we genotyped all cases 
for the eight independent colorectal risk SNPs (Table 2) and after adjusting for potential confounders and 
multiple comparisons, identified one SNP that predicted for an earlier age at disease onset as well as 2 SNPs 
that predicted for survival (ESMO Annual Meeting Proceedings, October 2010, Oral Presentation; 
manuscript in preparation). This incident cohort consisted of patients with stage I-IV disease receiving a 
variety of different treatment modalities. Although our group at MSKCC has looked at this heterogeneous 
incident group of colorectal cases for associations with clinicopathologic features, whether these colorectal 
cancer risk SNPs predict for clinical outcome and response to a specific treatment modality in a more 
homogenous population has not been assessed to date. 
   

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Design: To assess whether genetic risk variants identified in genome-wide association studies of colorectal 
cancer susceptibility are associated with rectal cancer clinical outcome and response to therapy  
 
Using the colorectal cancer risk genetic variants listed in Table 3, we will perform genotyping (see 
Methods) using genomic DNA on all study patients. Clinical outcome, as assessed by pathologic response 
to chemotherapy or radiation therapy at time of surgical resection, will be correlated with genotype for each 
SNP/genetic alteration. In addition, the study end-points of TLR and DFS may also be used for correlation 
with genotype.   
 
Table 3. Risk SNPs from GWAS of Colorectal Cancer  
Locus 
Implicated Gene 
SNP 
Per Allele 
 OR Ranges 
8q23.3 
EIF3H 
rs16892766 
1.27 
8q24.21 
LOC727677, POU5F1P1 
rs10505477 
1.17 
 
 
rs6983267 
1.17-1.27 
 
 
rs7014346 
1.19 
10p14 
intergenic 
rs10795668 
1.12 
11q23.3 
intergenic 
rs3802842 
1.12 
14q22-q23 
BMP4 
rs4444235 
1.11 
15q13 
intergenic 
rs4779584 
1.23-1.26 
15q13-q15 
GREM1 
rs10318 
1.19 
16q22.11 
CDH1 
rs9929218 
1.10  
18q21.1 
SMAD7 
rs4939827 
1.16-1.20 
20p12.3 
intergenic 
rs961253 
1.12 
Table 3 SNPs are from Stadler et al, 2010. 
 
 
Methods: Informed consent for pharmacogenomic studies using blood sampling will be obtained from each 
study subject. Genomic DNA will be extracted from peripheral blood cells using standard techniques and 
will be stored at 4°C before use. Genotyping for the selected germline genetic variants will be performed 
using the Sequenom-iPLEX Gold System CC according to manufacturer’s protocol (Sequenom, CA). The 
iPLEX Gold assay is based on multiplex PCR followed by a single base primer extension reaction. After 
the PCR, remaining nucleotides are deactivated by alkaline phosphatase (SAP) treatment. The single base 
primer extension step is performed, and the primer extension products analyzed using MALDI TOF MS. 
Alleles are distinguished on the basis of their masses and relative peak heights. The assay design is 
automated, all oligonucleotides are unlabeled and of standard quality. All primers and probes will be 
designed and multiplexed using Sequenom software and assistance through Sequenom web support 
(
).  
 
It is important to note that as pharmacogenomics is a rapidly evolving field, additional genetic variant(s) in 
candidate gene(s) of interest are likely to be added to the current lists in the above tables. In addition, with 
the rapidly decreasing cost of genotyping, an agnostic approach to the identification of genetic variants that 
predict for platinum-based chemotherapy and radiation response/toxicity may be an alternative acceptable 
method for this correlative study. 
 
Statistical Analysis: Univariate Cox proportional hazards regression will be used to investigate the 
association between each SNP and clinical endpoints of interest.  Each SNP will be analyzed under a co-
dominant model, with the association determined from a global test for differences in outcome between the 
3 genotypes (common homozygote, heterozygote, and rare homozygote), commonly referred to as a “2 
degree of freedom test”. The probability of freedom from the various events will be estimated using Kaplan-
Meier methods. For relevant clinical endpoints, time at risk will be calculated from the date of study registry 

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to the date of event or date of last contact, and patients without the event will be censored at their last follow 
up date. For SNPs significant at p < 0.05 under the co-dominant model, multivariable analyses will be 
conducted controlling for potential confounders. P values will be reported both with and without correction 
for multiple testing using a Bonferonni correction. The endpoints tested will include pathologic response to 
neoadjuvant chemotherapy and/or radiation therapy, NCI-CTCAE graded toxicities, including but not limited to 
hematologic toxicity, neurotoxicity and skin toxicity, and possibly LTR and DFS.  
 
References:   
 
Andreassen, C.N. and J. Alsner. (2009). “Genetic variants and normal tissue toxicity after 
radiotherapy: a systematic review.” Radiother Oncol. 92(3): 299-309. 
 
Barker, A.D. et al.. (2009). " I-SPY 2: an adaptive breast cancer trial design in the setting of  
neoadjuvant chemotherapy". Clin Pharmacol Ther.  86(1): 97-100. 
 
Barnett, G.C. et al.. (2009). “Normal tissue reactions to radiotherapy: towards tailoring treatment  
dose by genotype.”  Nat Rev Cancer.  9(2): 134-42. 
 
Berry, D.A.. (2011) "Adaptive clinical trials: the promise and the caution."  J Clin Oncol. 29(6):  
606-9. 
 
Boige, V., et al. (2010)  “Pharmacogenetic assessment of toxicity and outcome in patients with 
metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.” 
 J Clin Oncol  28(15): 2556-64. 
 
Chistiakov, D.A. et al. (2008). “Genetic variations in DNA repair genes, radiosensitivity to cancer and  
susceptibility to acute tissue reactions in radiotherapy-treated cancer patients.”. Acta Oncol. 47(5):809-24. 
 
Deenen, M.J. et al. (2011) “Relationship between single nucleotide polymorphisms and haplotypes in 
DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer.” Clin Cancer Res. 
 
Etienne-Grimaldi, M.C. et al. (2010) “Methylenetetrahydrofolate reductase (MTHFR) gene  
polymorphisms and FOLFOX response in colorectal cancer patients.”  Br J Clin Pharmacol.   69(1): 
58 - 66. 
 
Galon, J. et al.. (2006). “Type, density, and location of immune cells within human colorectal tumors  
predict clinical outcome.” Science. 313(5795): 1960-4. 
 
Goldberg, R.M., D.J. Sargent, et al. (2010) “Leveraging learning from a phase III colorectal  
cancer clinical trial: outcomes, methodology, meta-analysis and pharmacogenetics.” Trans Am 
Clin Climatol Assoc. 121: 21-32; discussion 32-3. 
 
Gremy, O., M. Benderitter, et al. (2008).  “Acute and persisting Th2-like immune response after 
fractionated colorectal gamma-irradiation.” World J Gastroenterol. 14(46):  7075-85. 
 
Hersh, E.M., et al. (2011). “A phase II multicenter study of ipilimumab with or without dacarbazine in 
chemotherapy-naive patients with advanced melanoma.” Invest New Drugs 29(3): 489-98. 
 
Inada, M., et al.. (2010)  “Associations between oxaliplatin-induced peripheral neuropathy and 
polymorphisms of the ERCC1 and GSTP1 genes.” Int J Clin Pharmacol Ther 48(11): 729-34. 
 

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Version Date: 08/25/2022 
 
 
  
 
 
 
Addendum 10 
171
Lamas, M.J. et al. (2011) “Use of a comprehensive panel of biomarkers to predict response to a  
fluorouracil-oxaliplatin regimen in patients with metastatic colorectal cancer.”  Pharmacogenomics.  
12(3): 433-42. 
 
Marsh, S. et al. (2001). “Polymorphism in the thymidylate synthase promoter enhancer region in  
colorectal cancer.”  Int J Oncol. 19(2):  383-6. 
 
McLeod, H.L. et al.. (2010) “Pharmacogenetic predictors of adverse events and response to  
chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal  
Intergroup Trial N9741.” J Clin Oncol 28(20): 3227-33. 
 
 
McWhinney, S.R. et al. (2009). “Platinum neurotoxicity pharmacogenetics.” Mol Cancer Ther 8(1): 10-6. 
 
Niu, N. et al. (20101) “Radiation pharmacogenomics: a genome-wide association approach to identify 
radiation response biomarkers using human lymphoblastoid cell lines.” Genome Res  20(11): 1482-92. 
 
Pages, F. et al.. (2005). “Effector memory T cells, early metastasis, and survival in colorectal cancer.” 
N Engl J Med. 353(25): 2654-66. 
 
Pare, L. et al. (2008a). “Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer  
patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy .” Br J Cancer. 99(7):  1050-5. 
 
Pare, L. et al. (2008b). “Transcription factor-binding sites in the thymidylate synthase gene: predictors of  
outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?”  
Pharmacogenomics J.  8(5):  315-20. 
 
Peggs, K.S., N.H Segal et al. (2007). “Targeting immunosupportive cancer therapies: accentuate the 
positive, eliminate the negative.” Cancer Cell 12(3): 192-9. 
 
Popanda, O. et al. (2009). “Genetic variation in normal tissue toxicity induced by ionizing radiation.”  
Mutat Res.  667(1-2):  58-69. 
 
Pugh, T.J. et al. (2009). “Sequence variant discovery in DNA repair genes from radiosensitive and  
radiotolerant prostate brachytherapy patients” Clin Cancer Res. 15(15):  5008-16. 
 
Ruzzo, A., et al.. (2007) “Pharmacogenetic profiling in patients with advanced colorectal cancer 
treated with first-line FOLFOX-4 chemotherapy.” J Clin Oncol. 25(10):  1247-54. 
 
Salonga, D. et al. (2000). “Colorectal tumors responding to 5-fluorouracil have low gene expression 
levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase.”  Clin 
Cancer Res.  6(4): 1322-7. 
 
Segal, N.H. et al. (2008). “Epitope landscape in breast and colorectal cancer.” Cancer Res. 68(3): 889-92. 
 
Sjoblom, T. et al.  (2006). “The consensus coding sequences of human breast and colorectal cancers.” 
Science. 314(5797): 268-74. 
 
Stadler, Z.K. et al. (2010)  “Genome wide association studies of cancer.” J Clin Oncol  28(27):  4255-67.  
PMID 20585100. 
 
 

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Addendum 10 
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Stoehlmacher, J. et al. (2004). “A multivariate analysis of genomic polymorphisms: prediction of clinical  
outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.”  Br J Cancer.  
91(2): 344-54. 
 
Tsavaris, N., et al.. (2010) Combined treatment with Bevacizumab and standard chemotherapy  
restores abnormal immune parameters in advanced colorectal cancer patients. Invest New Drugs. 
DOI 10.1007/s10637-010-9533-0 
 
Villafranca, E. et al. (2001). “Polymorphisms of the repeated sequences in the enhancer region of the  
thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal  
cancer.”  J Clin Oncol. 19(6): 1779-86. 
 
Wang Y., et al. (2009). “High quality copy number and genotype data from FFPE samples using 
molecular inversion probe (MIP) microarrays.” BMC Med Genomics 2: 8. 
  
Zhou, X. et al.. (2008) "Bayesian adaptive design for targeted therapy development in lung 
cancer--a step toward personalized medicine."  Clin Trials. 5(3):  181-93. 
 
 
 

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APPENDIX XIII: AJCC 7TH EDITION RECTUM CANCER STAGING  
AJCC 7th Edition Rectum Cancer Staging Definitions 
Source: The AJCC Cancer Staging Manual, 7th Edition (2010) published by Springer New York, Inc. 
 
Primary Tumor (T)  
TX  
Primary tumor cannot be assessed  
T0  
No evidence of primary tumor  
Tis  
Carcinoma in situ: intraepithelial or invasion of lamina propria1  
T1  
Tumor invades submucosa  
T2  
Tumor invades muscularis propria  
T3  
Tumor invades through the muscularis propria into pericolorectal tissues  
T4a  
Tumor penetrates to the surface of the visceral peritoneum2  
T4b  
Tumor directly invades or is adherent to other organs or structures 2, 3 
 
Regional Lymph Nodes (N) 4  
NX  
Regional lymph nodes cannot be assessed  
N0  
No regional lymph node metastasis  
N1  
Metastasis in 1–3 regional lymph nodes  
N1a  
Metastasis in one regional lymph node  
N1b  
Metastasis in 2–3 regional lymph nodes  
N1c  
Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues 
without regional nodal metastasis  
N2  
Metastasis in 4 or more regional lymph nodes  
N2a  
Metastasis in 4–6 regional lymph nodes  
N2b  
Metastasis in 7 or more regional lymph nodes 
 
Distant Metastasis (M)  
M0  
No distant metastasis  
M1  
Distant metastasis  
M1a  
Metastasis confined to one organ or site (for example, liver, lung, ovary, nonregional node)  
M1b  Metastases in more than one organ/site or the peritoneum  
 
Notes 
1 
Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal 
lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. 
 
2 
Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result 
of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion 
of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal 
location, direct invasion of other organs or structures by virtue of extension beyond the muscularis 
propria (that is, a tumor on the posterior wall of the descending colon invading the left kidney or lateral 
abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or 
vagina). 
 
3 
Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor 
is present in the adhesion, microscopically, the classification should be pT1-4a depending on the 
anatomical depth of wall invasion. The V and L classifications should be used to identify the presence 
or absence of vascular or lymphatic invasion, whereas the PN site-specific factor should be used for 
perineural invasion. 

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4 
A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without 
histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous 
invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes 
should be counted separately as positive nodes in the N category, whereas discontinuous spread or 
venous invasion should be classified and counted in the Site-Specific Factor category Tumor Deposits 
(TD). 
 
Anatomic Stage/Prognostic Groups: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: cTNM is the clinical classification, pTNM is the pathologic classification.  
Stage 
ypT 
ypN 
M 
0 
Tis 
N0 
M0 
I 
T1 
T2 
N0 
N0 
M0 
M0 
IIA 
T3 
N0 
M0 
IIB 
T4a 
N0 
M0 
IIC 
T4b 
N0 
M0 
IIIA 
T1-T2 
T1 
N1 or N1c 
N2a 
M0 
M0 
IIIB 
T3-T4a 
T2-T3 
T1-T2 
N1 or N1c 
N2a 
N2b 
M0 
M0 
M0 
IIIC 
T4a 
T3-T4a 
T4b 
N2a 
N2b 
N1-N2 
M0 
M0 
M0 
IVA 
Any T 
Any N 
M1a 
IVB 
Any T 
Any N 
M1b 

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APPENDIX XIV: INDEX OF ACRONYMS  
Index of Acronyms (in alphabetical order): 
 
2PC 
Second primary colorectal cancer 
5-FU 
5-Fluorouracil 
ACOSOG 
American College of Surgeons Oncology Group 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
AERS 
Adverse event reporting system 
AJCC 
American Joint Committee on Cancer 
AKA 
Also known as 
AML 
Acute Myelocytic Leukemia 
ANC 
Absolute neutrophil count 
APR 
Abdominaloperineal 
ASCO 
American Society of Clinical Oncology 
ATC 
Advanced Technology Consortium 
BDP 
Bi-dimensional product 
BP 
Blood pressure 
BWH 
Brigham and Women’s Hospital 
CALGB 
Cancer and Leukemia Group B 
CDUS 
Clinical Data Update System 
CEA 
Carcinoembryonic antigen 
CF 
Leucovorin Calcium 
CR 
Complete Response 
CRA 
Clinical research associate 
CRF 
Case report form 
CRM 
Circumferential resection margin 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTEP-AERS 
CTEP Adverse Event Reporting System 
CTMS 
Clinical trial management systems 
CTSU 
Cancer Trials Support Unit 
CTV 
Clinical target volume 
DCTD 
Division of Cancer Treatment and Diagnosis (NCI) 
DFCI 
Dana-Farber Cancer Institute 
DFS 
Disease Free Survival 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
ERUS 
Endorectal ultrasound 
FAME 
Foundation of Advanced Medical Education 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FOLFOX 
5FU + leucovorin + oxaliplatin 

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FSFI 
Female Sexual Function Index 
FTP 
File Transfer Protocol 
FUCMT 
5FU combined modality therapy 
GTV 
Gross tumor volume 
HRQL 
Health-related quality of life 
HUS 
Hemolytic Uremic Syndrome 
IIEF 
International index of erectile function 
IME 
Important medical events 
IMRT 
Intensity Modulated Radiation Therapy 
IND  
Investigational new drug 
IRB 
Institutional review board 
IROC 
Imaging and Radiation Oncology Core 
ITT 
Intention-to-treat 
IV 
Intravenous 
IVRS 
Interactive voice response system 
LAR 
Low Anterior Resection 
LLT 
Lowest Level Term 
LN 
Lymph node(s) 
MDS 
Myelodysplastic syndrome 
MIP 
Molecular Inversion Probe 
MRI 
Magnetic Resonance Imaging 
MSKCC 
Memorial Sloan-Kettering Cancer Center  
NAR 
Neoadjuvant Response Score 
NCCTG 
North Central Cancer Treatment Group 
NCI 
National Cancer Institute 
NCTN 
National Cancer Trials Network 
NE 
Not evaluated 
NED 
No evidence of disease 
NOS 
Not otherwise specified 
NSABP 
National Surgical Breast and Bowel Project 
OAR 
Organs at Risk 
OPEN 
Oncology Patient Enrollment Network 
OS 
Overall survival 
OSU 
Alliance Biorepository at Ohio State University  
OXAL 
Oxaliplatin 
PACS 
Picture archiving and communications system 
PBDP 
Post-Baseline Bi-Dimensional Product 
pCR 
Pathologic complete response 
PD 
Progressive disease 
PET 
Positron emission tomography 
PMB 
Pharmaceutical Management Branch 
PP 
Per-Protocol 
PR 
Partial Response 
PRO-CTCAE 
Patient-Reported Outcomes Version of the Common 
Terminology Criteria 

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PS 
Performance status 
PSR 
Protocol Specific Requirement 
PTV 
Planning target volume 
QARC 
Quality Assurance Review Center  
QOL 
Quality of Life 
REC 
Recurrence of disease 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPC 
Radiological Physics Center 
RRR 
R0 Resection Rate 
RSS 
Regulatory Support System 
RT 
Radiation therapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SD 
Stable disease 
SOC 
SYSTEM/ORGAN/CLASS 
SPEER 
Specific Protocol Exceptions to Expedited Reporting 
TLR 
Time to local recurrence 
TME 
Total Mesorectal Excision 
TRG 
Tumor Regression Grade 
UCSF 
University of California San Francisco 
ULN 
Upper limit of normal 
VOD 
Veno-occlusive disease 
 
 
 
 
 
 

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APPENDIX XV: SITE PREPARATION CHECKLIST 
Site Preparation Checklist 
 
This preparation checklist is intended to be a resource for site study teams to be used in conjunction with 
the official protocol document; it does not replace the official protocol. References to where the 
information may be located are included in parenthesis.   
 
 Is your site PI and study staff registered with CTEP and do they have active CTEP-IAM account(s)? 
(For assistance, please refer to protocol Section 6.0) 
 
 Is your site investigator an NCI registered investigator with an NCI investigator number? 
(For assistance, please refer to protocol Section 6.1) 
 
 Is your site IRB approved and activated? (Contact your site’s IRB office with questions.) 
 
 Did your site complete and submit documentation of the protocol specific requirement (PSR) to the 
CTSU Regulatory Office (one item is required BEFORE a site can open N1048)? 
 IRB approval of protocol   (Section 6.2) 
 
 Did your site complete and submit documentation of the following protocol specific requirements 
(PSRs) to the CTSU Regulatory Office (these two items can be done before OR after a site opens 
N1048)? 
 IMRT physics credentialing and/or 3D Conformal RT credentialing (Section 7.3) 
 PRO-CTCAE credentialing (Section 4.4.1 and Appendix V) 
 
 Is your study site listed as ‘approved’ in the CTSU RSS? (Log into the CTSU website; click the blue 
‘protocols’ tab. Click the beige ‘site registration’ tab. Enter your site CTEP code and the protocol 
number in the open text boxes and click GO. The website will indicate whether your site is approved 
or whether PSRs are still outstanding.) 
 
 Is your study staff registered/active with OPEN? (Section 6.2) 
 
 Has your study staff registered with and completed the training for RAVE? 
(You should automatically receive email invitations to activate your iMedidata account and/or join a 
site and study. Contact the CTSU Help Desk at 
if you did not receive the 
email invitations.) 
 
 Does your site have QOL Booklets on hand?  (Please order these using the “CTSU Supply Request 
Form” available at 
 
 
 Does your site have a system in place to collect, process, and ship blood and tissue specimens at the 
necessary time points?  (Please contact the clinical trial office at your site.) 
 
 Have you emailed 
to request log-in information for 
 the website that will enable you to electronically submit scans (MRI or 
CT) to the Alliance Imaging Core Lab? 
 

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APPENDIX XVI: IMAGE INTERPRETATION 
The following instructions should aid in the consistent interpretation of images. It is recognized that assessment 
of clinical staging based on imaging is necessarily inexact and involves estimation. Clinical staging should be 
estimated using the AJCC 7th edition criteria. The criteria set forth below are to foster consistency of interpretation 
across sites. 
 
1. Estimated radiographic tumor stage: T1, T2, T3, T4 Tumor length should be measured using calipers on the 
sagittal T2W image showing the greatest tumor extent craniocaudad. This may consist of several connecting 
vectors to follow the curvature of the rectum. Tumor width will be measured on sagittal T2W images as the 
greatest wall thickness (1-wall); a bi-dimensional product will be calculated.  
 
2. Estimated radiographic nodal stage will be derived from preoperative imaging procedures using the AJCC 7th 
edition staging criteria. It is essential to note that this categorical system (e.g., N0, N1, N2) (AJCC 7th edition) 
is designed to record pathologic staging at the time of surgical resection. Its application and use in clinical 
rectal cancer staging is necessarily imprecise and numerous studies have documented the fact that large nodes 
may be tumor free and small nodes may contain tumor.  
 
3. The total number of nodes to determine stage (N1 = 1-3, N2 = 4 or more) will include mesorectal and superior 
rectal stations.  
 
4. Final analysis criteria will be short axis measurement with nodes positive at any size N1=1-3, N2=4 or more. 
Changes in short axis must be applied only to evaluable nodes (5mm or greater) and include 3mm or more (5-
10mm baseline), 4mm (11-19mm baseline) or 25% (20mm or more). These changes will constitute PD 
(modification of RECIST 1.1 as defined for this protocol). Diminutive nodes (<5mm) are not considered. 
 
5. Internal iliac nodes are uncommonly affected and more closely follow size changes and minimum size 
requirements as for other nodes outside of the mesorectal and superior rectal regions. Therefore, for evaluation 
of change after treatment, a node must have been 1.0 cm in short axis and increase by the rules above for PD. 
 
6. Nodal stations considered suspicious for metastatic disease (M1) (AJCC 7th edition) are for rectal cancer: 
common iliac, external iliac nodes and inguinal nodes. Also bone metastases and peritoneal tumor implants.  
 
7. Distance of the tumor from the mesorectal fascia reflection (AKA radial margin, AKA CRM or circumferential 
resection margin). A distance of 1 mm or less will be considered to have close/threatened radial margins and 
are ineligible.  
 
8. Radiographic N2 status is estimated as: 4 or more nodes that measure 10mm or more in short-axis. 
Radiographic N1 status is estimated as: fewer than 4 lymph nodes that measure 10 mm or greater in short axis 
but 1 or more lymph nodes that measure 5 mm or greater. 
 
 

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APPENDIX XVII: SWISS SPECIFIC APPENDIX 
 
Swiss Specific Appendix: Information only applicable to SAKK site participants that are full members of 
the Alliance.
 
 
 

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SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH 
 
 
 
SWISS SPECIFIC APPENDIX 
 
Version 1.2 – 02.12.2016 
 
N1048 (PROSPECT**) A Phase II/III Trial of Neoadjuvant 
FOLFOX with Selective Use of Combined Modality 
Chemoradiation versus Preoperative Combined Modality 
Chemoradiation for Locally Advanced Rectal Cancer Patients 
Undergoing Low Anterior Resection with Total Mesorectal 
Excision 
 
** Pre-operative Radiation or Selective Preoperative Radiation and Evaluation before 
Chemotherapy and TME 
 
Protocol Version Date: February 3, 2016 
 
The  purpose  of  this  appendix  is  to  specify  information  applicable  for  sites  within  the  SAKK 
participating in this trial. 
 
 
Coordinating Investigator 
for SAKK sites 
 
 
 
 
 
CRA 
 
 
 
 
Internet-based registration: 
Alliance 
 
Website: 
 
 
 
 
 
 
Internet-based SAE 
Alliance 
 
Reporting and Information: 
via CTEP-AERS system via: 
 

 
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1 
ABBREVIATIONS 
5-FU 
5-Fluorouracil 
BioMS 
Biospecimen Management System 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CTEP-AERS   CTEP Adverse Event Reporting System 
CTSU 
Cancer Trials Support Unit 
CV 
Curriculum vitae 
EC 
Ethics committee* 
FOLFOX 
5FU + Leucovorin + Oxaliplatin 
GCP 
Good Clinical Practice 
HMO 
Head of Monitoring 
Swiss HRA 
Swiss Human Research Act 
ICH 
International Conference on Harmonization 
ID 
Identification 
IMP 
Investigational Medicinal Product 
NCI 
National Cancer Institute 
OPEN 
Oncology Patient Enrollment Network 
OSU 
 Alliance Biorepository at Ohio State University 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAKK 
 
Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung and 
SAKK Coordinating Center (SAKK CC) 
SDV 
Source data verification 
SM 
Swissmedic 
SPC 
Summary of Product Characteristics 
SUVA 
 
Swiss National Accident Insurance Fund / 
Schweizerische Unfallversicherungsanstalt 
TME 
Total Mesorectal Excision 
 
 
 
*EC is known as Institutional review board (IRB) in the US. 

 
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TABLE OF CONTENTS 
1 ABBREVIATIONS 
2 
2 RANDOMIZATION AND PATIENT INCLUSION 
4 
2.1 
Randomization procedure 
4 
3 DRUG SUPPLY AND HANDLING 
4 
3.1 
Drugs / Radiotherapy / surgery in protocol 
4 
3.2 
Drug safety and handling 
4 
3.3 
Precaution 
5 
4 SAFETY REPORTING 
5 
4.1 
Definition of Serious Adverse Event (SAE) 
6 
4.2 
Reporting of SAEs via CTEP-AERS system 
6 
4.2.1 
Pregnancy 
6 
4.3 
Definition of Serious Adverse Drug Reaction (SAR) 
6 
4.4 
Definition of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
7 
4.5 
Reporting of SAEs to the Swiss ethics committee and competent authorities. 
7 
4.6 
Periodic reporting on safety to principal investigators and ethics committees. 
7 
5 DOCUMENTATION 
7 
5.1 
Case report forms 
7 
5.2 
Quality of Life (QOL) 
7 
5.3 
Capecitabine medication diary 
7 
5.4 
Patient screening, enrollment and identification list 
8 
6 TRANSLATIONAL RESEARCH 
8 
6.1 
Procedure (to be performed by the sites) 
8 
6.1.1 
Scheduling of sampling 
8 
6.1.2 
Shipment 
8 
6.1.3 
Labeling and handling 
8 
6.2 
Sample banking 
9 
7 ETHICAL CONSIDERATIONS 
9 
7.1 
Patient information and informed consent 
9 
7.2 
Data confidentiality 
9 
7.3 
Trial categorization 
9 
8 ADMINISTRATIVE CONSIDERATIONS 
9 
8.1 
Insurance 
9 
8.2 
Monitoring and auditing 
10 
8.2.1 
Monitoring / auditing strategy 
10 
8.2.2 
Auditing / Inspections 
10 
8.3 
Trial activation procedure 
10 
8.4 
Protocol specific requirements (to be performed by the site) 
10 
8.5 
Activation requirements by SAKK CC (to be performed by sites) 
10 
8.6 
Local trial records 
11 
8.6.1 
Investigator’s file 
11 
8.6.2 
Useful tools 
11 
8.6.3 
Record retention 
11 
9 REFERENCES 
12 

 
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2 
RANDOMIZATION AND PATIENT INCLUSION 
 
2.1 
Randomization procedure 
 
Patient registration and randomization procedures are explained in detail in the protocol section 
6.3. 
 
 
3 
DRUG SUPPLY AND HANDLING 
 
3.1 
Drugs / Radiotherapy / surgery in protocol 
 
For this trial Fluorouracil, Leucovorin, Oxaliplatin and Capecitabine are the IMPs. 
Fluorouracil (5-FU) is licensed in Switzerland for the use in malignant tumors of the rectum, colon, 
stomach, pancreas, liver, breast, uterus, cervix, ovary and the bladder. 
Leucovorin is licensed in Switzerland for the treatment of advanced colorectal cancer in 
combination with 5-FU. 
Oxaliplatin is licensed in Switzerland for the use in both curatively resected advanced (“adjuvant” 
setting) and metastatic colorectal cancer in combination with Leucovorin and 5-Fluorouracil. This 
combination builds up the FOLFOX treatment regimen, which is now a standard in the treatment of 
colorectal cancers, showing high response rates [1]. 
In daily clinical practice FOLFOX is used to treat patients with metastatic rectal cancer and to 
bridge the time between first patient visit and start date of radiotherapy, as the latter is frequently 
delayed due to planning and scheduling issues. Small series [2], [3], [4] have reported response of 
the primary tumor before surgery, thus confirming clinical experience 
Capecitabine is licensed in Switzerland for the treatment of colorectal, esophageal, gastric and 
breast cancer. Capecitabine and 5-Fluorouracil are equally effective in the treatment of colorectal 
cancer. 
Especially in Europe, Capecitabine concomitant to radiotherapy is a treating standard [5], [1]. 
Recent trials in rectal cancer, a German [6] and an American study [7], confirm the effectiveness 
and safety of chemoradiotherapy with Capecitabine. 
For more details (e.g. regarding the treatment and dose levels with the IMPs) refer to the protocol 
section 7.0. 
 
Surgical considerations 
Photo documentation of every TME specimen is required and will be reviewed by the Surgical 
Quality 
Committee. 
These 
photos 
should 
be 
sent 
electronically 
to 
 within 2 weeks. For more details please refer to the 
Appendix VII of the protocol. 
 
3.2 
Drug safety and handling 
 
Handling and safety 
Leucovorin and Fluorouracil are applied within its approved indication and Capecitabine and 
Oxaliplatin according to standard of care. Therefore drugs will be prescribed by the investigator. 
For handling refer to the product information. SUVA guidelines on handling on cytostatics [8] and 
radiopharmaceuticals [9] have to be followed. 
Oxaliplatin, Leucovorin and 5FU are administered intravenously. Capecitabine will be taken orally. 

 
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Labeling, dispensing and accountability of Oxaliplatin, Leucovorin and 5FU 
For Oxaliplatin, Leucovorin and 5FU, which will be administered intravenously at the hospital, the 
SAKK will provide labels. It is the responsibility of the local pharmacist or designee to label each 
package of trial drug with the additional trial-specific label before dispensing Oxaliplatin, 
Leucovorin and 5FU. Each package will be labeled in English, stating the trial reference code, 
patient study ID, the contact details of the sponsor representative SAKK as well as the remark “for 
clinical trial use only”. The patient study ID has to be written on the label of the package before the 
study drug is dispensed to the patient. 
The principle investigator or designee has to ensure the use of the drug inventory log for Oxaliplatin, 
Leucovorin and 5FU, which must be kept up-to-date and identify the receipt and dispensing of 
the drug (including date, amount, batch number, patient study ID). If sites already have their own 
accounting system, it may be used instead of the SAKK drug inventory log only after inspection 
and approval by the CRA. 
Drug inventory logs are available from the SAKK website under the section useful tools 
 
Labeling, dispensing and accountability of Capecitabine 
For the medication Capecitabine, which is taken at home by the patient, the SAKK will provide 
labels. It is the responsibility of the local pharmacist or designee to label each package of trial drug 
with the additional trail-specific label before dispensing Capecitabine to the patient. 
Each package will be labeled depending on the local language in German, French and Italian, 
stating the trial reference code, patient study ID, the contact details of the sponsor representative 
SAKK, as well as the remark “for clinical trial use only”. The study drug must be dispensed in the 
original package with the label clearly visible. The patient study ID has to be written on the label of 
the package before the study drug is dispensed to the patient. 
Patients will be instructed to note the date of the drug intake in a diary (available on the SAKK 
website) and to return empty packages or unused medication (see also 5.3.). 
The principle investigator or designee has to ensure the use of the drug inventory log for 
Capecitabine, which must be kept up-to-date and identify the receipt and dispensing of the drug 
(including date, amount, batch number, patient study ID). If sites already have their own accounting 
system, it may be used instead of the SAKK drug inventory log only after inspection and approval 
by the CRA. 
Drug inventory logs are available from the SAKK website under the section useful tools. 
 
3.3 
Precaution 
 
In order to exclude a pregnancy before treatment start of women with child bearing potential, either 
and urine or a blood beta HCG test must be used. 
Women with child-bearing potential who take part in this trial must use effective contraception 
during the trial and 12 months thereafter. 
It can’t be excluded that the treatment damages the sperms. Therefore, to avoid procreation men 
should use effective contraception (condoms). In addition, the partner should use also an effective 
contraception method. The combination of barrier (e.g. condom) and hormonal (e.g. the pill) is 
recommended by most experts. 
If the partner gets pregnant during the trial or 12 months thereafter, please invite also the partner to a 
trial visit for an information exchange and ask permission to request information about the 
development of the pregnancy and the health of the baby. 
 
 
4 
SAFETY REPORTING 
(See protocol section 10.4 “Expedited Reporting Requirements”) 
 
As the SAKK is the Swiss sponsor representative of the trial, an agreement with the overall 

 
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sponsor Alliance was reached in such that serious adverse events (SAEs) (single cases) and 
pregnancy events have to be reported directly to Alliance and will be evaluated by Alliance. 
 
4.1 
Definition of Serious Adverse Event (SAE) 
 
In the trial protocol section 10.4 adverse events which will be considered as serious adverse 
events are explained in detail. Exceptions are described in the protocol section 10.4.1. 
In contrast to the reporting timeframes given in the protocol under section 10.4, all Swiss 
sites have to report all SAEs within 24 h to Alliance, without any exceptions. 
 
 
4.2 
Reporting of SAEs via CTEP-AERS system 
 
The evaluation of SAEs in this trial is to be based on CTCAE Version 4.0. SAE reporting will be 
done using the internet based CTEP-AERS system. Additionally all SAEs need to be reported on a 
Solicited Adverse Event Form. For further details please refer to the section 10.4 of the protocol. 
All SAEs must be immediately reported to Alliance via CTEP-AERS (within 24 hours of awareness of 
the SAE). 
 
Every Swiss SAE must be forwarded by email immediately (within 2 working days) by Alliance to 
the SAKK Coordinating Center for reporting to the Swiss authorities. The SAKK will forward all 
Swiss SAEs to the Swiss Coordinating Investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.1 
Pregnancy 
Pregnancy should be reported via CTEP-AERS. For further information refer to the trial protocol 
section 10.3.5. 
 
▪ 
NOTE: To be eligible for Prospect (N1048), the patient must not be pregnant or 
nursing at the time of enrollment and must be willing to employ adequate 
contraception during treatment (see protocol section 3.1) 
 
 
4.3 
Definition of Serious Adverse Drug Reaction (SAR) 
SARs are all SAEs considered to be related (possibly, probably, definitely) to the trial treatment. 
SAKK Coordinating Center 
Swiss Group for Clinical Cancer Research 
 
 
 
 
 

 
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4.4 
Definition of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
SUSARs are serious adverse reactions to the trial treatment. Drug related SUSARs are assessed 
as unexpected on the basis of the summary of product characteristics (SPC). 
 
4.5 
Reporting of SAEs to the Swiss ethics committee and competent 
authorities. 
The SAKK CC ensures that all reporting requirements according to applicable Swiss law are 
followed [10]. 
It is the responsibility of the SAKK CC to inform the local and Lead EC about fatal SAEs from 
Switzerland within 7 days. 
Alliance will evaluate if the SAE of a Swiss patient qualifies as a Serious Unexpected Adverse 
Reaction (SUSAR) and if so forwards all relevant information to the SAKK CC. The SAKK CC 
reports any SUSAR which occurred on the trial at a Swiss site to the PIs, Lead and local EC as 
well as to Swissmedic. The timelines for reporting are specified in the Swiss HRA and its ordinances. 
 
 
4.6 
Periodic reporting on safety to principal investigators and ethics 
committees. 
 
Alliance will make the annual study summary report available to SAKK CC. This annual study 
summary contains a listing of adverse events grade ≥ 3, which are at least possibly related to the 
treatment. This report will be available on the CTSU website. SAKK CC will provide this summary 
together with Swiss specific information to the investigators, to the local and lead EC and Swissmedic. 
 
 
5 
DOCUMENTATION 
 
5.1 
Case report forms 
All participant sites will submit study data electronically using the iMedidata Rave® System 
). A detailed submission table of data can be found in the protocol section 17. 
 
5.2 
Quality of Life (QOL) 
QOL will not be assessed in the Swiss cohort. The protocol section 4.5 and the Appendix VI do 
therefore not apply to Swiss sites. 
 
5.3 
Capecitabine medication diary 
Patients who receive Capecitabine have to complete the Capecitabine medication diary. 
The diary will be completed during the entire period of radiation and capecitabine therapy. This 
lasts usually for 5.5 weeks but may be longer for any reason. 
The diary  is  available  on  
  → Members  → Trials  → Gastrointestinal  Cancers→ 
Prospect → Patient Diary. 

 
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5.4 
Patient screening, enrollment and identification list 
Sites must use a patient screening and enrollment list and a patient identification list in order to 
allow identification of a patient (available from the SAKK website: 
 → Members → 
Trials → Gastrointestinal Cancers → Prospect → Useful tools). 
Patients will be identified with a patient study ID and the date of birth. These lists must be kept up 
to date at the site in the Investigator’s File (IF). 
 
 
6 
TRANSLATIONAL RESEARCH 
 
The translational research part of the PROSPECT study attempts to understand the molecular 
events related to tumor treatment using genomic characterizations, immunologic studies and 
pharmacogenomics. 
For this purpose, tumor material from baseline biopsy and from surgical resection, as well as whole 
blood samples are mandatory and will be sampled for both Group 1 and Group 2 patients. 
 
6.1 
Procedure (to be performed by the sites) 
No tube or shipping material will be provided by the SAKK CC or by the Alliance. All sites should 
use their own material (for details see section 14 of the protocol). 
 
 
6.1.1 
Scheduling of sampling 
The collection of tumor tissue samples and blood samples is a mandatory part of this trial. 
Scheduling as well as further information can be found in the protocol section 14.0. 
6.1.2 
Shipment 
Shipment of blood and tissue samples will be done separately. 
 
Blood samples 
Guidelines and more information for blood samples of Swiss sites can be found on the SAKK 
website: 
 → Members → Trials → Gastrointestinal Cancers → Prospect → Useful 
tools. The blood samples at baseline should be withdrawn only on Monday and Tuesday before 
the treatment starts. It has to be shipped to USA on the same day in order to reach the Pathology 
Department at the latest on Friday. 
 
Tumor block samples 
Sites will register the collected biospecimen with the BioMS system and send the tumor specimens 
directly to OSU by TNT/Swiss Post mail using a padded envelope. 
 
Costs 
Costs for shipment of the blood and tissue samples will be covered by the SAKK CC. 
 
 
6.1.3 
Labeling and handling 
All blood samples have to be clearly labeled according to the protocol section 14.4. 
 
All tumor tissue samples have to be clearly labeled according to the protocol section 14.3. 
The submission of paraffin blocks is described in detail in the section 14.5 of the protocol. 
All the specimen need to be logged and shipped via Alliance Biospecimen Management System 
(BioMS), for details see the trial protocol section 14.2. 

 
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6.2 
Sample banking 
Sampling of blood and tumor blocks is a mandatory part of this trial. The banking of the rest of the 
samples at Alliance Biorepository at OSU, according to the Biobank regulations [11], for future 
research is an optional part for which the patient has to give an additional consent (IC for Translational 
Research). 
The patient retains the right to have the sample material destroyed at any time by contacting the PI 
without giving any reasons. However, already obtained data from this material can be used for 
intended analysis. Alliance is responsible for the destruction of the sample(s) at the request of the 
research patient through the principal investigator or at the end of the storage period. The PI will 
provide the Alliance with the required trial and the patient’s study ID, so that any remaining tissue 
sample and any other components from the cells can be located and destroyed. 
Any new analysis on these samples not planned in the protocol Prospect has to be approved by 
the Alliance board and by the responsible Ethics committee according to local law. 
 
7 
ETHICAL CONSIDERATIONS 
This trial is to be performed in accordance with the Declaration of Helsinki, the Guidelines of Good 
Clinical Practice issued by ICH, and Swiss regulatory authorities requirements [12-15]. 
Before planning to enter any patients into this trial, the investigator has to make sure that the trial 
has been approved by the EC and Swissmedic and that his/her site has officially been opened by 
the SAKK CC (see chapter 8.5). 
 
7.1 
Patient information and informed consent 
There are two Informed consents for this trial: One for the main trial and an additional for the 
sample banking of blood and tissue material (Biobank). 
 
7.2 
Data confidentiality 
The personal information and the medical records of the patients will be kept private. The data will 
be anonymized with a code. The code(s) shall be kept secret and confidential by the principal 
investigator. Only anonymized data will be accessible to experts for scientific evaluation. During 
inspections professionals selected and designated by the sponsor and members of Swiss authorities 
may examine patient’s medical history. 
Identifiable personal details won’t be published in study reports and publications. The sponsor is 
responsible for compliance of the data protection with the national and international guidelines. 
 
 
7.3 
Trial categorization 
The trial is classified as a Category B in accordance with the new legal ordinance on clinical trials 
with investigational medicinal product (IMP) [13]. 
 
 
8 
ADMINISTRATIVE CONSIDERATIONS 
 
8.1 
Insurance 
The SAKK will indemnify patients included from Swiss centers for damages they have suffered as 
participants in the trial. For this purpose SAKK has taken out a special insurance for clinical trials 
with CHUBB, Insurance Company of Europe, UK. 

 
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8.2 
Monitoring and auditing 
Source data must be accessible for monitoring and auditing. 
 
 
8.2.1 
Monitoring / auditing strategy 
This trial will be monitored / audited by SAKK CC. SAKK will perform auditing as requested by 
Alliance. Alliance will perform the first audit of one Swiss site (probably the highest recruiting site) 
and will during this audit train SAKK CRAs who will perform thereafter audits according to Alliance 
guidelines for further Swiss sites. In addition to participating sites, Alliance has also the option to 
audit the SAKK CC. 
A trial initiation will be performed on site, before the enrollment of the first patient. At least two 
monitoring visits per site are planned, if patients are accrued at the site into the trial. The frequency of 
the visit will be adjusted according to the site recruitment, the monitoring tasks and the findings at a 
site. Extent of source data verification, topics to be audited as well as all the duties of the CRA during 
the visit are described in the monitoring plan. No monitoring is foreseen during the follow-up phase. 
The CRA must provide all monitoring reports for review to the Head of Monitoring (HMO) within 2 
weeks of the visit. After the review by HMO, the CRA forwards the reports to Alliance and keeps 
the original reports accessible for other involved persons. 
 
 
8.2.2    Auditing / Inspections 
Authorities have the right to perform inspections and SAKK CC as well as Alliance has the right to 
perform audits. 
 
 
8.3 
Trial activation procedure 
The activation of a site covers the fulfillment of different steps. The sites have to obtain an NCI ID / 
CTEP ID, must register all investigators, get access to OPEN, RAVE and CTEP- AERS systems. 
Further information is available in the Appendix XV of the protocol. A guideline to all of the above 
mentioned points is available on the SAKK website: 
→ Members → Trials → 
Gastrointestinal Cancers → Prospect → Useful tools. 
 
 
8.4 
Protocol specific requirements (to be performed by the site) 
Patients may not be registered to this trial, until the protocol specific requirements have been 
submitted to the CTSU Registration Office as described in the protocol section 6.2. 
 
▪ 
Note: PRO-CTCAE assessments will not be done in Swiss cohort of patients: the 
protocol specific requirement as described in the protocol section 4.4 is thus void 
for Swiss study sites. 
 
8.5 
Activation requirements by SAKK CC (to be performed by sites) 
To become activated, sites have to fulfill both the activation requirements of Alliance and those of 
SAKK. 
 
Prior to activation, investigators have to submit the following documents to the SAKK CC: 
• 
The signed and dated Principal Investigator’s Agreement, indicating that they will fully comply 
with the protocol, including an estimation of their annual accrual and additional items 
• 
Signed and dated sign-off page of the protocol by the principal investigator 

 
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• 
Signed and dated CV of the principal investigator (not older than 2 years), including proof of 
GCP training 
• 
The signed and dated radiation oncologist’s agreement and the signed and dated CV of the 
radiation oncologist (not older than 2 years) 
• 
The signed and dated surgeon’s agreement and the signed and dated CV of the surgeon (not 
older than 2 years) 
• 
Staff list 
• 
Infrastructure statement 
 
After both Alliance and SAKK activation steps were taken and after the successful initiation 
visit and having received EC and Swissmedic authorization, the site will receive an opening 
e-mail from the SAKK. 
Please note, that only thereafter the site can include the first patient to the study. 
 
8.6 
Local trial records 
8.6.1 
Investigator’s file 
All trial-related documentation and correspondence should be filed in the investigator’s file. A 
suggested table of contents (according to ICH E6, chapter 8) is provided on the website 
(
 → Members → Trials → Gastrointestinal Cancers → Prospect→ Useful tools). 
 
 
8.6.2 
Useful tools 
Useful tools can be downloaded from our website (
→ Members → Trials → 
Gastrointestinal Cancers → Prospect → Useful tools). 
8.6.3 
Record retention 
 
The site will retain all essential documents according to ICH GCP. This includes copies of the 
patient trial records, which are considered as source data, CRFs, patient informed consent statement, 
laboratory data and printouts and all other information collected during the trial as well as all 
necessary documentation requested by Alliance and SAKK for the site activation. These 
documents will be stored for at least 10 years after the termination of the trial. The end of this 
retention period will be communicated to the sites by the SAKK CC. 
For the patient trial records, which are entered into the EDC system, the sponsor guarantees the 
access and availability of the data at any time at least 15 years after the termination of the trial. 
In the event that the investigator retires or changes employment, custody of the records may be 
transferred to another competent person who will accept responsibility for those records. Written 
notice of such transfer will be given to the SAKK CC. The SAKK CC will notify the relevant EC and 
the foreign group. 

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9 
REFERENCES 
 
1. 
Schmoll HJ,  V.C.E., Stein A,  Valentini V,  Glimelius B,  Haustermans K,  et  al., 
ESMO Consensus Guidelines for management of patients with colon and rectal 
cancer. a personalized approach to clinical decision making. Ann Oncol., 2012. 23 
(10): p. 2479-516. 
2. 
Suárez J, A.I., Vera R, Balén E, Gómez M, Lera JM., Pathologic response of primary 
rectal cancer to oxaliplatin-based chemotherapy. Clin Colon Rectal Surg. , 2011. 24 
(2): p. 119- 24. 
3. 
Chua YJ, B.Y., Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, 
Massey A, Tebbutt NC, Chau I., Neoadjuvant capecitabine and oxaliplatin before 
chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal 
cancer: a phase 2 trial. Lancet Oncol., 2010. 11 (3): p. 241-8. 
4. 
Schrag, D., Weiser, M.R., Goodman, K.A., Gonen, M., Cercek, A., Reidy,D.L., et 
al. , Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal 
cancer. ASCO Meeting Abstracts. 2010. 28 (15_suppl): 3511. 
5. 
Glimelius B, P.L., Cervantes A; ESMO Guidelines Working Group., Rectal cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol., 2010. 21 (5): p. v 82-6. 
6. 
Hofheinz RD, W.F., Post S, Matzdorff A, Laechelt S, Hartmann  JT, Müller L, 
Link H, Moehler M, Kettner E, Fritz E,  Hieber  U,  Lindemann HW, Grunewald M,  
Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, 
Hochhaus A., Chemoradiotherapy with capecitabine versus fluorouracil for locally 
advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. 
Lancet Oncol. , 2012. 13 (6): p. 579-88. 
7. 
M. S. Roh, G.A.Y., M. J. O'Connell, R. W. Beart, H. C. Pitot, A. F. Shields, et al., 
The impact of capecitabine and oxaliplatin in the preoperative multimodality 
treatment in patients with carcinoma of the rectum: NSABP R-04. ASCO Meeting 
Abstracts, 2011. 29 (15 suppl.)(3503). 
8. 
SUVA, Schweizerische Unfallversicherungsanstalt: Sicherer Umgang mit 
Zytostatika/Sécurité dans l'emploi des cytostatiques. 2004. 6. 
9. 
Strahlenschutzverordnung (StSV) vom 22. Juni 1994 (Stand 1. Januar 
2008)/Ordonnance sur la radioprotection (ORaP) du 22 juin 1994 (Etat le 1er 
janvier 2008); http://www.admin.ch/ch/d/sr/8/814.501.de.pdf. 
10. 
Swiss Human research Act of 30 September 2011 (HRA / HFG/ LRH; SR 810.30) 
(*ordinance on clinical trials on research involving humans of 20 September 2013 
(KlinV / OClin; SR 810.305); *Ordinance on projects on research involving humans 
not considered as clinical trials of 20 September 2013 (HFV / ORH; SR 810.301); 
*Organisational ordinance of 20 September 2013 (OV-HFG / OrgLRH; SR 810.308)) 
http://www.admin.ch/opc/de/official-compilation/2013/index_41.html. 
11. 
Biobank regulations for the Trial: N1048 – (PROSPECT**) - A Phase II/III Trial of 
Neoadjuvant FOLFOX with Selective Use of Combined Modality Chemoradiation 
versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal 
Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision; 
** Pre- operative Radiation Or Selective Preoperative radiation and Evaluation 
before Chemotherapy and TME. 
12. 
Declaration of Helsinki (as amended by the 64th General Assembly Fortaleza,  
Brazil, October 2013; http://www.wma.net/en/30publications/10policies/b3/index.html. 
13. 
Swiss Human Research Act, Amtliche Sammlung des Bundesrechts, Ausgabe Nr. 41 

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vom 
22. Oktober 2013, http://www.admin.ch/opc/de/official-compilation/2013/index_41.html. 
14. 
Heilmittelgesetz, HMG Bundesgesetz über Arzneimittel und Medizinprodukte 
(Heilmittelgesetz, HMG) vom 15. Dezember 2000/Loi fédérale sur les médicaments 
et les dispositifs médicaux (Loi sur les produits thérapeutiques, LPT) du 15 
décembre 2000; (http://www.admin.ch/ch/d/sr/8/812.21.de.pdf). 
15. 
International Conference on Harmonization (ICH) (1996) E 6 Guideline for Good 
Clinical Practice; (http://www.ich.org/LOB/media/MEDIA482.pdf).