SHORT: SHOrt Course Radiation and TASOX (TAS102 Plus Oxaliplatin) Chemotherapy in Operable Rectal Cancer, a Phase II Trial
Phase: PHASE2
Conditions: Rectal Cancer
Sponsor: Providence Health & Services

 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
 
SHORT: SHOrt course Radiation and TASOX (TAS102 plus Oxaliplatin) chemotherapy in 
operable rectal cancer, a phase II trial. 
 
Clinical Trial Protocol No: 
CRP18085 
 
Protocol Version #: 
4.0 
 
Protocol Date: 
 
June 20, 2023 
 
Development Phase:  
 
 
II 
Sponsor:  
Providence Cancer Institute 
 
 
Sponsor Address:                     
 
 
 
Source of Agent: 
 
 
 
Protocol History 
 
Original: Version 3.0, dated June 14, 2022 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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Principal Investigators: Hagen Kennecke, MD 
Medical Oncology 
Providence Cancer Institute 
 
Sub-Investigators: Lisa Kachnic, MD 
Radiation Oncology 
Columbia University Irving Medical Center 
 
Jason A. Zell, DO, MPH 
Medical Oncology 
HH Chao Family Comprehensive Cancer Center 
University of California, Irvine 
 
Huong Pham, MD 
Radiation Oncology 
Virginia Mason Medical Center 
 
Val Simianu, MD 
Colorectal Surgery 
Virginia Mason Medical Center 
 
Joseph C Carmichael, MD 
Colorectal Surgery 
HH Chao Comprehensive Cancer Center 
University of California, Irvine 
 
Howard Hochster, MD 
Medical Oncology 
Rutgers Cancer Institute of New Jersey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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Contents 
1.0 BACKGROUND 
5 
1.1 Current therapy for stage II/III rectal cancer .............................................................. 5 
1.2 Potential Role for Neoadjuvant combination TAS102 plus Oxaliplatin (TASOX). .. 5 
1.3 Study Overview ................................................................................................................ 7 
2.0 OBJECTIVES 
8 
2.1 Primary Objective ........................................................................................................... 8 
2.2 Secondary Objective ........................................................................................................ 8 
2.3 Study Schema ................................................................................................................... 8 
3.0 REGISTRATION 
9 
3.1 Inclusion Criteria ............................................................................................................ 9 
3.2 Exclusion Criteria ............................................................................................................ 9 
4.0 SCHEDULE OF TESTS 
11 
5.0 REGISTRATION PROCEDURES 
12 
6.0 PROTOCOL TREATMENT 
13 
6.1 Radiation Therapy ........................................................................................................ 13 
6.2 Pre-Operative TASOX .................................................................................................. 19 
6.2.1 TAS102 
19 
6.2.2 Number of Tablets per Dose 
19 
6.2.3 Instruction to Patients for Handling Study Medication 
20 
6.3 Oxaliplatin ...................................................................................................................... 20 
6.4 Surgical Therapy ........................................................................................................... 21 
7.0 RADIOLOGIC IMAGING 
22 
8.0 SUGGESTED DOSAGE MODIFICATION BASED ON ADVERSE EVENTS 
22 
8.1 TASOX chemotherapy .................................................................................................. 23 
8.1.1 TAS-102 Dose Reduction Levels 
23 
8.1.2 Oxaliplatin Dose Reduction Levels 
25 
8.1.3 Dose Hold, Resumption and Modification in Response to Hematologic Toxicities 25 
8.1.4 Dose Modification in Response to Febrile Neutropenia 
27 
8.1.5 Dose Modification in Response to Non-Hematologic Toxicities 
28 
9.0 ANCILLARY TREATMENT/SUPPORTIVE CARE 
29 
9.1 Concomitant medications and therapies. .................................................................... 29 

 
 
 
 
 
 
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9.2 Antiemetics ..................................................................................................................... 29 
9.3 Blood Products ............................................................................................................... 29 
9.4 Neulasta and Neupogen ................................................................................................. 29 
9.5 Diarrhea ......................................................................................................................... 29 
10.0 ADVERSE EVENT (AE) REPORTING AND MONITORING 
30 
10.1 Adverse Event Characteristics ................................................................................... 30 
10.2 Expected vs. Unexpected ............................................................................................. 30 
10.3 Reporting Clinical Safety Data To Taiho .................................................................. 30 
10.3.1 Reporting Clinical Safety Information toTAIHO Oncology 
31 
10.3.2 Drug Exposure During Pregnancy and Lactation, or Paternal Drug Exposure 
Reports 
31 
11.0 TREATMENT EVALUATION 
32 
11.1 Guidance for radiological tumor evaluation ............................................................. 32 
11.2 Pathological Tumor Response .................................................................................... 33 
11.3 Definition of Surgical Margin Status ......................................................................... 33 
11.4 Definition of pathologic stage ..................................................................................... 33 
11.5 Definition of Pathological Complete Response (pCR): ............................................ 33 
12.0 POST-OPERATIVE THERAPY 
34 
13.0 TAS102 DRUG INFORMATION 
34 
14.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY 
34 
14.1 Statistical justification ................................................................................................. 34 
14.2 Sample Size .................................................................................................................. 35 
15.0 Oversight and Quality Assurance Plan 
36 
15.1 Quality Assurance ....................................................................................................... 36 
16.0 References 
38 
APPENDIX I: Baseline staging and post-treatment MRI interpretation. 
41 
 
 
 
 

 
 
 
 
 
 
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1.0 BACKGROUND 
1.1 Current therapy for stage II/III rectal cancer 
Tri-modality therapy with chemotherapy, radiation and surgery leads to improved outcomes for 
stage II/III rectal cancer and neoadjuvant chemotherapy is the current treatment paradigm to 
reduce toxicity and improve treatment delivery (1). Pre-operative chemotherapy has been shown 
to be less toxic than similar therapy given post-operatively and result in significantly higher 
degrees of treatment completion (2,3) and improved overall survival (4).  
 
The optimal chemotherapy regimen for locally advanced tumors is not well-defined and differs 
for patients with intermediate risk, small tumor with clear circumferential radial margins (CRM), 
versus those with large, bulky tumors (NCCN and ESMO guidelines). Among patients with 
resectable tumors, short-course preoperative irradiation (25 Gy in five fractions of 5 Gy) is a 
standard option for stage II/III tumors and has been shown to be equivalent to chemoradiation 
(50.4 Gy in 28 fractions of 1.8 Gy, bolus 5-fluorouracil and leucovorin or continuous infusional 
fluorouracil 225 mg/m(2) per day) (5,6).  The Stockholm III study demonstrated that a delay in 
surgery after short-course radiation is safe and reduces operative morbidity compared to 
immediate surgery. (7) 
 
While current prospective trials are actively exploring novel treatments for different risk 
populations of rectal cancer, there are no trials of short-course radiation followed by novel 
systemic agents. Myerson et al (8) previously reported a 70% rate of downstaging to stage ypT0-
2 among 76 patients with stage II-IV rectal cancer treated with short-course pelvic radiation 
followed by 4 cycles of FOLFOX prior to definitive surgery. In the NRG TNT study 
(NCT02921256) patients with large (T4, N2) or low tumors and are treated with 8 cycles of 
intravenous (IV) FOLFOX followed by long-course chemoradiation and are randomized to 
investigational systemic agents given in combination with long-course chemoradiation.   
 
 
1.2 Potential Role for Neoadjuvant combination TAS102 plus Oxaliplatin (TASOX). 
Single agent TAS102. TAS-102 is a novel type of chemotherapeutic agent being an orally 
available two-drug combination of a 1M Trifluoridine (FTD, a thymidine-based nucleoside 
analogue), and 0.5 M Tipiracil Hydrochloride (TPI). Following uptake into cells through 
nucleoside transporters, FTD is converted to its monophosphate F3dTMP by thymidine kinase. 
After further phosphorylation steps, its triphosphate F3dTTP is incorporated into DNA as 
substitute for thymidine triphosphate.  In addition to its potent effects as an anti-metabolite as an 
inhibitor of thymidine synthase, FTD has additional effects causing DNA breaks (9, 10). TPI 
functions to inhibit degradation of FTD and thereby increases its bioavailability and TPI also 
exerts antiangiogenic effects by inhibiting thymidine phosphorylase (TP) (10).   
 
Two phase III studies have demonstrated the benefit of TAS102 in patients with metastatic 
colorectal cancer (mCRC) refractory or not candidates for standard therapy (11,12). Compared to 
placebo, TAS102 improved overall survival (OS) with a Hazard Ratio of 0.56 (CI 0.44-0.71) in 

 
 
 
 
 
 
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patients refractory to Fluorouracil, Oxaliplatin and Irinotecan. Therapy was well tolerated and 
the predominant grade 3/4 toxicities were neutropenia (50%) and anemia (17%) (11). Similar 
benefits were seen in a more advanced population of patients refractory to 5-Fluorouracil, 
Oxaliplatin, Irinotecan, Bevacizumab and epidermal growth factor rector inhibitor (EGFRi) 
therapy with an improvement in OS [Hazard Ratio 0.68 (0.58-0.81)] and similar, predominantly 
hematologic toxicities. The rate of febrile neutropenia was 4% (12).  
 
In a head-to- head trial against capecitabine, TAS102 was evaluated in TASCO1 
(ClinicalTrials.gov number: NCT02743221), a multicentre, randomized, open-label, phase 2 trial 
(13). Patients with mCRC were randomized to TAS102 plus bevacizumab (TAS102-B) or 
capecitabine plus bevacizumab (C-B) as first-line therapy. The primary endpoint was 
progression-free survival (PFS), based on investigator assessment of radiologic images, per 
RECIST 1.1 criteria. Median PFS was 9.2 months with TAS102-B and 7.8 months with C-B, 
giving a hazard ratio (HR) of 0.71 (95% confidence interval [CI] 0.48, 1.06) for TAS102-B 
versus C-B. Preliminary median OS was 18 months with TAS102-B and 16.2 months with C-B 
giving a HR of 0.56 (95% CI 0.32, 0.98) for TAS102-B versus C-B. In pre-planned sub-group 
analysis, an enhanced effect of TAS102-B over C-B was seen on PFS was seen in tumors arising 
in the left colon and rectum, HR 0.5 (95% CI 0.31-0.82).  
 
TASOX, Combination TAS102 and Oxaliplatin: Three phase I studies have established the 
safety of combination TAS102 and Oxaliplatin in mCRC (14-16) with the recommended dose of 
TAS102 35 mg/m2 po BID days 1-5 and oxaliplatin IV 85 mg/m2 on day 1 of a q2weekly cycle. 
In a dose escalation phase I, Hollebecque et al. (14) performed a two-part trial of 
trifluridine/tipiracil (FTD/TPI) plus oxaliplatin in patients with previously treated mCRC. A total 
of 17 patients were treated by at least one line of standard chemotherapy and the maximum 
tolerated dose (MTD) was FTD/TPI 35 mg/m2 BID with oxaliplatin 85 mg/m2. One DLT was 
reported at the MTD at which the patient experienced grade 3 febrile neutropenia. This patient 
recovered and continued with a decreased FTD/TPI dose of 30 mg/m2 BID. Patients received a 
mean of 7.65 treatment cycles and stable disease was achieved in eight patients. One patient 
previously treated with mFOLFOX6 (folinic acid-fluorouracil-oxaliplatin) achieved a confirmed 
partial RECIST response.   
 
Calvo et al. (15) reported results from the dose-expansion phase on which 12 patients were 
administered TAS102 in combination with oxaliplatin with either nivolumab or bevacizumab. 
TAS102 35 mg/m2 was given BID on Days 1‒5, followed q2weekly, in combination with 
oxaliplatin 85 mg/m2 and either nivolumab 3 mg/kg or bevacizumab 5 mg/kg, all administered 
on Day 1. The disease control rate was 83.3% in the safety run-in period. Neutropenia was the 
most common grade 3-4 treatment-related AE reported. Three (25%) patients had AE related 
treatment interruptions, primarily due to neutropenia. Two patients reported oxaliplatin-related 
grade ≥ 2 neurotoxicity; one patient discontinued oxaliplatin therapy. Treatment-related deaths 
were not observed. Pharmacokinetic analysis revealed that FTD/TPI did not appear to be affected 
by co-administration of oxaliplatin. 
 

 
 
 
 
 
 
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In a third study (16), TASOX was dose-escalated in a 3+3 fashion starting at TAS102 25 
mg/m2 and escalating to 35 mg/m2  day 1-5 using a fixed dose of oxaliplatin 85 mg/m2 on day 1, 
q2weekly. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate 
biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. Among 12 
patients evaluable for dose limiting toxicity (DLT), no DLTs were observed. Treatment related 
grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in 
treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for 
prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease 
control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 
(59%) SD and 4 (33%) PD. 
 
The neoadjuvant benefit of TASOX in rectal cancer is unknown. While the most commonly 
chosen pre-operative therapy for stage II/III rectal cancer in North America remains capecitabine 
or 5-fluorouracil in combination with 50.4 Gy radiation, there is a lack of novel systemic agents 
being evaluated in the curative, neoadjuvant setting.  The documented efficacy of TASOX in 
both early and advanced line therapy for mCRC justifies its application in the neoadjuvant 
setting where the pathologic and clinical response rate offers an early estimate of treatment 
benefit.  
 
 
1.3 Study Overview  
The study investigators hypothesize that TASOX can be safely and efficaciously delivered after 
short course radiation, resulting in significant pathologic downstaging, allowing for an R0 pelvic 
resection, and providing local control in appropriately selected stage II/III rectal cancer patients 
treated with contemporary TME-based surgery. It is expected that 3 months (6 cycles) of 
TASOX at standard doses will allow total neoadjuvant therapy introducing a new systemic agent, 
a shorter duration of pre-operative radiation and timely delivery of pre-operative systemic 
therapy. It is anticipated that if this study meets its primary endpoint, the strategy will be 
prospectively compared to long-course chemoradiation with capecitabine and that the reduced 
duration of radiation and the introduction of a new systemic agent will improve outcomes for 
appropriately selected patients with stage II/III rectal cancer.  
 
In this phase II study patients will be treated with short-course preoperative irradiation (25 Gy in 
five fractions of 5 Gy) followed by 6 (six) 2-week cycles of TASOX followed by total 
mesorectal excision (TME) for patients with resectable rectal cancer (clinical T3c/dN0, T3c/dN1, 
T2N1). 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 low tumors who need an Abdominal-Perineal Resection (APR).   The primary measurement of 
efficacy will be the Neoadjuvant Rectal (NAR) score, a validated surrogate of local and systemic 
disease control in stage II/III rectal cancer (17).  
 

 
 
 
 
 
 
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Figure 1. NAR Score derivation. 
 
The required elements of the NAR score will be prospectively collected as defined in the 
protocol. 
 
2.0 OBJECTIVES  
2.1 Primary Objective 
The primary objective of this study is to determine whether pre-operative short-course radiation 
therapy (SRT) and 6 cycles of TASOX offers condensed radiation and total neoadjuvant therapy 
for intermediate risk rectal cancer. The primary endpoint is to achieve a reduction in 
Neoadjuvant Response (NAR) score compared to historic controls.  
 
2.2 Secondary Objective  
The secondary objective is to describe the adverse event profile and surgery complications 
among treated subjects. 
 
2.3 Study Schema 
 
 

 
 
 
 
 
 
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3.0 REGISTRATION 
3.1 Inclusion Criteria  
3.1.1 Age of at least 18 years. 
3.1.2 Newly diagnosis of rectal adenocarcinoma. 
3.1.3 ECOG Performance Status (PS): 0, 1 or 2. 
3.1.4 Candidate for sphincter-sparing surgical resection prior to initiation of neoadjuvant therapy 
according to the primary surgeon. 
3.1.5 Clinical Stage: T1/N1, T2/N1, T3/N1, T3 a/b/c/dN0. 
3.1.6 Absence of metastatic disease. 
• Clinical staging is based on physical exam by the primary surgeon, CT scan of the 
chest/abdomen, and pelvic MRI. 
• 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 8 mm or 
greater in short axis. 
• Radiographic N2 status is estimated as: 4 or more nodes that measure 8mm or more in 
short-axis. 
• Radiographic N1 status is estimated as: fewer than 4 lymph nodes that measure 8 mm or 
greater in short axis but 1 or more lymph nodes that measure 8 mm or greater. 
• Nodal Metastatic Disease: nodal stations considered suspicious for metastatic disease 
(M1) for rectal cancer are common iliac, external iliac and inguinal nodes. 
3.1.7 Ability to perform a curative intent sphincter-sparing TME resection at diagnosis.  
3.1.8 The following laboratory values obtained ≤ 28 days prior to registration. 
• 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 
3.1.9 Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing 
potential only. 
3.1.10 A patient of child-bearing potential is willing to employ adequate contraception. It 
includes any of the followings: abstinence, oral contraceptives, implantable hormonal 
contraceptives, or double barrier method (diaphragm plus condom). See exclusion criterion 3.2.8 
3.1.11 Provide informed written consent. 
3.1.12 Willing to return to enrolling medical site for all study assessments. 
 
3.2 Exclusion Criteria 
3.2.1 Clinical T4 tumors. 
3.2.2 Clinical N2 disease estimated as four or more lymph nodes that are ≥8 mm. 
3.2.3 Primary surgeon indicates need for abdominoperineal (APR) at baseline.  
3.2.4 Tumor is causing symptomatic bowel obstruction or patients who have had a temporary 
diverting ostomy are ineligible.  

 
 
 
 
 
 
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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 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 
3.2.8 Co-morbid illnesses or other concurrent disease which, in the judgment of the treating 
investigator 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. 
3.2.9 Patients with threatened radial margins, defined as tumors with distance of 1mm or less, 
or adherent to the mesorectal fascia. 
 
 
 

 
 
 
 
 
 
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4.0 SCHEDULE OF TESTS 
Test & procedures 
≤ 28 days 
pre-
registration 
≤60 days 
prior to 
therapy 
Prior to 
each cycle 
TASOX,  
- 3 days1 
Pre-op 
visit after 
completion 
of cycle 6 
TASOX, 
ie. ≤ 56 
days after 
day 14 , 
cycle 
68,10,12 
Post- 
Surgery 2-8 
weeks post -
op 
History and 
physical 
X 
 
x 
x 
x 
Pulse, BP and 
temperature 
X 
 
x 
x 
x 
ECOG 
 
 
x 
x 
x 
Weight  
X 
 
x 
x 
x 
Height 
X 
 
 
 
 
Adverse Events10 
 
 
x 
x 
 
Hematology2 
X 
 
x 
x 
 
Chemistry3 
X 
 
x 
x 
 
CEA 
X 
 
x 
x 
x 
Pregnancy test4 
X 
 
x– cycle #1 
only 
 
 
Pathology 
confirmation of 
rectal adenoca. 
 
x 
≤ 90 days 
 
 
 
Rectal exam and 
proctoscopy5 
 
x 
 
 
 
MRI of pelvis6,8 
 
x 
 
x 11,8  
 
CT Chest or chest 
Xray 7,8 
 
x 
 
 
 
CT of abdomen 
with contrast 7,8 
 
x 
 
 
 
Documentation of 
post-operative 
complications- see 
Section 6.4. 
 
 
 
 
x 
 
1. Recommendations for timing of therapy:  
- Radiation must commence within 3 weeks of study registration. 
- Chemotherapy with TAS-102 must begin within 1-3 weeks after completion of radiation. 

 
 
 
 
 
 
12 
 
- 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.  
4. Urine or serum pregnancy test per institutional standard required for females of childbearing 
potential ≤ 7 days of registration. 
5. Rectal exam and proctoscopy are ideally to be performed by the primary surgeon. Proctoscopy 
should be performed ≤ 90 days prior to registration or after registration but before the start of 
treatment. Proctoscopy may be accomplished using rigid proctoscopy or as part of a flexible 
sigmoidoscopy or colonoscopy. 
6. Pelvic MRI Scan, with or without contrast per treating investigator/institutional standards, is to 
be performed within 60 days prior to treatment start. Use same imaging modality throughout the 
study.  
7. A PET/CT scan may be performed in lieu of a CT scan with contrast, but a CT scan is 
preferred.  
8. 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.  
9. Recommendation: Surgery should be performed within 10 weeks AFTER the 6th cycle of 
neoadjuvant TASOX, and restaging investigations should be obtained within 8 weeks (56 days) 
AFTER day #14, cycle 6.  
10. Adverse Events form to be completed at the start of radiation therapy. 
11. Pelvic MRI should be booked within 56 days of completion of cycle #6 of TASOX, i.e. 
within 1-56 days AFTER day #14, cycle 6. 
12. Patients that achieve a complete or near complete Clinical Response (cCR or ncCR) may 
choose to pursue a course of watch and wait with agreement of their treating surgeon. A 
thorough discussion is recommended with their surgeon concerning the risks and benefits of 
watch and wait and both they and their physician agree with the intended approach. Patients that 
pursue a course of watch and wait remain evaluable on study and will be classified as having a 
ypT0N0 response for the purposes of the NAR score if they do not proceed to TME surgery 
within 24 months of completing cycle 6, day 14. 
 
5.0 REGISTRATION PROCEDURES  
To be completed after eligibility determination and at least 24 hours prior to first day of radiation 
therapy. It will be done by completing the registration form and emailing the following 
information to tas-short-communications@providence.org.   
 
All the following information will be required: 
• Name of institution. 
• Patient initials. 

 
 
 
 
 
 
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• Age. 
• Sex. 
• Race. 
• Date of diagnosis. 
• Informed consent signed date. 
• Projected treatment start date. i.e., start date of radiation therapy. 
 
6.0 PROTOCOL TREATMENT 
Therapy: Study schema is summarized in Section 2.3. Patients are initially treated with 25 Gy in 
five fractions of 5 Gy conformal pelvic radiation. Radiation is to be started within 3 weeks of 
registration. TASOX should be commenced within 3 weeks of radiation completion. Patients are 
treated with 6 x 14 day cycles of TASOX. Within 4 weeks of the end of cycle #6 of TASOX 
patients undergo re-staging. Surgery should be performed within 4 weeks AFTER day 14, 
cycle#6 of TASOX, i.e., 28 days after day 14, cycle 6. 
 
6.1 Radiation Therapy 
CT Simulation Techniques 
Prone position with use of a bowel displacement device ‘belly board’ is recommended and may 
be particularly advantageous for patients with a larger body habitus to improve small bowel 
sparing (Figure 2). At the time of simulation, placement of a radiopaque anal marker may be 
useful to determine the distance of the disease from the verge for contouring purposes. For 
males, it is important to pull the external genitalia center and downward. Oral contrast is 
recommended to be given approximately 30 minutes prior to simulation for better small bowel 
visualization. If oral contrast is used, the contrast needs to be overwritten to a normal density or 
planning needs to occur on a pre-contrast scan. Intravenous contrast may be useful in visualizing 
and contouring the elective nodal vessels, particularly in patients who are thin; however, more 
commonly, fusion with the patient’s CT with contrast staging study is used. For additional small 
bowel sparing, 16-20 oz of water should be administered PO 30 minutes before the CT for 
bladder filling,but remember to reproduce the same filling prior to each treatment. Additionally, 
it is important for the patient to maintain good regular bowel function in order to keep the rectum 
empty. Once the patient is appropriately positioned, CT images at 2-3 mm intervals from the 
upper lumbar spine to the mid-femur should be obtained. 
 

 
 
 
 
 
 
14 
 
Figure 2: Prone CT simulation using a belly board. Blue arrow delineates the gap in the 
prone belly board that allows for geometric displacement of small bowel. Yellow arrow 
shows that bladder filling may provide additional small bowel displacement.  
 
 
Target Volumes 
According to the International Commission on Radiological Units 50 guidelines, all target and 
normal tissue structures are contoured on the planning CT slices. Multiple consensus atlases now 
exist from the RTOG (18), Australasian Gastrointestinal Trial Group (19) and the EORTC (20) 
that illustrate target definitions with representative case examples. RTOG also has a pelvic 
normal tissue contouring atlas (21). When contouring the GTV, one should use all available 
clinical and radiographic information (digital rectal exam, endoscopy, pelvic MRI, and other 
imaging as available) including anal verge markers at the time of simulation. Include all 
macroscopic tumor in the GTV (primary, nodal GTV adjacent to the rectal wall and extramural 
vascular invasion) on each CT slice and any adjacent normal rectal wall on the same slice. 
Contouring of the GTV may be aided by registration of the diagnostic MRI (and/or pelvic CT 
with contrast and/or PET if available) in the treatment planning system. Other large nodal (> 1 
cm) disease that either shows increased uptake on PET or has abnormal architecture on CT may 
also be included in the GTV.  
 
Construction of the clinical target volume (CTV) of the primary tumor (CTV_2500) is performed 
by an isotropic expansion of 1.0 cm from the GTV. The CTV_2500 should include the entire 
GTV. This structure should be modified to account for the natural barriers of bone and muscle if 
the tumor does not involve these structures.  
 

 
 
 
 
 
 
15 
 
An elective nodal dose volume (CTV_2000) should be constructed that includes the CTV_2500 
and all elective nodal CTVs. Elective nodal CTVs include the entire mesorectum, internal iliac, 
and presacral lymph node regions. The CTV_2000 superior limit should be the more superior 
of 1 cm above the most superior limit of GTV, or the L5/S1 interspace. This structure should 
be modified to account for the natural barriers of bone and muscle if tumor does not involve 
these structures. Common errors in contouring the elective nodal volume include failure to 
correctly contour the entire extent of the mesorectum. When contouring the CTV_2000 internal 
iliac lymph node region, a 7 mm isotropic expansion around the vessels should be performed.  
When contouring the CTV_2000 presacral lymph node region, a 10 mm expansion in front of the 
sacrum should be performed. 
 
PTV_2500 and PTV_2000 are then constructed by placing a 5 mm isotropic expansion around 
the CTVs. If daily IGRT cannot be used (kV kV match or CBCT) or if 3-D planning is 
performed, PTVs should be developed using a 10 mm expansion around the CTVs. In contouring 
of the normal pelvic organs at risk (OARs), the small bowel, left femoral head, right femoral 
head, genitalia, bladder, pelvic bones, large bowel, and skin should all be outlined on each axial 
CT slice. The external contours of all pelvic bones, including iliacs, lumbosacral spine and lower 
pelvic bones, should be contoured together as a surrogate for pelvic bone marrow. Bowel should 
be drawn as individual loops without the intertwining mesentery from L3 down. The tissue 
within the skin surface and outside all other critical normal structures and PTVs is designated as 
unspecified tissue. Excellent definitions of normal pelvic organs may be found in the RTOG 
atlas (Gay 2012). A representative IMRT plan and radiation targets are shown in Figure 3.    
 
Although IMRT is preferred, if 3-D is performed, one can perform sequential plans (i.e. initial 
PTV_2000 over four days followed by a single boost fraction). 
 

 
 
 
 
 
 
16 
 
 
Figure 3. High dose distribution of 3D-CRT vs IMRT planning. This is a patient for whom 
prone positioning on belly board device did not displace bowel. Sagittal (A and C) and axial (B 
and D) views of 3D-CRT (A and B) and IMRT (C and D) plans are presented. The IMRT plan 
demonstrates reduction in high dose region to bowel and bladder. Dose color wash reflects 2000 
cGy in blue and 2500 cGy in red. 
 
Dosimetric Planning and Delivery 
Conformal radiation with IMRT is preferred using 6MV photon energy and either static field or 
VMAT, but 3-dimensional 6-18MV photon treatment will be allowed. Proton therapy is not 
allowed. When using VMAT, consider 270 degree arc fields to avoid a field directly entering the 
genitalia. IMRT is preferred as planning allows for differential doses to the gross disease, 
elective nodal regions and the OARs. The OARs used in optimization typically include the small 
bowel, femoral heads, genitalia, bladder, pelvic bones, and large bowel. In addition, when 
performing IMRT, all PTVs should spare non-target skin surfaces manually or automatically 
trimmed by 3-5 mm (unless there is skin involvement). For bone marrow sparing, pelvic bones 
including the iliac crests, lumbosacral spine, and lower pelvic bones should be contoured 

 
 
 
 
 
 
17 
 
together as a surrogate for pelvic bone marrow. Representative target dose coverage and normal 
tissue constraints are outlined in Table 2 and Table 3.  
 
Treatment planning priorities should be considered in order of decreasing importance:  
1. PTV_2500  
3. PTV_2000  
4. Small bowel 
5. Femoral heads 
6. Bladder 
7. Large bowel 
 
Of note, pelvic bone marrow and genitalia should be kept as low as possible. However, we do 
not have standard five fraction constraints for these organs.  
 
Table 2. Target Dose and Coverage Parameters 
 
Target 
Coverage 
Total Dose 
Max Point Dose 
(Gy) 
GTV 
100% of 
the 
volume to 
100% of 
the dose 
           25 Gy 
110% to be within 
GTV 
CTV_2500 
98% of 
the 
volume to 
100% of 
the dose 
  25 Gy 
110% to be within 
GTV 
PTV_2500 
95% of 
the 
volume to 
95% of 
the dose 
  25 Gy 
110% to be within 
GTV 
CTV_2000 
98% of 
the 
volume to 
100% of 
the dose 
 20 Gy 
110%  
PTV_2000 
95% of 
the 
volume to 
98% of 
the dose 
 20 Gy 
105% 
 

 
 
 
 
 
 
18 
 
 
Table 3. Normal Organs at Risk Treatment Planning Parameters for Rectal Cancer  
 
 
Organ at Risk 
 
Suggested Constraints 
Small Bowel  
V20 < 50cc 
max point dose 25 Gy 
Femoral Head (L) 
V20 < 10% 
Femoral Head (R) 
V20 < 10% 
Large Bowel 
V20 < 50cc 
max point dose 27 Gy 
Bladder 
V20 < 50cc 
max point dose 27 Gy 
Large Bowel 
V20 < 50cc 
max point dose 27 Gy 
 
For IMRT plans, patient specific quality assurance (QA) is highly recommended. QA is 
performed by delivering the plan onto a phantom or portal imager to measure the 2D/3D dose. 
Measured dose distribution will be compared to planned dose distribution using a Gamma 
criterion of 4% dose difference and 3 mm distance to agreement. The pass rate should be at least 
90% measured for the entire plan. 
 
Image-guided radiation therapy (IGRT): Patients should receive daily KV images for set up and 
treatment verification. Bone should be used as the surrogate. Corrections should be made for 
shifts of 3 mm or greater and recorded. Daily cone beam CT images (CBCTs), if available, may 
also be helpful and strongly recommended to evaluate the relationship of the CTV to the 
bladder/rectum and to verify male genitalia position.  
 
For IMRT systems where the isocenter is not defined (e.g., tomotherapy), setup verification 
images may consist of a series of axial CT images (megavoltage or kilovoltage) obtained over at 
least 5 cm length, to be compared with simulation CT images. It is recommended that there be an 
option to display target structures on the simulation images. It is also recommended that the 
setup verification images be obtained at levels where cephalocaudad positioning, as well as 
transverse positioning, can be verified. Appropriate levels would include either around the mid to 
upper sacrum or around the upper border of the acetabulae.  
 
Daily doses: PTV_2500 will receive 500 cGy daily x five fractions for a total of 2500 cGy to the 
gross cancer PTV over 5-7 days. Fractions should be consecutive but may be spread out over two 
weeks (i.e. over the weekend). The CTV_2000 will simultaneously receive 400 cGy daily x five 
fractions for a total of 2000 cGy to the elective nodal disease. While IMRT is strongly preferred, 
3-D planning with a sequential approach (PTV_2000 over four consecutive fractions followed by 
the PTV_2500 volume in one treatment as a boost of 500 cGy to the gross cancer PTV) is 

 
 
 
 
 
 
19 
 
allowed. There should be no treatment break. If a treatment break of more than 3 days is needed, 
please contact the study PI. No bolus should be used. 
 
 
6.2 Pre-Operative TASOX 
6.2.1 TAS102  
Each treatment cycle will be 14 days in duration.  TAS-102 dosage is calculated according to 
body surface area.   
One treatment cycle consists of the following: 
Days 1-5: 
TAS-102 (35 mg/m2/dose) orally BID 
Days 6-14: 
Rest 
Repeat for a total of 6 cycles. 
Study medication should be taken on Days 1-5.  If doses are missed or held on those days, the 
patient should not make up for missed doses.   
TAS-102 should be taken with a glass of water within 1 hour after completion of morning and 
evening meals.   
6.2.2 Number of Tablets per Dose 
Tablet calculation is presented in Table 2.  TAS-102 should only be given on Days 1 through 5 
of each cycle even if doses are missed or held for any reason during Days 1 through 5.   
 
Table 2: 
TAS-102 Tablets per Dose 
TAS-102 Dose 
(2x daily) 
BSA 
(m2) 
Dosage in 
mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
35 mg/m2 
< 1.07 
35 
70 
1 
1 

 
 
 
 
 
 
20 
 
TAS-102 Dose 
(2x daily) 
BSA 
(m2) 
Dosage in 
mg 
(2x daily) 
Total daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
1.07 - 1.22 
40 
80 
0 
2 
1.23 - 1.37 
45 
90 
3 
0 
1.38 - 1.52 
50 
100 
2 
1 
1.53 - 1.68 
55 
110 
1 
2 
1.69 - 1.83 
60 
120 
0 
3 
1.84 - 1.98 
65 
130 
3 
1 
1.99 - 2.14 
70 
140 
2 
2 
2.15 - 2.29 
75 
150 
1 
3 
≥2.30 
80 
160 
0 
4 
BSA=body surface area (calculate to 2 decimal places) 
 
 
6.2.3 Instruction to Patients for Handling Study Medication 
The patient must be instructed in the handling of study medication as follows: 
• To store the study medication at room temperature 
• To only remove from the study medication kit the amount of tablets needed at the 
time of dosing 
• To wash their hands after handling study medication 
• Not to remove doses in advance of the next scheduled dosing 
• To make every effort to take doses on schedule 
• To report any missed doses 
• To take study medication within 1 hour after completing a meal (morning and 
evening meal) with a glass of water 
• If the patient vomits after taking study medication, the patient should not take another 
dose 
• To keep study medication in a safe place and out of reach of children 
• To bring all used and unused study medication to the site at each visit 
 
6.3 Oxaliplatin  
 
Day 1: Oxaliplatin 85mg/m2 IV in 500 ml of D5W over 2 hours 

 
 
 
 
 
 
21 
 
 
Days 1-14: see TAS102 schedule. 
 
Repeat for a total of 6 cycles 
Oxaliplatin may be administered via peripheral or central IV, per institutional policy. 
 
 
6.4 Surgical Therapy 
Standard surgical therapy with a total mesorectal excision (TME) is to be done within 10 weeks 
of completion of cycle #6 of chemotherapy with TASOX with staging to be done within 8 weeks 
after day 14 of cycle 6.  
 
Operative approach will be at the discretion of surgeon, and can include either laparoscopic (or 
robotic-assisted laparoscopic) or open anterior or low anterior resection with or without 
temporary fecal diversion. Preoperative antibiotics and bowel preparation are institution specific 
will be at the discretion of the operating surgeon. The mobilization of the proximal colon and 
splenic flexure may be performed by laparoscopic, laparoscopic-assisted, robotic-assisted or 
hand-assisted at the discretion of the surgeon to limit the incision to the lower abdomen. The 
pelvic dissection should include TME, division of inferior mesenteric vascular pedicle, 
transection of the specimen, and anastomosis. Anastomosis may be stapled or hand-sewn. 
Variation in technical approaches will be at the surgeon’s discretion as they are impacted by the 
patient’s body habitus, incisions, and tumor location.  
 
Patients that achieve a complete or near complete Clinical Response (cCR or cCR), may choose 
to pursue a course of watch and wait with agreement of their treating surgeon. A thorough 
discussion is recommended with their surgeon concerning the risks and benefits of watch and 
wait and both they and their physician agree with the intended approach. Patients that pursue a 
course of watch and wait remain evaluable on study and will be classified as having a ypT0N0 
response for the purposes of the NAR score if they do not proceed to TME surgery within 24 
months of completing cycle 6, day 14. 
 
Surgical Complications  
Perioperative and postoperative complications will be collected and submitted; see Section 10.0.  
 
Early complications (within 30 days) 
Morbidity and mortality will be closely monitored and recorded using the study data forms with 
the following definitions:  
1. Pulmonary, urinary tract, and intraabdominal infections will be defined by the need for 
antibiotic treatment and/or interventional radiology drainage.  
2. 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  
3. 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.  

 
 
 
 
 
 
22 
 
4. Any documented medical or anesthetic complications that result in patient disability or 
that requires intervention will be recorded.  
5. Problems with healing, function or management of the ostomy that requires intervention 
or additional hospital stay will be considered complication and recorded. 
 
 
 
7.0 RADIOLOGIC IMAGING 
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 T and N status 
Estimated Radiographic T Stage (Using AJCC 8th Edition Definitions): 
This should be estimated as T1, T2, or T3c/d ( ie. T3c, >5 to 15 mm; T3d, >15 mm beyond 
muscularis propria). T4 tumors are ineligible. See APPENDIX I.  
 
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 8mm in short axis. 
Radiographic N2 status is estimated as: 4 or more nodes that measure 8mm or more in short-axis. 
Radiographic N1 status is estimated as: fewer than 4 lymph nodes that measure 8 mm or greater 
in short axis but 1 or more lymph nodes that measure 10 mm or greater. 
 
Distance of the Tumor from the Mesorectal Fascia Reflection: patients with tumors with a 
distance of 1mm or less, or adherent to the mesorectal fascia reflection have threatened radial 
margins and are ineligible.  
 
Presence of Distant Disease: 
Nodal stations considered suspicious for metastatic disease (M1) for rectal cancer are: common 
iliac, external iliac and inguinal nodes. 
8.0 SUGGESTED DOSAGE MODIFICATION BASED ON 
ADVERSE EVENTS 

 
 
 
 
 
 
23 
 
8.1 TASOX chemotherapy 
8.1.1 TAS-102 Dose Reduction Levels 
Study medication dose reductions in case of toxicity and number of tablets for each calculated 
BSA are described in Table 3.  Patients are permitted dose reduction(s) to a minimum dose of 20 
mg/m2 bid(40 mg/m2/day) in 5 mg/m2 steps.   

 
 
 
 
 
 
24 
 
Table 3: 
TAS-102 Dose Reduction Levels and Number of Tablets per Dose 
TAS-102 
Dose (2x 
daily) 
BSA 
(m2) 
Dosage in 
mg 
(2x daily) 
Total 
daily 
dose (mg) 
Tablets per dose 
15 mg 
20 mg 
Level 1 Dose Reduction:  From 35 mg/m2 to 30 mg/m2 
30 mg/m2 
< 1.09 
30 
60 
2 
0 
1.09 - 1.24 
35 
70 
1 
1 
1.25 - 1.39 
40 
80 
0 
2 
1.40 - 1.54 
45 
90 
3 
0 
1.55 - 1.69 
50 
100 
2 
1 
1.70 - 1.94 
55 
110 
1 
2 
1.95 - 2.09 
60 
120 
0 
3 
2.10 - 2.28 
65 
130 
3 
1 
≥ 2.29 
70 
140 
2 
2 
Level 2 Dose Reduction:  From 30 mg/m2 to 25 mg/m2 
25 mg/m2 
< 1.10 
25(1) 
50(1) 
2 (PM)(1) 
1 (AM)(1) 
1.10 - 1.29 
30 
60 
2 
0 
1.30 - 1.49 
35 
70 
1 
1 
1.50 - 1.69 
40 
80 
0 
2 
1.70 - 1.89 
45 
90 
3 
0 
1.90 - 2.09 
50 
100 
2 
1 
2.10 - 2.29 
55 
110 
1 
2 
≥ 2.30 
60 
120 
0 
3 
Level 3 Dose Reduction:  From 25 mg/m2 to 20 mg/m2 
20 mg/m2 
< 1.14 
20 
40 
0 
1 
1.14 – 1.34 
25(1) 
50(1) 
2 (PM)(1) 
1 (AM)(1) 
1.35 – 1.59 
30 
60 
2 
0 
1.60 – 1.94 
35 
70 
1 
1 
1.95 – 2.09 
40 
80 
0 
2 
2.10 – 2.34 
45 
90 
3 
0 
≥ 2.35 
50 
100 
2 
1 
(1) 
At a total daily dose of 50 mg, patients should take 1 x 20-mg tablet in the morning and 2 
x 15-mg tablets in the evening. 
BSA=body surface area (calculate to 2 decimal places) 

 
 
 
 
 
 
25 
 
If dose modification fails to result in achieving minimal criteria to resume treatment, the 
Investigator should discontinue study medication.   
Study medication should be discontinued if toxicities that require dose reduction recur after dose 
reduction to 20 mg/m2. 
8.1.2 Oxaliplatin Dose Reduction Levels 
Dose Modifications levels for oxaliplatin are listed in Table 6: 
 
Table 4: 
Oxaliplatin dose modification levels 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
Oxaliplatin 
85 mg/m2 
65mg/m2 
50mg/m2 
 
8.1.3 Dose Hold, Resumption and Modification in Response to Hematologic Toxicities 
Criteria for dose HOLD and RESUMPTION in response to hematologic toxicities related to 
myelosuppression are described in Table  5 and 6, respectively.   
For all patients with decreases in neutrophils and/or platelets noted in Table 5, the next cycle of 
study treatment should not be started until the resumption criteria in Table 6 are met; these 
resumption criteria apply to the start of the next cycle for all patients regardless of whether or not 
the hold criteria were met. Table 7 and Table 8 summarize the relative dose reduction 
requirements for the TASOX regimen. 
 
Table 5: 
TAS-102 and Oxaliplatin DOSE HOLD CRITERIA for Hematologic 
Toxicities Related to Myelosuppression 
Parameter 
Hold Criteria 
Conventional Units 
SI Units 
Neutrophils 
<1,000/mm3 
<1.0 × 109/L 
Platelets 
<50,000/mm3 
<50 × 109/L 
SI=International System 
Table 6: 
TAS-102 and Oxaliplatin RESUMPTION Criteria for Hematologic Toxicities 
Related to Myelosuppression 
Parameter 
Resumption Criteria(1) 
Conventional Units 
SI Units 
Neutrophils 
≥1200/mm3  
≥1.2 × 109/L 
Platelets 
≥75,000/mm3 
≥75 × 109/L 

 
 
 
 
 
 
26 
 
(1) 
These resumption criteria apply to the start of the next cycle for all patients regardless of 
whether or not the hold criteria were met. 
SI=International System 
 
Table 7: 
Combined dose MODIFICATION for TASOX regimen for Absolute 
Neutrophil Counts (ANC).  
 
Prior to cycle 
 
ANC SI Units 
× 109/L 
Dose level of subsequent cycles 
-If ANC is less than 
1.2 within 3 days of 
day 1 of cycle, hold 
treatment. Perform 
weekly CBC, 
maximum of 4 times. 
-If ANC is greater 
than or equal to 1.2 
within 4 weeks, 
proceed with 
treatment at the dose 
level noted across the 
lowest ANC result of 
the delayed weeks (s) 
-If ANC remains less 
than 1.2 after 4 
weeks, discontinue 
treatment. 
Oxaliplatin 
TAS102 
Greater than or equal 
to 1.2 
Maintain dose level 
Maintain dose level 
1.0 to less than 1.2 
Maintain dose level 
Maintain dose level 
0.5 to less than 1.0 
Decrease 1 dose level 
Maintain dose level 
Less than 0.5 
Decrease 1 dose level 
Decrease 1 dose level 
 
 
 

 
 
 
 
 
 
27 
 
Table 8: 
Combined dose modification for TASOX regimen for Absolute Neutrophil 
Counts (Plt).  
Prior to cycle 
Platelets SI Units 
× 109/L 
Dose level of subsequent cycles 
-If Plts are less than 
75 within 3 days of 
day 1 of cycle, hold 
treatment. Perform 
weekly CBC, 
maximum of 4 times  
-If Plts are greater 
than or equal to 75 
within 4 weeks, 
proceed with 
treatment at the dose 
level noted across the 
lowest Plt result of 
the delayed weeks(s) 
If Plts remain less 
than 75 after 4 weeks, 
discontinue 
treatment. 
Oxaliplatin 
TAS102 
Greater than or equal 
to 75 
Maintain dose level 
Maintain dose level 
50 to less than 75 
Maintain dose level 
Maintain dose level 
10 to less than 50 
Decrease 1 dose level 
Maintain dose level 
Less than 10 
Decrease 1 dose level 
Decrease 1 dose level 
 
8.1.4 Dose Modification in Response to Febrile Neutropenia 
In the event of febrile neutropenia: 
• Interrupt dosing until toxicity resolves to treatment resumption level (Table 6).  
• When resuming dosing, decrease the dose level by 1 dose level from the previous dose 
level for both oxaliplatin and TAS102 (as per Tables 3 and 4). 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
28 
 
 
8.1.5 Dose Modification in Response to Non-Hematologic Toxicities 
In Table 9 dose modifications for non-hematologic toxicities are defined. For grading of 
neurologic toxicity please see Table 10. 
 
Table 9: 
TASOX Dose Modification Criteria for Non-hematologic Toxicities 
Gradea 
Dose Hold/Resumption 
within a 14-day Treatment Cycle 
Dose Adjustment for  
Next Cycle 
Grade 1 or 2 
Any occurrence 
Maintain treatment at the same dose 
level 
None 
Grade 3(1) or Higher 
1st, 2nd, or 3rd 
occurrence 
Suspend treatment until Grade 0 or 1 
Reduce by 1 dose level from the 
previous level 
4th occurrence 
Discontinue treatment 
Discontinue treatment 
• 
(1) 
Except for Grade 3 nausea and/or vomiting controlled by aggressive antiemetic 
therapy or diarrhea responsive to antidiarrheal medication. 
 
Table 10:  
Oxaliplatin Neurotoxicity Definitions and Dose Modifications 
Grade1 
Paresthesias / dysesthesias of short duration 
that resolve; do not interfere with function 
Grade 2 
Paresthesias / dysesthesias interfering with 
function, but not activities of daily living 
(ADL) 
Grade 3 
Paresthesias / dysesthesias with pain or with 
functional impairment which interfere with 
ADL 
Grade 4 
Persistent paresthesias / dysesthesias that are 
disabling or life-threatening 
Pharyngo-laryngeal dysesthesias (investigator discretion used for grading): Grade 0 = none; 
Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe 
Overdose   
There is no known antidote available in case of TAS-102 overdose.  Overdose should be 
managed aggressively with close monitoring and administration of prophylactic and 
symptomatic therapies to prevent or correct potential side effects. 
Dosage Forms and Strengths 
TAS-102 (15 mg trifluridine/7.065 mg tipiracil hydrochloride) is a white, film-coated tablet. 
Tablets can be printed or unprinted.  

 
 
 
 
 
 
29 
 
TAS-102 (20 mg trifluridine/9.42 mg tipiracil) is a pale red, film-coated tablet Tablets can be 
printed or unprinted. 
 
TAS 102 tablets are supplied by way of a pouch containing a 20ct blister card.   
 
9.0 ANCILLARY TREATMENT/SUPPORTIVE CARE 
9.1 Concomitant medications and therapies. 
All concomitant medications and treatments must be recorded from the time the participant signs 
the ICF until 28 days after the last dose of study treatment.  
 
Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. Such drugs, if used concomitantly with TAS-102, may compete with the effector, 
trifluridine, for activation via thymidine kinases. Therefore, when using antiviral drugs that are 
human thymidine kinase substrates, monitor for possible decreased efficacy of the antiviral 
agent, and consider switching to an alternative antiviral agent that is not a human thymidine 
kinase substrate, such as lamivudine, zalcitabine, didanosine and abacavir. 
• Trifluridine is a substrate of thymidine phosphorylase, and is not metabolized by 
cytochrome P450 (CYP) enzyme.  
• Tipiracil is not metabolized in either human liver or hepatocytes. 
 
9.2 Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
 
9.3 Blood Products 
Blood products are permissible.  
 
9.4 Neulasta and Neupogen 
Neulasta and Neupogen should not be started as part of initial therapy and are not usually 
necessary with TAS102 but may be used.  
 
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. 
 
 
 
 
 

 
 
 
 
 
 
30 
 
10.0 ADVERSE EVENT (AE) REPORTING AND MONITORING 
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 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  
 
Adverse event monitoring and reporting is a routine part of every clinical trial. First, identify and 
grade the severity of the event using the CTCAE v5.0. Next, determine whether the event is 
expected or unexpected and if the adverse event is related to the medical treatment or procedure. 
With this information, determine whether the adverse event must be reported as an expedited 
report. 
 
The safety reporting period begins after the subject has signed the informed consent and ends 28 
days after the last dose of study drug.It is only required that SAEs be reported following consent 
and prior to radiation therapy initiation, while all AEs (serious and non-serious) be reported 
thereafter.  
 
10.2 Expected vs. Unexpected 
The determination of whether an AE is expected is based on the agent-specific information 
provided in this protocol. Unexpected AEs are those not listed in the agent-specific information 
provided in 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. 
 
10.3 Reporting Clinical Safety Data to Taiho 
For the purposes of this Agreement an Adverse Event (AE) shall mean any untoward medical 
occurrence whether thought to have been caused by the study drug(s) or the Clinical Trial 
procedures or not and Serious Adverse Event (SAE) shall mean any adverse event which is fatal, 
life threatening, disabling or Incapacitating, requires in-patient hospitalization or prolongs 
existing hospitalization, Is a congenital anomaly In the off-spring of the patient or which may 
require Intervention to prevent the previously stated outcomes. 
 
For the purposes of this Clinical Trial, other experiences with the TAIHO Investigational 
Medicinal Product(s) IMP shown below should also be reported to TAIHO: 
 
A. Drug exposure during pregnancy and lactation, or paternal drug exposure 
B. Experience In patients below 18 years of age (depending on Inclusion criteria) 
C. Lack of drug effect 
D. Unintended beneficial effect 

 
 
 
 
 
 
31 
 
E. Any suspected transmission of an infectious agent by a medicinal product 
F. Product quality complaints associated with possible safety issue(s)  
G. Drug or food interaction 
H. Overdose 
I. Medication error 
J. Misuse 
K. Occupational exposure 
 
10.3.1 Reporting Clinical Safety Information to TAIHO Oncology 
 
a. The Principal Investigator shall monitor the Clinical Trial Subject for adverse events and 
fulfil all the reporting requirements to FDA in accordance with Applicable Laws.  The 
Principal Investigator shall also inform Taiho Oncology of serious adverse events: 
o Unexpected Fatal or Life Threatening Suspected Adverse Reactions- Report to 
Taiho Oncology within 24 hours  
o Serious & Unexpected Suspected Adverse Reactions- Report to Taiho Oncology 
within 24 hours. 
o All other Serious cases (Expected and Related; Expected and Not related; 
Unexpected and Not related)- Report to Taiho Oncology within 2 weeks of 
awareness. 
b. All serious adverse events are to be reported via a MedWatch Form and are to be sent to 
the Taiho Oncology, via fax: 609-750-7371 or e-mail: TAS-
102_Safety@taihooncology.com (please note the underscore between ‘102’ and 
‘Safety’). 
c. MedWatch reports must clearly specify SAE term(s) and corresponding Principal 
Investigator causality assessment. 
d. Taiho Oncology will send SUSARs to Regulatory Authorities via a MedWatch form 
within 7 Calendar Days for all fatal/life threatening events and 15 Calendar Days for all 
other serious events. 
 
10.3.2 Drug Exposure During Pregnancy and Lactation, or Paternal Drug Exposure Reports 
 
The Institution will report Exposure During Pregnancy and Lactation, or Paternal Drug Exposure 
on any Clinical Trial Subject while participating in the Clinical Trial, and following exposure to 
a TAIHO IMP, to TAIHO (as specified below) using copies of the original Pregnancy Report 
Form and within two weeks of first becoming aware of the pregnancy or exposure. If the partner 
of a Clinical Trial Subject becomes pregnant, the Institution may collect information about the 
pregnancy and birth if the partner agrees. 
 
The Clinical Trial Subject will also be followed by the Institution to determine the outcome of 
the pregnancy (including any premature termination of the pregnancy). Information on the status 
of the mother and child will be forwarded to TAIHO. The Institution must provide final outcome 
of pregnancy to TAIHO. If any SAE(s) is observed in Clinical Trail Subject or fetus/child, then 
SAE(s) must also be reported to TAIHO following SAE Reporting guidelines.  

 
 
 
 
 
 
32 
 
 
Routing of Drug Exposure During Pregnancy and Lactation, or Paternal Drug Exposure Reports 
 
Such reports and Information as outlined above, Including Investigator causality assessments 
against all concerned TAIHO IMP(s) and English translations where reporting Is from a non-
English speaking country, shall be sent: 
• by facsimile to PV CONTACT NUMBER :609-750-7371 OR 
• by e-mail to: TAS-102_Safety@taihooncology.com (please note the underscore between 
'102' and 'Safety') 
 
Requesting Follow up information: 
 
The institution will provide TAIHO with details of whom TAIHO shall address requests for 
follow up Information on SAE and pregnancy cases reported from this Clinical Trial, and further 
agree to update such contact details as necessary. At the time of this Agreement, all such requests 
should be addressed to: Hagen Kennecke, MD 
 
SAE Reconciliation 
 
Reconciliation shall be performed quarterly as an exchange of Line Listings or other means in 
English. On a quarterly basis, the institution shall provide to TAIHO a line listing or other means 
of cumulative SAE received to date.  At the end of the Clinical Trial a global reconciliation shall 
be performed. Please reference contact information when sending this reconciliation.  All serious 
adverse events via a MedWatch Form need to be sent to the FDA and to Taiho Oncology, Inc., 
via fax: 609-750-7371 or e-mail: TAS-102_Safety@taihooncology.com (please note the 
underscore between ‘102’ and ‘Safety’).   
 
DSUR 
 
If requested by Institution, TAIHO shall provide the Institution with the final version of this 
DSUR report within 15 calendar days after submission to health agencies and ethics committees.  
 
 
11.0 TREATMENT EVALUATION 
11.1 Guidance for radiological tumor evaluation   
Repeat non-contrast pelvic MRI to rule out progressive disease and ensure surgical resectability 
is required as per standard of care recommendations (22). Pelvic MRI should be booked within 
56 days of completion of cycle #6 of TASOX, ie within 1-56 days AFTER day #14, cycle 6. 
Radiographic tumor staging should be performed and reported per the initial, staging MRI. See 
APPENDIX I for guidance.  
 

 
 
 
 
 
 
33 
 
11.2 Pathological Tumor Response 
Pathology reports for the TME resection must be submitted de-identified reports via email to tas-
short-communications@providence.org.  
 
11.3 Definition of Surgical Margin Status 
Margins to be considered are:   
- Proximal Margins 
- Distal Margins 
- Radial Margins, synonymously termed circumferential margin.  
 
Margin Positivity:  A surgical margin is POSITIVE if the pathologist notes tumor within ≤  1mm 
of any edge of the primary tumor specimen. 
 
A surgical margin is NEGATIVE if the pathologist notes that there is NO tumor within > 1mm 
of any edge of the primary tumor specimen. 
 
11.4 Definition of pathologic stage 
Derivation of the Neoadjuvant response (NAR) score requires pathologic staging information 
from the TME resection specimen staged according to the AJCC8th 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 
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 
 
11.5 Definition of 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. 

 
 
 
 
 
 
34 
 
 
12.0 POST-OPERATIVE THERAPY 
Recommendations for post-operative systemic therapy are not protocol specified and are 
according to recommendation of the investigator based clinical evidence and NCCN guidelines. 
Post-operative FOLFOX or 5-Fluorouracil plus Leucovorin/Capecitabine may be recommend 
taking into consideration clinical and pathologic stage and patient preference. 
 
13.0 TAS102 DRUG INFORMATION 
Storage and Handling 
• Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 
86°F) [See USP Controlled Room Temperature]. 
• TAS102 LONSURF is a cytotoxic drug. Follow applicable special handling and disposal 
procedures. “OSHA Hazardous Drugs”. OSHA. 
(http://www.osha.gov/SLTC/hazardousdrugs/index.html) 
• If stored outside of original bottle, discard after 30 days. 
 
14.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY 
14.1 Statistical justification 
The primary endpoint will be the Neoadjuvant Response (NAR) Score. This is an established 
efficacy endpoint for phase II/III rectal cancer trial, offering an early indicator of treatment 
effectiveness (17). In table I, inclusion criteria, pre-operative therapy and the corresponding pCR 
rate of published phase II and phase III trials of total neoadjuvant chemotherapy are summarized. 
The wide range of reported pCR rates is a reflection of treatment efficacy and the pre-treatment 
tumor stage of eligible patients.  
 
 
Table 11. Evidence for neoadjuvant chemotherapy in stage II/III rectal cancer. 
Study 
Inclusion 
Preoperative Therapy 
N 
pCR (95% CI) 
Polish II (4) 
High Risk 
T3/T4 
5x5 RT FOLFOX4 x 3 
261 16% 
RAPIDO (2) 
High Risk  
 
CRT 
5x5 RT CAPOX x 6 
460 
460 
Pending  
(19%  full 
cohort) 
Garcia-
Aguilar(23) 
Stage II/III 
CRT 
CRT FOLFOX x2 
CRT FOLFOX x4 
CRT FOLFOX x6 
60 
67 
67 
65 
18% (10-30) 
25% (16-37) 
30% (19-42) 
38% (27-51) 

 
 
 
 
 
 
35 
 
EXPERT-C(24) 
High-Risk 
CAPOX x 4  CRT 
CAPOX Cetux x 4  CRT 
44 
46 
9% 
11% 
AVACROSS(25) High-Risk 
CAPOX +Bev x 4  CRT 
+Bev 
45 
36% (22-51%) 
GCR-3(1)  
High Risk 
CAPOX x 4  CRT 
59 
14.3% (6.4-26%) 
FOWARC(26) 
 
Stage II/III  
Inf5FUCRTInf5FU 
FOLFOX6CRT-
OxFOLFOX6 
130 
141 
13.1% 
29.1% 
High Risk: stage II/III rectal cancer with radiographic high-risk features; 5x5 RT: 25 Gy in five 
fractions of 5 Gy; CRT: chemoradiation (50.4 Gy in 28 fractions of 1.8 Gy plus fluorouracil 
based chemotherapy); Cetux: Cetuximab; Bev: Bevacizumab;  
 
14.2 Sample Size 
In table 2, the NAR scores of comparable patients enrolled in the phase III R04 study (27) and 
treated with long-course chemoradiation are presented (personal communications G Yothers). 
Patients with cT3N0 tumors and similar in stage to those to be enrolled in the proposed concept 
achieved a NAR score of 14.59 (SD 13.41). Prospective data suggests a 5.8 reduction in NAR 
score would be a clinically significant improvement in long terms outcomes. (15) For declared 
target 5.8 NAR reduction from 14.59 to 8.79 a sample size of 24 patients would be required, one-
sided alpha=0.1 and beta=0.2 (Power 80.2%). Assuming an ineligibility rate of 10%, the final 
sample size is 27. 
 
Patients who pursue a course of watch and wait remain evaluable on study and will be classified 
as having a ypT0N0 response for the purposes of the NAR score if they do not proceed to TME 
surgery within 24 months of cycle 6 day 14. 
 
Table 12. pCR and NAR scores in R04 patients. 
R04 similar 
subgroup 
Inclusion 
Preoperative Therapy 
N 
ypT0N0  Rate 
NAR Score 
 
cT1-3 
cN any 
LRT 
50.4/25 plus 
Fluorouracil  
631 
18.4% 
15.77 
SD 14.17 
 
cT3 
Non-Low 
“ 
402 
18.4% 
16.05 
SD 14.32 
 
cT3 cN0 
Non-Low 
“ 
293 
20.2% 
14.59 
SD 13.41 
 
 
 

 
 
 
 
 
 
36 
 
15.0 Oversight and Quality Assurance Plan 
Oversight of patient safety will include review of adverse events as well as study progress and 
outcomes.  Patient updates, outcomes, and recruitment and retention of patients will be reviewed 
on a regular basis by the PI, research nurse, and data coordinator.  Deviations will be reviewed 
during oversight meetings and/or through internal reporting procedures.  Aggregate protocol 
deviations are monitored for trends to be reviewed by the Providence Cancer Institute Clinic and 
Research Quality Committee. In addition, a “first patient review” is conducted and documented 
for all clinical trials.  This review includes treatment administration, deviations, and SAEs to 
ensure any compliance and/or safety issues are addressed prior to the enrollment of additional 
patients. 
 
Study monitoring activities (Quality Control Reviews) are performed by clinical research staff 
members who have completed specialized training in study monitoring procedures and human 
subjects’ protections.  Individuals who perform study monitoring activities do not report to 
principal investigators or research scientists and may not monitor studies for which they have 
direct responsibility.  Results of study monitoring activities will be reported to applicable study 
personnel, Clinical Trials Manager and Quality Assurance.  Study monitoring activities are 
conducted regularly and include (but are not limited to) review and verification of the following:  
• Eligibility 
• Informed Consent process 
• Adherence to protocol treatment plan 
• Case Report Forms (CRFs) 
• Source Documentation 
• Adverse Events 
• Regulatory Reporting 
 
15.1 Quality Assurance  
 
Quality Assurance (QA) personnel review study monitoring reports and if necessary, determine 
follow-up actions to resolve significant findings. QA has the authority to request immediate 
corrective action if significant patient safety issues are identified.  QA will track and trend results 
from study quality assurance reports as well as associated corrective and preventive actions. QA 
personnel do not have a direct reporting relationship to the principal investigator and are not 
responsible for enrollment or coordination of care for study participants. 
 
A review of 20% of the case report forms, per site, will undergo quality assurance review.  All 
quality assurance reviews will include verification of the accuracy and integrity of data entered 
onto case report forms.  Incorrect data will be identified and corrected.  The existence of 
adequate source documents for data will be verified. Each site is responsible for their own 
implementation of internal monitoring and/or auditing plans for this trial as appropriate. These 
plans will be revised as necessary during the life of the trial based upon a variety of factors, 
including but not limited to: protocol amendments, staff turnover, enrollment metrics, and 

 
 
 
 
 
 
37 
 
compliance issues noted. All subsite quality reports will be submitted to the coordinating center 
quarterly. 
 
 
 

 
 
 
 
 
 
38 
 
16.0 References 
1. Ludmir EB, Palta M, Willett CG, Czito BG, Total neoadjuvant therapy for rectal cancer: An 
emerging option. Cancer. 2017;123(9):1497. Epub 2017 Mar 10. 
 
2. RAPIDO Preliminary Data, ESTRO, March 2017 
 
3. Fernández-Martos C, Pericay C, Aparicio J, et al. Phase II, randomized study of concomitant 
chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) 
compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in 
magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 
study. J Clin Oncol. 2010;28(5):859. Epub 2010 Jan 11.  
 
4. Bujko K, Wyrwicz L, Rutkowski A, et al. Long-course oxaliplatin-based preoperative 
chemoradiation versus 5×5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal 
cancer: results of a randomized phase III study. Polish Colorectal Study Group. Ann Oncol. 
2016;27(5):834. Epub 2016 Feb 15.  
 
5. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-
term results of a randomized trial comparing preoperative short-course radiotherapy with 
preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 
2006;93(10):1215.  
 
6. Ngan SY, Burmeister B, Fisher RJ, Solomon M, et al. Randomized trial of short-course 
radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients 
with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 
2012;30(31):3827. Epub 2012 Sep 24. 
 
7. Erlandsson J, Holm T, Pettersson D, et al. The Stockholm III Trial on optimal fractionation of 
preoperative radiotherapy and timing to surgery for rectal cancer – a randomised controlled trial. 
Lancet Oncol. 2017;18:336–346. 
 
8. Myerson RJ, Tan B, Hunt S, et al.  Five fractions of radiation therapy followed by 4 cycles of 
FOLFOX chemotherapy as preoperative treatment for rectal cancer. Int J Radiat Oncol Biol 
Phys. 2014 Mar 15;88(4):829-36. doi: 10.1016/j.ijrobp.2013.12.028. 
 
9. Temmik O, De Bruin M, Fukushima M, et al. Therapeutic potential of the dual‐targeted TAS‐
102 formulation in the treatment of gastrointestinal malignancies. Cancer Science, 2007. 
https://doi.org/10.1111/j.1349-7006.2007.00477.x 
 
10. Overman M, Varadhachary GR, et al, Phase 1 study of TAS-102 administered once daily on 
a 5-day-per-week schedule in patients with solid tumors. Published 2008 in Investigational New 
Drugs DOI:10.1007/s10637-008-9142-3 
 

 
 
 
 
 
 
39 
 
11. Mayer RJ, Van Cutsem E, Falcone A, Randomized Trial of TAS-102 for Refractory 
Metastatic Colorectal Cancer. N Engl J Med 2015; 372:1909-1919May 14, 2015DOI: 
10.1056/NEJMoa1414325 
 
12. Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic 
colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 
2012 Oct;13(10):993-1001. doi: 10.1016/S1470-2045(12)70345-5. Epub 2012 Aug 28. 
 
13. Lesniewski-Kmak K, et al. Phase II study evaluating trifluridine/tipiracil+bevacizumab and 
capecitabine+bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) 
patients who are non-eligible for intensive therapy (TASCO1): results of the primary analysis, GI 
ESMO, June 2018, O-022. 
 
14. Hollebecque A, Calvo A, Andre T, et al. Phase I multicenter, open-label study to establish 
the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin 
combination in patients (pts) with metastatic colorectal cancer (mCRC). Poster presented at 
the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) 
2018; 1-19 January 2018; San Francisco, CA [816]. 
 
15. Calvo A, Dahan L, Hollebecque A, et al. Safety run-in evaluation of the phase I trial of 
trifluridine/tipiracil (FTD/TPI) in combination with oxaliplatin and a monoclonal antibody 
(bevacizumab or nivolumab) in patients with metastatic colorectal cancer. Poster presented 
at the European Society for Medical Oncology (ESMO) 2018 Congress; 19-23 October 2018; 
Munich, Germany [470P]. 
 
16. Michael C, et al. A phase I study of TAS-102 in combination with oxaliplatin (TAS-OX) for 
refractory metastatic colorectal cancer (mCRC). J Clin Oncol 37, 2019 (suppl 4; abstr 630) 
 
17 George TJ, Allegra CJ, Yothers G. Neoadjuvant Rectal (NAR) Score: as new surrogate 
endpoint in rectal cancer clinical trials. Curr Colorectal Cancer Rep. 2015;11(5):275-280 
 
18. Myerson RJ, Garofalo MC, El Naqa I, Abrams RA, Apte A, Bosch WR, Das P, Gunderson 
LL, Hong TS, Kim JJ, Willett CG, Kachnic LA: Elective Clinical Target Volumes for Conformal 
Therapy in Anorectal Cancer: A Radiation Therapy Oncology Group Consensus Panel 
Contouring Atlas. Int J Radiat Oncol Biol Phys 2009; 74(3): 824-30. 
 
19. Ng M, Leong T, Chander S, Chu J, Kneebone A, Carroll S, Wiltshire K, Ngan S, Kachnic L: 
Australasian Gastrointestinal Trials Group (AGITG) Contouring Atlas and Planning Guidelines 
for intensity-Modulated Radiotherapy in Anal Cancer. Int J Radiat Oncol Biol Phys 2012; 83(5): 
1455-62. 
 
20. Valentini V, Gambacorta MA, Barbaro B, Chiloiro G, Coco C, Das P, Fanfani F, Joye 
I, Kachnic L, Maingon P, Marijnen C, Ngan S, Haustermans K. International Consensus 
Guidelines in Rectal Cancer. Radiother Oncol 2016; 120(2): 195-201. 

 
 
 
 
 
 
40 
 
 
21. Gay HA, Barthold HJ, O’Meara E, Bosch WR, El Naqa I, Al-Lozi R, Rosenthal SA, Lawton 
C, Lee WR, Sandler H, Xietman A, Myerson R, Sawson LA, Willett C, Kachnic LA, Jhingran A, 
Portenlance L, Ryu J, Small W Jr, Gaffney D, Viswanathan AN, Michalski JM: Pelvic Normal 
Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group 
Consensus Panel Atlas. Int J Radiat Oncol Biol Phys 2012; 83(3): 353-62. 
 
22. Al B. Benson III, AB,  Venook AP, MM Al-Hawary, et al.  Rectal Cancer, Version 2.2018, 
NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw2018;16:874-901 
23. Garcia-Aguilar J, Chow OS, Smith DD, et al. Timing of Rectal Cancer Response to 
Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in 
locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):957-
66. Epub 2015 Jul 14.  
 
24. Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical 
trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or 
without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer 
(EXPERT-C). J Clin Oncol. 2012;30(14):1620. Epub 2012 Apr 2 
 
25. Miguel Nogué, a Antonieta Salud,b Pilar Vicente, et al. Oncologist. Addition of Bevacizumab 
to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in 
Magnetic Resonance Imaging–Defined Poor-Prognosis Locally Advanced Rectal Cancer: The 
AVACROSS Study. 2011 May; 16(5): 614–620. doi:  10.1634/theoncologist.2010-0285 
PMCID: PMC3228198  
 
26. Deng Y, Chi P, Lan P, et al.  Modified FOLFOX6 With or Without Radiation Versus 
Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced 
Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized 
Three-Arm Phase III Trial. J Clin Oncol. 2018;36, suppl. abstr 3502 
 
27. Allegra CJ, Greg Yothers, Michael J. O’Connell MJ, et al.  J Natl Cancer Inst. Neoadjuvant 
5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A 
Phase III Randomized Clinical Trial. 2015 Nov; 107(11): djv248. 
Published online 2015 Sep 14. doi:  10.1093/jnci/djv248 PMCID: PMC4849360 
 
 

 
 
 
 
 
 
41 
 
APPENDIX I: Baseline staging and post-treatment MRI 
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 8th edition criteria. The criteria 
set forth below are to foster consistency of interpretation across sites. 
 
T stage coding: 
T1 
T2 
T2/early T3 (including spiculations) is coded T3 
T3 
T3/possible T4 is coded T4 (not eligible) 
T4 (not eligible) 
 
N stage coding:   
Estimated radiographic nodal stage will be derived from preoperative imaging procedures using 
the AJCC 8th edition staging criteria.  The total number of nodes to determine stage (N1 = 1-3, 
N2 = 4 or more) will include mesorectal and superior rectal stations. 
 
Final analysis criteria will be short axis measurement with nodes positive at any size N1=1-3, 
N2=4 or more. Diminutive nodes (<8mm) are not considered. 
 
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 8 mm or greater. 
 
Radiographic N2 status is estimated as: 4 or more nodes that measure 8mm or more in short-axis 
(not eligible). 
 
 
Metastatic nodal disease: Nodal stations considered suspicious for metastatic disease (M1) 
(AJCC 8th edition) are for rectal cancer: common iliac, external iliac nodes and inguinal nodes. 
Also bone metastases and peritoneal tumor implants. 
 
Circumferential Radial Margin: Distance of the tumor from the mesorectal fascia reflection (also 
known as radial margin, also known as CRM or circumferential resection margin).