Conditions: Rectal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out the effects of chemotherapy followed by less invasive surgery on patients and their early rectal cancer. The approach of this trial will be considered a success if at least 65% of participants are able to keep the rectum.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Folfox Protocol intervention 2: Capox
Intervention descriptions: intervention 1: 6 cycles of q2weekly FOLFOX, or intervention 2: 4 cycles of q3weekly CAPOX

Protocol document:
Prot_000.pdf: 
 
PROTOCOLADMINISTRATIVE UPDATE #3: 2020-JAN-21 
 
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CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION: 2017-AUG-16 
 
ADMINISTRATIVE UPDATE #1: 2018-FEB-07 
 
ADMINISTRATIVE UPDATE #2: 2018-MAY-25 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
NEOADJUVANT CHEMOTHERAPY, EXCISION AND OBSERVATION  
FOR EARLY RECTAL CANCER:  
The NEO Trial. 
 
CCTG Protocol Number: CO.28 
 
 
 
STUDY CHAIRS: 
Hagen Kennecke 
 
 
Carl Brown 
 
 
TRIAL COMMITTEE: 
Rebecca Auer 
 
 
Sebastien Drolet 
 
 
Cathy Eng 
 
 
Vallerie Gordon 
 
 
David Hochman 
 
 
Derek Jonker 
 
 
Hussein Moloo 
 
 
SENIOR INVESTIGATOR: 
Chris O’Callaghan 
 
 
BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
QUALITY OF LIFE COORDINATOR: 
Jolie Ringash 
 
 
HEALTH ECONOMICS COORDINATOR: 
Kelvin Chan 
 
 
STUDY COORDINATOR: 
Max Sherry 
 
 
REGULATORY SPONSOR: 
CCTG 
 
(For contact information of study personnel see Final Page.) 
 


 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 1 
 
1.0 
OBJECTIVES ......................................................................................................................................... 3 
1.1 
Primary Objective ................................................................................................................................... 3 
1.2 
Secondary Objectives .............................................................................................................................. 3 
1.3 
Tertiary Objectives .................................................................................................................................. 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 4 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.......................................................................... 10 
3.1 
Oxaliplatin ............................................................................................................................................. 10 
3.2 
Leucovorin Calcium (CF) ..................................................................................................................... 11 
3.3 
Fluorouracil ........................................................................................................................................... 12 
3.4 
Capecitabine .......................................................................................................................................... 14 
 
4.0 
STUDY POPULATION ....................................................................................................................... 16 
4.1 
Eligibility Criteria ................................................................................................................................. 16 
4.2 
Ineligibility Criteria ............................................................................................................................... 18 
 
5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT....................................................................................................................................... 19 
5.1 
Follow-up for Ineligible Patients ........................................................................................................... 20 
 
6.0 
ENTRY/ENROLLMENT PROCEDURES .......................................................................................... 20 
6.1 
Entry Procedures ................................................................................................................................... 21 
6.2 
BSA Calculation .................................................................................................................................... 21 
6.3 
Enrollment ............................................................................................................................................. 21 
 
7.0 
TREATMENT PLAN ........................................................................................................................... 21 
7.1 
Chemotherapy Treatment Plan .............................................................................................................. 22 
7.2 
Radiation Treatment Plan ...................................................................................................................... 30 
7.3 
Surgical Treatment Plan ........................................................................................................................ 30 
7.4 
Concomitant Therapy ............................................................................................................................ 32 
 
8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 33 
8.1 
Definitions ............................................................................................................................................. 33 
8.2 
Evidence of Disease Progression/No Response After Chemotherapy .................................................. 33 
8.3 
Organ Preservation Rate........................................................................................................................ 34 
8.4 
Locoregional Relapse ............................................................................................................................ 34 
8.5 
Distant Disease ...................................................................................................................................... 34 
8.6 
Dating of First Recurrence .................................................................................................................... 35 
8.7 
Disease Free Survival ............................................................................................................................ 35 
8.8 
Management Following Relapse ........................................................................................................... 35 
 
9.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 36 
9.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 36 
9.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 36 
 
 


 
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9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting............................ 37 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 38 
9.5 
Reporting Safety Reports to Investigators ............................................................................................. 38 
 
10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 40 
10.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 40 
10.2 
Therapy After Protocol Treatment ........................................................................................................ 40 
10.3 
Follow-up Off Protocol Treatment ........................................................................................................ 40 
 
11.0 
CENTRAL REVIEW PROCEDURES ................................................................................................. 41 
11.1 
Retrospective ypstaging Central Pathology Review ............................................................................. 41 
11.2 
Central Surgery Review ........................................................................................................................ 41 
 
12.0 
CORRELATIVE STUDIES .................................................................................................................. 42 
12.1 
Protocol-Mandated Correlative Studies ................................................................................................ 42 
12.2 
Optional Banking of Samples ............................................................................................................... 43 
 
13.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 44 
13.1 
Objectives and Design ........................................................................................................................... 44 
13.2 
Endpoints and Analysis ......................................................................................................................... 44 
13.3 
Sample Size and Duration of Study ...................................................................................................... 44 
13.4 
Safety Monitoring ................................................................................................................................. 45 
13.5 
Interim Analysis .................................................................................................................................... 45 
13.6 
Quality of Life Analysis ........................................................................................................................ 45 
13.7 
Economic Analysis ................................................................................................................................ 45 
 
14.0 
PUBLICATION POLICY ..................................................................................................................... 47 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 47 
14.2 
Responsibility for Publication ............................................................................................................... 47 
14.3 
Submission of Material for Presentation or Publication ........................................................................ 47 
 
15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 48 
15.1 
Regulatory Considerations .................................................................................................................... 48 
15.2 
Inclusivity in Research .......................................................................................................................... 48 
15.3 
Obtaining Informed Consent ................................................................................................................. 49 
15.4 
Discontinuation of the Trial .................................................................................................................. 50 
15.5 
Retention of Patient Records and Study Files ....................................................................................... 50 
15.6 
Centre Performance Monitoring ............................................................................................................ 50 
15.7 
On-Site Monitoring/Auditing ................................................................................................................ 51 
 
16.0 
REFERENCES ...................................................................................................................................... 52 
 
APPENDIX I - PERFORMANCE STATUS SCALES/SCORES ...................................................................... 57 
APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL ........................................................... 58 
APPENDIX III - DOCUMENTATION FOR STUDY ...................................................................................... 58 
APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ........................ 60 
APPENDIX V - QUALITY OF LIFE ASSESSMENT ...................................................................................... 62 
APPENDIX VI - HEALTH UTILITIES ASSESSMENT .................................................................................. 77 
APPENDIX VII - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS ........................................ 84 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, in accordance with any modifications that may 
occur over the duration of the study, and according to Good Clinical Practice and any applicable local 
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that 
I and study personnel participating under my supervision have adequate resources to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice to CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
I attest that all surgeons from our institution who will perform Transanal Endoscopic Microsurgery (TEM) 
or Transanal Minimally Invasive Surgery (TAMIS) for CO.28 patients have previously performed the 
procedure in at least 20 previous rectal cancer patients. 
 
 
___________________________________________________ _________________________ 
Qualified Investigator Date 
(printed name and signature) 
 
Protocol Number: CCTG CO.28 
 
CENTRE: __________________________________________ 
 
 


 
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TREATMENT SCHEMA 
 
This is a two staged, single arm phase II trial of chemotherapy (FOLFOX or CAPOX) followed by tumour 
excision in patients with early stage rectal cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
yp Staging:  
• ypT0/T1goodN0 
• Disease Progression 
• No Response in Pre-excision MRI 
reporting at least one of these 
findings: 
- 
cT3ab stage  
- 
node positive disease  
- 
not clear circumferential 
radial margin (CRM) 
yp Staging:  
• ypT2 
• ypT1 tumours with: 
- poorly differentiated 
histology, and/or 
- lymphovascular invasion, 
and/or 
- positive margin within 
<1mm. 
yp Staging:  
• yp N+ 
• ypT3 
Early Stage Rectal Cancer  
cT1-3a,b N0 
6 cycles of q2weekly FOLFOX or 
4 cycles of q3weekly CAPOX 
TEMS/TAMIS 
Radiotherapy  
(as per institutional 
standard) 
Surveillance 
Total Mesorectal 
Excision 
Total Mesorectal 
Excision 
Optional Radiotherapy  
(as per institutional 
standard) 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine the organ preservation rate in patients with early (cT1-3a,bN0) rectal cancer treated 
with neoadjuvant FOLFOX or CAPOX and TEMS or TAMIS.  
 
1.2 
Secondary Objectives 
 
1. To describe the 3-year Locoregional Relapse Rate (LRR) in patients treated with organ 
preservation. 
2. To describe the 3-year Distant Relapse Rate (DRR) in patients treated with organ preservation. 
3. To describe the 3-year Disease Free Survival (DFS) rate in patients treated with organ 
preservation. 
4. To evaluate the rate of post-operative complications following neoadjuvant FOLFOX/CAPOX 
and tumour excision/surgery. 
5. To evaluate nature, severity and frequency of acute and long term toxicities in all patients. 
6. To evaluate Quality of Life (QoL) in all patients.  
7. To evaluate the cost-effectiveness of the neo-adjuvant chemotherapy approach vs. the current 
standard approach. 
 
1.3 
Tertiary Objectives 
 
To evaluate the prognostic value of baseline ctDNA as an independent prognostic value in addition 
to ypstage and histology.  
 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Colorectal cancer is the second most common cause of cancer death in North America, with rectal 
neoplasms accounting for one third of incident cases. The introduction of provincial colorectal 
cancer screening programs has led to earlier diagnosis and 35-40% of rectal tumours present with 
localized disease [Jemal 2008]. Current standard therapy for T1-3 tumours includes radical surgery 
with Total Mesorectal Excision (TME), and preoperative chemoradiation for patients with T3 
tumours or N1 tumours. Locoregional relapse rates with modern adjuvant therapy are generally 5% 
[Hong 2014; O’Connell 2014; Rodel 2014]. Even with laparoscopic surgery, surgical complication rates 
are significant and temporary diverting ostomies are associated with significant morbidity and the 
requirement for second surgery for reversal [Alberts 2012]. In patients treated with radical resection, 
ongoing issues with bowel function, incontinence, sexual function and depression persist. These 
are significantly worse in patients treated with neoadjuvant or adjuvant radiotherapy [Wiltink 2014]. 
 
Patients with low tumours, < 5 cm from the anal verge, commonly require permanent colostomies 
and the rates of non-sphincter sparing surgery in phase III trials of stage II/III rectal cancer is 
consistently 25% [Gerard 2012; Allegra 2014]. Loss of the rectum and a permanent colostomy has 
dramatic effects on quality of life, sexual/urinary and social function and at high economic cost. 
 
Multiple single arm and randomized phase II studies have explored the use of pelvic 
chemoradiation (chemoXRT) followed by Transanal Endoscopic Microsurgery (TEMS) or 
Transanal Minimally Invasive Surgery (TAMIS) as a means to increase rectal organ preservation 
[Lezoche 2012]. However, even with minimally invasive surgery like TEMS/TAMIS, neoadjuvant 
radiation significantly increases wound-healing complications [Marks 2009] and adversely affects 
sphincter [Hupkens 2015] and sexual function. Furthermore, patients who develop recurrence with 
this strategy are difficult to salvage as radiotherapy is no longer an option. Conversely, there is 
virtually no prospective experience of neoadjuvant FOLFOX/CAPOX chemotherapy and 
excision/surgery for early rectal tumours. 
 
Population based studies have documented an increasing use of local excision/minimally invasive 
surgery in the treatment of T1N0 or T2N0 rectal tumours [Stitzenberg 2013; You 2007]. In the United 
States, 2010 rates of local excision (LE) for T1 and T2 tumours were 62% and 21%, respectively 
[Stitzenberg 2013]. The use of adjuvant radiation with LE has decreased between 1998 and 2010 to an 
estimated frequency of 10% (T1) and 35% (T2) [Stitzenberg 2013]. Nevertheless, a significant 
proportion of clinical T1-2N0 tumours are pathologically node positive and the literature 
demonstrates an increased rate of local relapse with LE versus surgical resection [Sgourakis 2011; 
Sajid 2014]. Neoadjuvant chemotherapy has been shown to reduce locoregional recurrence in stage 
II/III rectal cancer (Bosset et al. 2006) and prospective trials are required to establish the role of 
chemotherapy in T1-T3, N0 rectal tumours treated without proctectomy. Induction chemotherapy 
is justified as a novel approach to reduce local and distant relapse for rectal tumours treated with 
excision alone and without the toxicities of pelvic radiation. 
 
This two staged phase II trial will determine if patients with stage 1-2 rectal tumours will have 
better outcomes if they are treated with chemotherapy (FOLFOX or CAPOX) followed by 
minimally invasive surgery (TEMS or TAMIS). The primary objective of the study is to determine 
the rate of organ preservation and the trial will be a success if more than 65% of patients treated in 
the study end up having a rectum-sparing surgery. Similar studies in Europe use chemoradiation, 
which has a higher surgical complication rate and more long-term toxicity. If this study’s primary 
endpoint is met, a randomized trial of radical surgery versus induction chemotherapy and organ 
preservation would be justified. 
 
 


 
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The shortened duration of induction FOLFOX chemotherapy proposed by this study reduces 
toxicity and is similar in duration to the ongoing phase III CRC.7 “PROSPECT” study to evaluate 
the role of induction chemotherapy as a means to avoid pelvic radiation. Pathologic stage after 
induction therapy (ypStage) remains the strongest and most consistent prognostic factor in rectal 
cancer and allows the safe stratification to observation after minimally invasive surgery or to radical 
surgery for those with ypT2 or higher stage tumours. The combination of reduced local recurrence 
and less radical surgery will substantially benefit patients while decreasing surgical and hospital 
resources and complications. The NEO Trial builds on the concept established by CRC.7 of 
neoadjuvant FOLFOX chemotherapy without pelvic irradiation as an experimental treatment for 
early rectal tumours. 
 
Radical surgery for invasive rectal cancer aims to remove the primary tumour and locoregional 
nodes and tumour deposits. While local excision can successfully remove the primary tumour, 
complete nodal clearance is not possible with this technique. The role of neoadjuvant chemotherapy 
is to treat locoregional tumour spread and improve locoregional tumour control. In table I, the 
frequency of pathologic node involvement in cT1-3 tumours is summarized, and both standard and 
exploratory treatment approaches are listed. 
 
Table 1. Pathologic node involvement (pN+) in cT1-3 tumours, with standard and exploratory 
treatment approaches. 
 
Clinical 
Stage 
pN+Rate 
Standard 
Treatment 
Exploratory Therapy 
cT1N0 
11-15% 
TME 
Excision/TEMS/TAMIS in low risk 
cT2N0 
22-28% 
TME 
Chemoradiation + TEMS =  
Chemoradiation + TME post  
(Randomized Phase II) 
cT3N0 
>30% 
ChemoRT + TME 
“Watch & Wait”: multiple retrospective case series report a 
50% organ preservation rate among patients with cT3+ 
tumours with a clinical response to induction chemoRT +/- 
chemotherapy. 
[Verseveld 2015; Perez 2014; Minsky 1989; Brodsky 1992; Salinas 2011; Lezoche 2012; Habr-Gama 2013] 
Abbreviations: c: clinical; pN+: pathologic node positive; TME: total mesorectal excision (radical surgery); LE: local 
excision; ChemoRT: chemoradiation; TEMS: transanal excisional microsurgery.  
 
T1N0 Tumours 
 
While proctectomy remains the standard for patients with T1N0 rectal cancer, a significant 
proportion of patients are treated with local excision alone due to lower morbidity and to allow 
organ preservation [Ptok 2007]. In 2010, 62% of T1 tumours were treated with LE of which < 10% 
received adjuvant radiation [Stitzenberg 2013]. The overall rate of nodal positivity for T1 tumours is 
reported to be 11-15% and predictors of lymph node metastasis include tumour size > 3 cm, high 
tumour grade (i.e. poorly differentiated), depth of tumour invasion into the lower third of the 
submucosa, the presence of lymphovascular invasion and lesions in the lower third of the rectum 
[Nascimbeni 2004; Salinas 2011; Minsky 1989; Brodsky 1992; Nascimbeni 2002]. Local excision is considered 
an appropriate treatment modality for carefully selected T1 rectal cancer patients without high-risk 
features who want to avoid surgery [Monson 2013]. 
 
 


 
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T1 tumours treated with LE are at increased risk of locoregional relapse and optimal adjuvant 
therapy for disease control and long-term organ preservation is not established. Numerous 
retrospective studies have described pelvic relapse rates of 6-14% among patients with T1 tumours 
[You 2007; Endreseth 2005; Ptok 2007; Borschitz 2008] and distal rectal tumours are at increased risk of 
both local and distant relapse [Nascimbeni 2004]. CALGB 8984 was a prospective study in which 59 
patients with T1 rectal tumours were treated with local excision alone and had an observed 
locoregional relapse rate of 8% and a 10 year DFS of 75% [Greenberg 2008]. 
 
T2N0 Tumours 
 
A National Cancer Database study described that 17% of T2 tumours were treated with LE in 2010, 
of which an estimated 40% of patients received adjuvant radiation [Stitzenberg 2013]. The overall rate 
of nodal positivity in T2 tumours is reported to be 22-28% [You 2007; Salinas 2011; Minsky 1989; Brodsky 
1992] and LE alone is not considered an acceptable standard among patients eligible for 
proctectomy. In CALGB 8984, 51 patients with T2 rectal tumours were treated with local excision 
and pelvic chemoradiation, and an 18% local relapse rate was observed [Greenberg 2008]. A 
randomized trial of 100 patients with clinical T2N0 tumours treated with chemoradiation compared 
subsequent modified TEMS (including significant perirectal fat/lymph node harvest) to 
laparoscopic TME. This RCT demonstrated pathological downstaging to ypT0/1 stage in half of 
patients. Rates of local and distant disease control were similar between the two arms, suggesting 
a combination of neoadjuvant therapy and expert TEM/TAMIS could be oncologically acceptable 
[Lezoche 2012; Lezoche 2005].  
 
T3N0 Tumours 
 
Standard therapy for patients with T3N0 rectal tumours is trimodality therapy with radical surgical 
resection plus combination 5-fluorouracil chemotherapy and external beam radiation therapy 
(EBRT). Patients with pathologic high-risk features are considered for post-operative 
chemotherapy. Retrospective case series have reported favourable outcomes among highly select 
groups of stage II/III rectal cancer after complete clinical response to induction therapy. Survival 
outcomes of patients treated with local excision after complete clinical or pathologic response 
(excisional biopsy) to induction chemoradiation were similar to patients treated with surgical 
resection [Smith 2012; Belluco 2011; Callender 2010]. One centre reported an actuarial local recurrence 
rate of 11% among 47 clinical T3, N0/N+ patients treated with full-thickness excision and EBRT. 
In this cohort, 49% had achieved a pCR and an additional 36% a complete clinical response after 
EBRT and excision. The reports have demonstrated that response to induction EBRT may be used 
as a means to select T3 patients for non-surgical management of rectal cancer. 
 
Other studies are currently exploring the role of induction chemotherapy with FOLFOX 
(NCT01515787) as a means to avoid the toxicities associated with pelvic radiation for stage II/III 
rectal tumours that do not approach the circumferential radial margin on MRI. A prior phase II 
study demonstrated a R0 resection rate of 100% and a pCR rate of 25% (8 of 32 patients) using a 
similar approach [Schrag 2014]. The current study similarly aims to evaluate the ability of induction 
FOLFOX/CAPOX chemotherapy and minimally invasive surgery to allow organ sparing therapy 
of early stage rectal cancer. 
 
 


 
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A further approach to management of stage T3N0/N+ rectal cancer is a “watch-and-wait” strategy 
whereby patients with a complete clinical response to induction chemoradiotherapy with or without 
chemotherapy are treated with close surveillance. Retrospective studies have documented high 
salvage rates for patients with recurrent tumours and disease specific survival rates that are similar 
to patients treated with initial surgical resection [Habr-Gama 2013; Glynne-Jones 2012; Callender 2010]. 
The rate of surgery avoidance is reported to be 50% [Habr-Gama 2013]. A study of FOLFOX/CAPOX 
chemotherapy and chemoradiation followed by surveillance for patients with significant clinical 
response is underway to prospectively document 3-year disease free survival in patients with T3-
4N1-2 low rectal tumours treated with non-operative management (ClinicalTrials.gov Identifier: 
NCT02008656). A “watch-and-wait” approach does not generally include the planned excision of 
the primary tumour and requires an intensive surveillance strategy.  
 
ypT0/T1 as a Surrogate of Local Control 
 
Multiple studies have demonstrated a very low risk of lymph node positivity and locoregional 
recurrence if downstaging to ypT0/T1 is achieved after chemoradiation. These risks significantly 
increase with ypT2 or more advanced tumours [Mignanelli 2010; Kim 2006; Belluco 2011]. The concept 
of ypT0/T1 as a surrogate of locoregional tumour control has been applied in multiple prospective 
phase II studies including the Dutch CARTS study in which patients with T1-3N0 low rectal 
tumours were treated with pelvic chemoXRT and those without clinical regression or with yp>T1 
tumours after TEMS were recommended for radical surgical resection. Patients with ypT0-1 
tumours were treated with TEMS only [Bökkerink 2011; Callender 2010]. The study did not proscribe 
systemic therapy, and tumour excision occurred after irradiation of the tumour bed, which has been 
shown to be associated with increased toxicity (see below).  
 
Excision Strategies 
 
Tumour excision can be performed via transanal excision or by transanal endoscopic microsurgery 
(TEM) approach. Transanal endoscopic microsurgery may have transanal approach in terms of 
visualization and resection of higher lesions. TAMIS is an alternative to TEMS that uses the same 
surgical principles of endoscopic illumination/magnification of the endoluminal operative field and 
minimally invasive instruments for tumour excision. A recent metanalysis demonstrated superiority 
of TEMS techniques over conventional transanal excision. The authors reported higher rates of R0 
resection (OR 5.281; 95% CI, 3.201–8.712; p < 0.001) and fewer lesion recurrences (OR, 0.248; 
95% CI, 0.154–0.401; p < 0.001) with TEM compared to transanal excision [Clancy 2015]. Despite 
the demonstrated superiority of minimally invasive techniques for locoregional control, a recent 
US Database study revealed that traditional LE is still performed in up to 34% of all patients treated 
by local excision [Stitzenberg 2013]. This may explain the higher than expected local recurrence rates 
observed on a population level. While the introduction of MIS techniques for transanal excision 
have made classic approaches to local excision obsolete, there is a role for the traditional approach 
with anal retractors and direct visualization in very low tumours that extend below the anorectal 
junction.  In these patients, once the dissection has extended above the anorectal junction, the MIS 
platform can be introduced to complete the procedure.  
 
Standard TEMS/TAMIS approach for early rectal malignancy includes a full-thickness excision of 
the lesion down to the perirectal fat and a 1 cm mucosal margin to achieve best results [Monson 
2013]. However, Lezoche et al recommend a more extensive resection of mesorectal fat with the 
specimen, termed “endoluminal locoregional resection” (ELRR) [Lezoche 2012]. With this approach, 
the authors demonstrated similar outcomes to radical resection in patients with T2 tumours after 
chemoXRT. These data suggest inclusion of some mesorectal fat in the local excision specimen 
may improve local control. 
 
 


 
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Several studies have demonstrated the importance of individual surgeon skill on both perioperative 
and oncologic outcomes. [Yeo, 2016; Massarotti, 2016; McColl, 2015]. Thus, control of this factor is 
crucial in the assessment of a novel oncologic strategy. Two established strategies to ensure surgeon 
ability are minimum volume thresholds and, where possible, video assessment of surgeon 
performance [Stevenson, 2015; Fleschman, 2015; Bonjer, 2015]. Helewa et al. have demonstrated that 
surgeons overcome the learning curve for TEM/TAMIS technique after performing 16 procedures 
[Helewa, 2016]. Large, randomized control trials involving minimally invasive techniques have 
utilized minimum experience thresholds of 20 procedures for enrollment of patients, in addition to 
a surgeon evaluation of an unedited video of the performance of a single procedure [Stevenson, 2015; 
Bonjer, 2015; Fleschman, 2015].  
 
Correlative Studies 
 
Few validated prognostic biomarkers have been established in rectal cancer. Prognostic multi-gene 
signatures such as Coloprint® and the Oncotype Recurrence Score® were developed to estimate 
prognosis and facilitate decision-making in the adjuvant setting [Salazar 2011; O'Connell 2010; Gray 
2011; Venook 2013; Sanz-Pamplona 2012]. More recently, the utility of the Oncotype Recurrence Score 
(RS) has also been defined in a randomized phase III trial of oxaliplatin-containing adjuvant 
chemotherapy [Yothers 2013] and in the setting of rectal cancer [Reimers 2014]. However there is a lack 
of predictive biomarkers that can be used to predict whether colorectal subtypes will benefit from 
adjuvant FOLFOX chemotherapy. 
 
The Nanostring PanCancer Pathways and Immune Panels® include a set of 700 genes representing 
major cancer pathways and key driver genes and can be used to score and rank each gene in 13 
pathways and immune cell-types and relate these to prior therapy. This study offers the unique 
opportunity to prospectively collect diagnostic and centrally reviewed TEM surgical specimen for 
Ncounter® based gene-expression studies. Matched pair analysis of rectal tumours prior to, and 
after FOLFOX/CAPOX chemotherapy will be characterized with the PanCancer Pathways and 
Immune Panels to characterize key cancer pathways and the most important immune-related genes 
altered by chemotherapy. 
 
ctDNA is a promising prognostic marker in early stage colon cancer [Diehl 2008; Diaz 2014; Lin 2014], 
but limited data has described its utility in rectal cancer. In a small study, the decrease of cell-free 
DNA levels after chemoradiation was associated with tumour downstaging to ypT0-T2 while 
ctDNA levels increased in nonresponders with ypT3-T4 tumours [Zitt 2008]. The utility of ctDNA 
to risk stratify patients with stage I/II rectal tumours has not yet been described. Measuring ctDNA 
after neoadjuvant therapy may serve as an early surrogate of response to FOLFOX therapy and 3 
year locoregional relapse rate and disease free survival. 
 
Quality of Life 
Rectal cancer treatment can adversely affect functional outcomes and quality of life. Total 
mesorectal excision (TME) and the use of chemoradiation have negative impact on short and long 
term function and QoL. Fourteen years following TME, patients who undergo TME have more 
sexual dysfunction and reduced quality of life. The addition of radiation therapy in addition to TME 
led to inferior bowel function [Wiltink 2014]. We anticipate that organ sparing therapy may result in 
better functional and quality of life outcomes than radical surgical resection with the potential for 
temporary or permanent stoma formation. 
 
 


 
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Quality of life will be evaluated by European Organization for Research and Treatment in Cancer 
(EORTC) Quality of Life Questionnaire QLQ-30 and EORTC QLQ-CR29 subscale. The EORTC 
QOL-C30 is a multidimensional, 30-item questionnaire which assesses five functional scales 
(physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and 
nausea/vomiting), a global health /QOL scale, as well as 6 single items [Groenvold 1997; Aaronson 
1993]. 
 
The EORTC QLQ-CR29 subscale supplements the core questionnaire with 29 items specific for 
patients with colorectal cancer. There are 18 items that deal with gastrointestinal symptoms, 
separate items for those with stomas and four sexual function items. These items comprise 6 scales 
and 11 individual items [Gujral 2007; Whistance 2009]. The EORTC core and subscale have been 
validated in various patient groups and translated into several languages. 
 
Two rectal cancer specific functional scales will be used by this trial, the Fecal Incontinence Quality 
of Life (FIQL) and the Low Anterior Resection Syndrome (LARS) instruments [Rockwood 2000; Juul 
2014]. These instruments have been developed to follow patients undergoing standard rectal surgery 
(i.e. TME) and have been previously reported for patients undergoing organ sparing transanal 
procedures [Planting 2013]. 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
The chemotherapy agents that may be used for patients enrolled on this trial are commercially 
available.  
 
3.1 
Oxaliplatin 
 
3.1.1 
Background Drug Information 
 
See the current oxaliplatin Product Monograph for details and up to date information. 
 
3.1.2 
Chemical Structure 
 
Oxaliplatin is a platinum alkylating agent, which contains platinum complexed to oxalate and 
diaminocyclohexane 
(DACH) 
complex. 
Its 
full 
chemical 
name, 
oxalate(trans-l-1,2-
diaminocyclohexane)platinum. The molecular weight of oxaliplatin is 397.3. It is slightly soluble 
in water, less so in methanol, and almost insoluble in ethanol and acetone.  
 
3.1.3 
Mechanism of Action 
 
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. 
 
3.1.4 
Human Toxicology 
 
The most common adverse reactions associated with the combination oxaliplatin/5-FU/LV were 
peripheral sensory neuropathies, fatigue, myelosuppression, GI toxicity and increased 
transaminases. 
 
The acute, reversible, primarily peripheral, sensory neuropathy associated with oxaliplatin is of 
early onset, and can occur within hours or one to two days of dosing. It usually resolves within 14 
days, and frequently recurs with further dosing. Symptoms include sensory dysesthesia, paresthesia 
and hypoesthesia of the limbs, mouth, throat and larynx. Jaw spasm, abnormal tongue sensation, 
dysarthria, eye pain, and a feeling of chest pressure have also been observed. 
 
Pharyngolaryngeal dysesthesia is common, with severe symptoms in 1-2% of patients shortly after 
drug infusion. Symptoms usually resolve within hours of onset. The feeling of difficulty in 
breathing or swallowing may be distressing to the patient. Cold avoidance should be exercised. 
Treatment is usually not needed, although antihistamines and bronchodilators have been used. To 
prevent recurrence, infusion time should be extended to 6 hours with subsequent treatments. 
 
The persistent (>14 days), primarily peripheral, sensory neuropathy is usually characterized by 
paresthesias, dysesthesias, hypoesthesias and altered proprioception. It can interfere with daily 
activities (e.g. buttoning clothing, holding objects, writing) and occurs in most patients receiving 
oxaliplatin with 5-FU/LV. Lhermittes sign and urinary retention are seen rarely. Persistent 
neuropathy can occur without prior acute neuropathy event. Symptoms may improve in some 
patients upon discontinuation of oxaliplatin. Calcium gluconate 1 g and magnesium sulphate 1 g 
infusions pre ± post-oxaliplatin did not appear to be effective neuroprotective agents in a 
randomized study. 
 
 


 
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Anaphylaxis has been reported, including severe events in 2-3% of patients, and can occur during 
any cycle. Patients should not be re-challenged. 
 
Pneumonitis has been reported rarely, and presents with cough, dyspnea, crackles and pulmonary 
infiltrates; oxaliplatin should be held pending investigation and discontinued if pneumonitis is 
confirmed. 
 
Incidences of adverse events are generally similar between oxaliplatin used as single agent or with 
fluorouracil and leucovorin, although severe (grades 3-4) diarrhea, nausea and vomiting, and 
neurotoxicity are more common with combination therapy. 
 
Hepatotoxicity, transaminitis, veno occlusive disease and nodular regenerative hyperplasia have 
been reported. 
 
Oxaliplatin is fetotoxic, mutagenic, clastogenic, teratogenic, genotoxic and is probably 
carcinogenic, and can affect fertility. It is contraindicated in pregnancy. Adequate contraception 
for both sexes is mandatory during treatment and for at least 6 months after the last dose. Breast 
feeding is contraindicated due to the potential secretion into breast milk. 
 
3.1.5 
Pharmacokinetic Studies 
 
Approximately 15% of the administered platinum is present in the systemic. The remaining 85% is 
rapidly distributed into tissues or eliminated in the urine. It does not cross blood brain barrier. 
Oxaliplatin has more than 90% irreversible plasma protein binding, primarily albumin and gamma 
globulin. It also binds irreversibly to erythrocytes. It has a rapid and extensive non-enzymatic (no 
cytochrome P450-mediated metabolism) biotransformation to reactive platinum complexes which 
are both active and inactive metabolites. It has a triphasic elimination with terminal half-time of 
391 hours. The major elimination route of platinum and its metabolites is renal excretion (54% 
within 5 days). Renal clearance of ultrafilterable platinum is significantly related to glomerular 
filtration rate.  
 
3.1.6 
Pharmaceutical Data 
 
Refer to the package insert. 
 
3.2 
Leucovorin Calcium (CF) 
 
3.2.1 
Background Drug Information  
 
See the current leucovorin calcium Product Monograph for details and up to date information. 
 
3.2.2 
Chemical Structure 
 
Leucovorin calcium (folinic acid) is a reduced form of folic acid. 
 
3.2.3 
Mechanism of Action 
 
Leucovorin is used to enhance the activity of fluorouracil by binding to the enzyme thymidylate 
synthetase and decreasing intracellular levels of thymidylate. 
 
 


 
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3.2.4 
Human Toxicology 
 
Deaths from severe enterocolitis, diarrhea and dehydration have been reported in elderly or 
debilitated patients receiving leucovorin and fluorouracil. Seizures or syncope have been reported 
rarely, usually in combination with fluorouracil and in patients with cerebral metastases, although 
a causal relationship has not been confirmed. Immediate allergic reactions and anaphylaxis can 
occur. Diarrhea and mucositis are common in combination with fluorouracil. Hand-foot syndrome 
and myelosuppression also occur in this combination. 
 
3.2.5 
Pharmacokinetic Studies 
 
It is rapidly and extensively converted to 5-methyltetrahydrofolate derivatives in the intestine prior 
to abruption. 5-methyltetrahydrofolate is an active metabolite and inactive metabolites are also 
formed. It rapidly absorbs with 97% absorption at a 25 mg dose. Leucovorin has a 35 – 45 % of 
plasma protein binding. It distributes to all tissues with maximum accumulation in liver and CSF. 
Leucovorin crosses the blood brain barrier. Volume of distribution is 3.2 L/kg. It is mainly 
eliminated in urine (80 – 90 %) and small amounts in feces. Elimination half-life is 32 min for 
parent drug and 227 min for active metabolite with a clearance of 3.9 mL/min/kg. 
 
3.2.6 
Pharmaceutical Data 
 
Refer to the package insert. 
 
3.3 
Fluorouracil 
 
3.3.1 
Background Drug Information 
 
See the current fluorouracil Product Monograph for details and up to date information. 
 
3.3.2 
Fluorouracil Chemical Structure 
 
Its chemical name is 5-Fluoro-1H,3H-pyrimidine-2,4-dione, chemical formulae is C4H3FN2O2 with 
a molar mass of 130 g/mol. 
 
3.3.3 
Mechanism of Action 
 
Fluorouracil was developed based on the observation that tumour cells utilized the base pair uracil 
for DNA synthesis more efficiently than did normal cells of the intestinal mucosa. It is a fluorinated 
pyrimidine antimetabolite that is metabolized intracellularly to its active form, fluorouridine 
monophosphate (FdUMP). The active form inhibits DNA synthesis by inhibiting thymidylate 
synthetase and the normal production of thymidine. Effects on RNA (incorporation into RNA and 
RNA inhibition) occur especially with bolus administration. Fluorouracil is cell cycle phase-
specific (S-phase). 
 
3.3.4 
Human Toxicology 
 
Following longer IV infusions, mucositis, hand-foot syndrome and diarrhea occur most commonly. 
Diarrhea may be profuse and life-threatening following administration of leucovorin with 
fluorouracil. Leukopenia is the usual dose-limiting toxicity after IV bolus administration 
 
 


 
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Patients with dihydropyrimidine dehydrogenase deficiency (DPD) are at risk of severe 
lifethreatening toxicity with fluorouracil. While severe deficiency is rare, 3-4% of the population 
has some degree of DPD deficiency. 
 
Excessive lacrimation occurs frequently. Transient blurring of vision, eye irritation and excessive 
nasal discharge have also been reported. The onset of eye symptoms may occur at any time during 
treatment. Fluorouracil has been demonstrated in tear fluid causing acute and chronic conjunctivitis 
that can lead to tear duct fibrosis. 
 
Acute cerebellar syndrome is manifested as ataxia of the trunk or extremities, disturbance of gait 
and speech, coarse nystagmus and dizziness. The ataxia syndrome is related to peak plasma levels 
of the drug rather than to cumulative dose, and is therefore more common with bolus doses than 
with infusions. It usually resolves after treatment is discontinued, but may persist in some cases. 
 
Palmar-plantar erythrodysesthesia or hand-foot syndrome has been noted with protracted and high 
dose continuous infusion (23-82%). The syndrome begins with dysesthesias of the palms and soles 
that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the 
hand and foot. The syndrome resolves gradually over 5 to 7 days with cessation of drug infusion. 
 
Cardiotoxicity has been reported and may be caused by coronary vasospasm, endothelial cell 
damage or increased thrombogenicity. It occurs in less than 10% of patients, of which up to 8% 
may be fatal. Cardiac effects include ECG changes, angina, arrhythmias, myocardial infarction, 
heart failure and are usually reported within 72 h of the first cycle of fluorouracil. Cardiotoxicity is 
independent of dose or underlying cardiac risk factors, but may be more common with infusions. 
Patients should be rechallenged only when there are no other treatment options. 
 
Fluorouracil has the potential to enhance radiation injury to tissues. While often called radiation 
recall reactions, the timing of the radiation may be before, concurrent with or even after the 
administration of the fluorouracil. Recurrent injury to a previously radiated site may occur weeks 
to months following radiation. 
 
Hemolytic-uremic syndrome has been reported when used in combination with mitomycin C. 
 
Brivudine, sorivudine or their chemically related analogues irreversibly inhibit DPD, resulting in a 
significant increase in fluorouracil exposure. This may lead to increased fluoropyrimidinerelated 
toxicities with potentially fatal outcome. Therefore, either a different antiviral therapy may be used 
or there should be an interval of at least 4 weeks between the administration of brivudine, 
sorivudine, or the analogues and the start of fluorouracil treatment. In the case of accidental 
administration of nucleoside analogues that inhibit DPD activity to patients treated with 
fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate 
hospitalization is recommended. 
 
Treatment with cimetidine for several weeks before initiation of fluorouracil treatment may 
increase plasma fluorouracil concentrations. This effect is probably due to both inhibition of hepatic 
enzymes and reduction of hepatic blood flow. Caution should be taken if the patient receives 
fluorouracil and cimetidine concurrently. 
 
Metronidazole may enhance the toxicity of fluorouracil. The mechanism of interaction is presumed 
to be reduced clearance of fluorouracil by metronidazole. Concurrent administration should be 
avoided. 
 
 


 
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Elevated INR levels and occasional episodes of bleeding have been reported during concomitant 
use of warfarin and fluorouracil or its analogues. In these cases, fluorouracil has usually been 
administered as one component of an antineoplastic combination regimen. Adequate anticoagulant 
response to warfarin and other coumarin-derivative therapy should be monitored regularly in 
patients taking fluorouracil. 
 
3.3.5 
Pharmacokinetic Studies 
 
Fluorouracil distributes into all body water by passive diffusion, crosses placenta and blood brain 
barrier, reaches high and persistent concentration in malignant effusions and has only 10% plasma 
protein binding. Eighty percent of the dose is degraded in liver by dihydropyrimidine 
dehydrogenase to active and inactive metabolites. It is mainly excreted as respiratory CO2 (60 – 80 
%), with 15 -20% excreted in the urine as intact drug within 6 hours after administration and 2-3% 
by biliary system. Higher clearance occurs in IV infusions than IV injections, due to saturation of 
metabolic or transport processes at higher drug concentrations. Elimination half-life is 6 – 20 mins 
dose dependent. 
 
3.3.6 
Pharmaceutical Data 
 
Refer to the package insert. 
 
3.4 
Capecitabine 
 
3.4.1 
Background Drug Information  
 
See the current capecitabine calcium Product Monograph for details and up to date information. 
 
3.4.2 
Chemical Structure 
 
Capecitabine is an antimetabolite, belonging to the fluoropyrimidine carbamate class. The 
molecular formulae is C15H22FN3O6 and molecular weight is 359 g/mol. 
 
3.4.3 
Mechanism of Action 
 
It causes cell injury via RNA- and DNA-related mechanisms. It is an orally administered precursor 
of 5- fluorouracil (5FU). Capecitabine is converted to 5FU by carboxyesterase, cytidine deaminase 
and thymidine phosphorylase (present in the liver and in tumours). Docetaxel appears to upregulate 
thymidine phosphorylase. The daily oral administration of capecitabine mimics the continuous 
intravenous infusion of 5-FU. 
 
3.4.4 
Human Toxicology 
 
The most common side effects for capecitabine include hand-foot syndrome, diarrhea, nausea, 
vomiting, mucositis, abnormal liver function tests, fatigue, abdominal pain, anorexia, weight loss, 
edema and headache. 
 
 


 
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The median time to onset of diarrhea, a dose-limiting adverse effect of capecitabine, is 34 days. 
The diarrhea may respond to standard anti-diarrheal therapy (e.g. loperamide). Patients with severe 
diarrhea should be closely monitored and given fluid and electrolyte replacement for dehydration 
as indicated. Dehydration may result in acute renal failure, particularly with other risk factors 
(preexisting renal dysfunction, concomitant nephrotoxic agents). Capecitabine should be held and 
the dose reduced after recovery. Older patients (≥ 65 years) may be at higher risk. 
 
Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome) is characterized 
by numbness, dysesthesia or paresthesia, tingling, painless or painful swelling, erythema, 
desquamation, blistering, and severe pain of the hands and/or feet and is more common in patients 
also receiving docetaxel. The median time to onset was 79 days. Dosage interruption/adjustment is 
required according to severity. In addition to dose interruption and subsequent dose reduction, 
topical emollients (e.g. hand creams, udder balm) may ameliorate the manifestations of hand-foot 
syndrome in patients receiving capecitabine. Current evidence indicates that oral pyridoxine may 
not be effective in ameliorating hand-foot syndrome in patients receiving capecitabine. (Kang 
2010). 
 
Severe rashes have been reported (Stevens-Johnson syndrome, Toxic Epidermal Necrolysis). 
Capecitabine must be permanently discontinued and the patient treated appropriately. 
 
Hyperbilirubinemia associated with capecitabine therapy occurs more frequently in patients with 
hepatic metastases. 
 
Patients with very low or absent dihydropyrimidine dehydrogenase (DPD) deficiency (ratelimiting 
enzyme of 5-fluorouracil catabolism) are at increased risk of severe or lifethreatening toxicity (i.e. 
neutropenia, GI and neurotoxicity, including fatalities) and should not receive capecitabine. In 
patients with partial DPD deficiency, capecitabine should be used with extreme caution, where the 
benefits outweigh the risks of treatment. 
 
Cardiac toxicity is similar to that reported for other fluorinated pyrimidines and includes ECG 
changes, angina, infarction, EKG changes, dysrhythmias and cardiac failure. The risk may be 
increased in patients with prior coronary artery disease. 
 
Very rare cases of leukoencephalopathy have been reported. 
 
3.4.5 
Pharmacokinetic Studies 
 
It has 70% oral absorption reaching Cmax in 1.5 hours. Pharmacokinetics is largely dose 
proportional with insignificant food effect. The pharmacokinetics is altered with advanced age and 
renal function but nor with gender, race, performance status, liver function and albumin. It is widely 
distributed with less than 60% plasma protein binding, primary to albumin (35%). Capecitabine is 
extensively bioactivated and metabolized in the liver. Elimination is mainly in the urine (70%) with 
a terminal half-life of 45 – 60 mins. 
 
3.4.6 
Pharmaceutical Data 
 
Refer to the package insert. 


 
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4.0 
STUDY POPULATION 
 
This study population includes patients with stage I-II (cT1-3ab/N0) rectal cancer. 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
4.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of enrollment. Questions 
about eligibility criteria should be addressed prior to enrollment. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy and to ensure that the results of this study can be useful for making treatment decisions 
regarding other patients with similar disease. 
 
 These eligibility criteria are expected to be followed. Any proposed variance must be discussed 
with CCTG prior to patient enrollment: 
 
4.1.1 
Histologically confirmed invasive well-moderately differentiated rectal adenocarcinoma diagnosed 
within 90 days prior to enrollment. 
 
Note: it is recommended that surgeons take a biopsy of the tumour during sigmoidoscopy / 
colonoscopy to ensure tissue availability and adequate pathology report confirming invasive well-
moderately differentiated rectal adenocarcinoma and no evidence of pathologic high risk factors. 
 
4.1.2 
Tumour stage cT1-T3abN0 based on pelvic MRI: 
• 
cT1N0– tumour invasion into submucosa, no radiographic evidence of mesorectal nodal 
metastasis, tumour deposits or vascular invasion. 
• 
cT2N0 – tumour invasion into muscularis propria, no radiographic evidence of mesorectal 
nodal metastasis, tumour deposits or vascular invasion. 
• 
cT3a,bN0– tumour invasion through the muscularis propria no more than 5 mm into the 
subserosa/perirectal tissue and clear of the circumferential radial margin (CRM). Absence of 
radiographic evidence of mesorectal nodal metastasis, tumour deposits or lymphovascular 
invasion [Glimelius 2010]. 
Note: If the tumour is not visualized in the MRI but there is histological confirmation of rectal 
adenocarcinoma the patient is eligible. 
 
4.1.3 
cN0 stage based on pelvic MRI. Any nodes ≥ 10 mm in longest dimension are considered 
malignant, regardless of nodal morphology. For pelvic nodes < 10 mm in longest dimension, if 
nodes are seen and are deemed to be morphologically benign in the opinion of the radiologist and 
surgeon, the patient is eligible. Patients with visible pelvic sidewall nodes are excluded. 
 
4.1.4 
M0 stage based on no evidence of metastatic disease by CT imaging. 
 
4.1.5 
Mid to low-lying tumour eligible for local tumour excision in the opinion of the treating surgeon. 
 
 


 
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4.1.6 
Age of at least 18 years. 
 
4.1.7 
Medically fit to undergo radical surgery as per treating surgeon’s discretion. 
 
4.1.8 
No contraindications to protocol chemotherapy. 
 
4.1.9 
Adequate normal organ and marrow function as defined below (must be done within 30 days prior 
to enrollment):  
• 
ANC ≥ 1.5 x 109/L  
• 
platelet count ≥100 x 109/L  
• 
bilirubin < 1.5 ULN, excluding Gilbert’s syndrome 
• 
Calculated creatinine clearance of ≥ 50 ml/min. 
• 
Clearance to be calculated using Cockcroft formula: 
 
Males: 
1.23 x (140 - age) x weight (kg) 
 
serum creatinine (μmol/l) 
 
Females: 
1.05 x (140 - age) x weight (kg) 
 
serum creatinine (μmol/l) 
 
4.1.10 The patient must have an ECOG performance status of 0, 1. 
 
4.1.11 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health utility 
questionnaires. The baseline assessment must be completed within required timelines prior to 
enrollment. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the 
questionnaires will not make the patient ineligible for the study. However, ability but unwillingness 
to complete the questionnaires will make the patient ineligible. 
 
4.1.12 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate. 
 
4.1.13 Must be accessible for treatment and follow-up. Patients enrolled on this trial must be treated with 
chemotherapy and followed at the enrolling centre. This implies there must be reasonable 
geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered 
for this trial. The patient’s city of residence may be required to verify their geographical proximity. 
(Call the CCTG office (613-533-6430) if questions arise regarding the interpretation of this 
criterion.) Investigators must assure themselves the patients enrolled on this trial will be available 
for complete documentation of the treatment, adverse events, follow-up and response assessments. 
 
Patients must agree to return to their primary care facility for any adverse events which may occur 
through the course of the trial. 
 
4.1.14 Protocol treatment is to begin within 5 working days of patient enrollment. 
 
 


 
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4.1.15 Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method during and for 6 months after completion of chemotherapy. A woman is considered to be 
of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive 
months. In addition to routine contraceptive methods, "effective contraception" also includes 
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy 
prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or 
vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to 
become heterosexually active during the time period for use of contraceptive measures outlined in 
the protocol, he/she is responsible for beginning contraceptive measures. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Section 5.0); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
4.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
4.2.1 
Patient has pathologic high risk factors on either the initial biopsy specimen report or follow up 
biopsy (if done): high histologic grade, mucinous histology, lymphatic or vascular invasion. 
 
4.2.2 
History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively 
treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of 
disease for ≥ 5 years. 
 
4.2.3 
Synchronous cancer. 
 
4.2.4 
Prior treatment for rectal cancer. 
 
4.2.5 
Previous pelvic radiation for any reason. 
 
4.2.6 
Patients with known dihydropyrimidine dehydrogenase deficiency  
 
4.2.7 
Treatment with other investigational drugs or anti-cancer therapy within 28 days prior to 
enrollment. 
 
4.2.8 
Clinically significant (i.e. active) cardiovascular disease for example cerebro vascular accidents 
(< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable 
angina, New York Heart Association (NYHA) grade II or higher, congestive heart failure, serious 
cardiac arrhythmia requiring medication. 
 
4.2.9 
Any contra-indications to undergo MRI imaging. 


 
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5.0 
PATIENT EVALUATION FLOWSHEET: PRE-TREATMENT, ON STUDY, AND AFTER 
TREATMENT  
 
All patients entered on study must be evaluated according to the schedule outlined below with 
documentation submitted according to the schedule in Appendix II. 
 
Required Investigations 
Prior To Enrollment 
During 
Protocol 
Treatment 
Prior to each 
FOLFOX or 
CAPOX cycle 
Pre-Excision 
2 weeks 
(FOLFOX) or 3 
weeks (CAPOX) 
after last injection 
in last cycle of 
chemotherapy 
Excision 
within 3 
weeks after 
pre-excision 
visit 
After Excision 1 
First 
Disease 
Relapse 2 
After First 
Disease Relapse 
(Phone Contacts 
Acceptable)3 
Within 
90 days 
Within 30 
days 
30 d 
Months 6, 
12, 18, 24, 
30 and 36. 
Months 48 
and 60 
(phone 
contacts 
acceptable) 
History and Physical Exam 
 
 
 
 
 
 
 
 
 
 
Including: height (baseline only), 
weight, ECOG performance 
status  
 
X 
X4 
X 
 
X 
X 
 
 
 
Concomitant Medications 
 
X 
X4 
X 
X 
X 
 
 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
CBC, differential (including 
lymphocytes), platelets  
 
X 
X4 
X 
 
 
 
 
 
 
Coagulation 
 
 
 
 
 
 
 
 
 
 
PTT, PT/INR 
 
X 
 
X 
 
 
 
 
 
 
Biochemistry 
 
 
 
 
 
 
 
 
 
 
ALT, serum creatinine, total 
bilirubin 
 
X 
X4 
X 
 
 
 
 
 
 
Creatinine Clearance (calculated) 
 
X 
X4 
X 
 
 
 
 
 
 
Serum CEA 
 
X 
 
X 
 
 
X 
 
 
 
Correlative Studies 
 
 
 
 
 
 
 
 
 
 
Tumour tissue specimen banking 
5 
X 
 
 
 
X 
 
 
 
 
 
Whole blood (for ctDNA), whole 
blood, serum and plasma 5, 6 
 
X 
 
X 
 
 
12, 24 
and 367 
 
X 7, 8 
 
Radiology 
 
 
 
 
 
 
 
 
 
 
MRI pelvis  
X 
 
 
X 
 
 
6, 18  
and 307 
 
X 
 
CT pelvis 9 (optional if pelvic MRI 
performed) 
X 
 
 
 
 
 
12, 24  
and 36 
 
X 
 
CT chest 9 
X 
 
 
 
 
 
12, 24  
and 36 
 
X 
 
CT abdomen with contrast 10 
X 
 
 
 
 
 
12, 24 
and 36 
 
X 
 
Sigmoidoscopy/Colonoscopy 11 
X 
 
 
X 
 
 
X 12 
 
X 
 
Other Investigations 
 
 
 
 
 
 
 
 
 
 
Biopsy confirming invasive well-
moderately differentiated rectal 
adenocarcinoma 
X 13 
 
 
 
X 
 
 
 
X 14 
 
Pregnancy test 13 
 
X 
 
 
 
 
 
 
 
 
Submission of tumour tissue for 
retrospective central ypstaging 
confirmation (mandatory) 
 
 
 
 
X 
 
 
 
 
 
Capecitabine patient diary  
 
 
Daily 16 
 
 
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment 17 
 
X 
X 
X 
X 
X 
X 18 
X 18 
X 18 
X 18 
table continues on next page 
 
 


 
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Required Investigations 
Prior To Enrollment 
During 
Protocol 
Treatment 
Prior to each 
FOLFOX or 
CAPOX cycle 
Pre-Excision 
2 weeks 
(FOLFOX) or 3 
weeks (CAPOX) 
after last injection 
in last cycle of 
chemotherapy 
Excision 
within 3 
weeks after 
pre-excision 
visit 
After Excision 1 
First 
Disease 
Relapse 2 
After First 
Disease Relapse 
(Phone Contacts 
Acceptable)3 
Within 
90 days 
Within 30 
days 
30 d 
Months 6, 
12, 18, 24, 
30 and 36. 
Months 48 
and 60 
(phone 
contacts 
acceptable) 
Quality of Life 
 
 
 
 
 
 
 
 
 
 
EORTC QLQ-30 and EORTC 
QLQ-CR29 
 
X 
 
X 
 
 
6, 12, 24 
and 36 
 
 
 
LARS and the Fecal 
Incontinence Quality of Life 
Instrument 
 
X 
 
X 
 
 
6, 12, 24 
and 36 
 
 
 
Health Economics 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L  
 
X 
X 19 
X 
 
X 
6, 12, 24 
and 36 
 
 
 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
Survival information  
 
 
 
 
 
 
 
X 
 
X 
1. Timing for visits after excision are scheduled from last tumour excision date: 
a. 
For patients having TME as first protocol excision: from TME date  
b. For patients having TEMS/TAMIS as first protocol excision: from TEMS/TAMIS date 
c. 
For patients having TEMS/TAMIS as first protocol excision and then having a TME: from TME date 
2. See protocol section 8 for definitions. 
3. Phone contacts or visits after first disease relapse are required every 6 months from date of relapse. 
4. Tests may be done on the date of treatment or, if not possible, the previous working day before treatment day. If treatment is to begin on a Monday, 
may be done on the previous Friday (maximum 72 hours prior to treatment). 
5. Please also see protocol Section 12.0 and details for collection, processing, storing, and shipping these samples provided in the CO.28 Correlative 
Studies Manual. 
6. Whole blood (that is not for ctDNA testing) will only be collected prior to enrollment. 
7. Not required for patients that had a TME. 
8. To be obtained within 28 days as close to the time of relapse as possible. Blood for correlatives done within 28 days PRIOR to date of relapse does 
not need to be repeated. 
9. For CT pelvis and chest, a CT scan with contrast is preferred but not mandated. Patients with contrast allergies may undergo chest X-ray and /or 
Chest MRI. 
10. Contrast is REQUIRED for the CT scan of the abdomen. Patients with contrast allergies may undergo liver ultrasound and /or MRI. 
11. Rectal exam and proctoscopy are ideally to be performed by the primary surgeon. Proctoscopy should be performed < 90 days prior to enrollment. 
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. 
12. For patients that had a TME it is only required at month 36. 
13. If a rectal tumour tissue biopsy was performed within 90 days prior to enrollment, a repeat biopsy is not necessary. It is recommended that surgeons 
take a biopsy of the tumour during sigmoidoscopy/colonoscopy to ensure tissue availability and adequate pathology report confirming invasive well-
moderately differentiated rectal adenocarcinoma and no evidence of pathologic high risk factors. 
14. It is strongly encouraged that suspicious or unequivocal evidence of first local relapse be confirmed definitively by either biopsy (preferred) or by 
repeat/confirmatory imaging. Where imaging evidence of first local relapse is, in the opinion of the investigator and radiologist, absolutely 
unequivocal and not requiring subsequent confirmation by either biopsy or follow-up imaging, this must be clearly indicated in supporting 
documentation 
15. Urine pregnancy test in women of childbearing potential and if a false-positive is suspected this may include an ultrasound to rule-out pregnancy. 
16. To be completed daily for patients receiving Capecitabine. 
17. Adverse Events to be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) (see Appendix III). 
18. Only protocol chemotherapy or surgery related adverse events have to be reported after the 30 days post-excision visit. 
19. After 3 cycles of FOLFOX or after 2 cycles of CAPOX. 
 
5.1 
Follow-up for Ineligible Patients 
 
The follow-up requirement for ineligible patients who have received no protocol chemotherapy and 
have not had excision procedure only includes submission of the Baseline Report. 
 
Ineligible participants who have received at least one dose of protocol chemotherapy and/or have 
had TEMS/TAMIS procedure should be followed as per protocol requirements to allow for 
treatment and adverse event assessment. 
 
 


 
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6.0 
ENTRY/ENROLLMENT PROCEDURES 
 
6.1 
Entry Procedures 
 
All enrollments will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
enrolling patients will be provided at the time of study activation and will also be included in the 
“EDC Data Management Guidebook”, posted on the CO.28 trial specific web-site. If sites 
experience difficulties accessing the system and/or enrolling patients please contact the help desk 
(link in EDC) or the CO.28 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG CO.28) 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking/optional consent version date 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
BSA, height and weight  
 
6.2 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to "ideal" weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. In those rare cases where a patient's surface area is greater than 2.2, 
the actual surface area or 2.2 may be used. CCTG BSA calculations are based on the Mosteller 
formula. 
 
6.3 
Enrollment 
 
Enrollment will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting enrollment. 
 
All enrolled patients are to be followed until death or until sites are informed by CCTG that further 
follow-up is no longer required. The follow-up requirements for ineligible patients are outlined in 
Section 5.1. 
 
 


 
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7.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient 
enrollment. 
 
7.1 
Chemotherapy Treatment Plan 
 
FOLFOX or CAPOX is selected based on investigator discretion. 
 
7.1.1 
Drug Administration 
 
7.1.1.1 FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Oxaliplatin 
85 mg/m2 
IV over 
2 hours 
Day 1 
Repeat every 14 days 
for a total of 6 cycles 
Leucovorin 
400 mg/m2 bolus 
IV over 
2 hours 
Day 1 
Repeat every 14 days 
for a total of 6 cycles 
5FU 
400 m/m2 bolus over 5 - 15 
minutes then 2400 mg/m2 
continual infusion over 46 - 48h 
total dose 
IV 
Days 1 to 2 
Repeat every 14 days 
for a total of 6 cycles 
1. Oxaliplatin could be administered first, prior to leucovorin; or concurrently with leucovorin 
administered via separate infusion containers. 
2. If necessary to accommodate holidays, patient schedule or other justified circumstance, the 
schedule may be delayed up to 7 days. 
3. Patients who cannot tolerate six cycles of FOLFOX or those that require dose modification 
below dose level -2 (see Section 7.1.3.1) may receive preoperative 5FU chemoradiotherapy 
based on investigator decision. If chemoradiotherapy is given, it should be given according to 
local institutional guidelines for FOLFOX administration. There are no restrictions on dose 
modifications for the 6th cycle of neoadjuvant FOLFOX. 
4. Alternate folinic acids (i.e. levo-leucovorin) may be substituted for Leucovorin if 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. 
5. The dose modification schema for FOLFOX (see Section 7.1.3.1) 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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7.1.1.2 CAPOX (capecitabine + oxaliplatin) 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Capecitabine 
1000 mg/m2 BID 
PO 
14 days starting 
on Day 1 
Repeat every 21 days 
for a total of 4 cycles 
Oxaliplatin 
130 mg/m2 
IV over 2 hours 
Day 1 
Repeat every 21 days 
for a total of 4 cycles 
1. Patients must be counseled about the importance of compliance with capecitabine. Compliance, 
with mention of missed doses, must be documented in the patient’s medical record by site study 
personnel. 
2. Missed doses must be documented on the appropriate CRF and by patients on their provided 
diary. 
3. Patients should take their doses of capecitabine orally daily, one dose in the morning and one 
dose in the evening, approximately 12 hours apart. Patients should swallow capecitabine 
tablet(s) whole with a full glass of water, about 8 ounces, 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 
their next study visit. 
 
7.1.2 
Premedication 
 
All patients should be pre-medicated as per institutional guidelines. 
 
7.1.3 
Dose Adjustments 
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix III). 
 
The major toxic effects which limit dose are hematologic. The guidelines which follow outline dose 
adjustments for several of these toxic effects. If a patient experiences several adverse events and 
there are conflicting recommendations, please use the recommended dose adjustment that reduces 
the dose to the lowest level. 
 
7.1.3.1 FOLFOX 
 
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 Dose levels of FOLFOX is a guideline. 
Leucovorin dose may be decreased in concert with bolus 5-FU dose. If 5-FU is not administered, 
leucovorin should not be administered. 
1. Dose reduction: If a patient requires a dose reduction below level -2 during cycles 1-5 
preoperative therapy, consider discontinuing FOLFOX and referring the patient for TME. This 
does not apply for cycle 6. 
2. Dose delay: If FOLFOX is held due to toxicity for more than 30 days from planned next cycle 
date consider discontinuing FOLFOX and referring the patient for TME. This does not apply 
for cycle 6. 
 
 


 
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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 standard surgical therapy. Dose reduction to level -3 is 
only permitted during cycle 6. 
 
Suggested FOLFOX Dose Modifications Based on Interval Adverse Events 
 
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  
 
SYSTEM/ORGAN/
CLASS (SOC) 
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT (Occurring before Day 1 of Cycle) 
Other  
Non-hematologic  
Grade ≥ 2 
(excluding 
alopecia) 
5-FU 
Oxaliplatin 
Hold treatment until ≤ grade 1 then resume at next lower dose 
level.  
 
 
 


 
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Dose Modifications Based on Retreatment (days 2-14 during previous cycle) 
 
SYSTEM/ORGAN
/CLASS (SOC) 
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 2-14 during cycle) 
Gastrointestinal 
disorders 
Nausea grade 2 
Oxaliplatin 
Intensify antiemetic therapy and proceed with FOLFOX at 
current dose level. Maximal antiemetic therapy includes a 
5HT inhibitor (i.e. granisteron, ondansetron, palonestron) as 
well as compazine, lorazepam, aprepitant, and decadron 
Nausea grade 3 
 
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. 
Nausea grade 4 
 
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. 
Vomiting grade 2 
5-FU 
Oxaliplatin 
Intensify antiemetic therapy and proceed with FOLFOX at 
current dose level. Maximal antiemetic therapy includes a 
5HT inhibitor (i.e. granisteron, ondansetron, palonestron) as 
well as compazine, lorazepam, aprepitant, and decadron. 
Vomiting grade 3 
 
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. 
Vomiting grade 4 
 
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. 
Diarrhea grade 2  
 
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. 
Diarrhea grade 3 
 
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 one dose level when resolved to < grade 2 
Diarrhea grade 4 
 
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 
 
table continues on next page 
 
 


 
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SYSTEM/ORGAN
/CLASS (SOC) 
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 2-14 during cycle) - CONTINUED 
Gastrointestinal 
disorders 
continued 
 
Oral mucositis, 
Esophagitis, 
gastritis, pharyngeal 
mucositis, small 
intestinal mucositis, 
colitis, rectal and/or 
anal mucositis 
grade 3 
5-FU 
Oxaliplatin 
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  
Oral mucositis, 
Esophagitis, 
gastritis, pharyngeal 
mucositis, small 
intestinal mucositis, 
colitis, rectal and/or 
anal mucositis 
grade 4 
 
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  
 
AT TIME OF RETREATMENT (occurring at Days 11-14 during cycle) 
Blood and lymphatic 
system disorders 
Neutropenia 
ANC 1.0 to 1.199 
x 109/L 
5-FU 
Oxaliplatin 
Hold FOLFOX until ANC ≥ 1200 then resume at previous 
dose levels. 
Neutropenia 
ANC < 1.0 x 109/L 
 
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 GCSF at 
standard doses. 
Febrile neutropenia 
ANC < 1.0 x 109/L 
and temp ≥ 38.5o C 
 
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 GCSF at standard doses. 
Thrombocytopenia 
 Platelets 50 to  
 74.999 x 109/L 
 
Hold FOLFOX until platelets ≥ 75,000 then resume at 
previous dose levels. except bolus 5-FU which is reduced by 
one dose level.  
Thrombocytopenia 
 Platelets < 50 x 
109/L 
 
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 
Pharyngolaryngeal 
dysesthesia 
Oxaliplatin 
Increase the duration of oxaliplatin infusion to six hours for 
all subsequent cycles. See section 8.4 
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. 
 
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SYSTEM/ORGAN
/CLASS (SOC) 
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
AT TIME OF RETREATMENT (occurring at Days 11-14 during cycle) CONTINUED 
Immune system 
disorders 
Allergic reaction 
grade 1 
Oxaliplatin 
Leucovorin 
Decrease infusion rate by 50% until symptoms resolve, then 
resume at initial planned rate. 
Allergic reaction 
grade 2 
 
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. 
Allergic reaction 
 grade 3 or 4 
 
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. DO NOT apply COLD. 
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 
Oxaliplatin 
 
Continue FOLFOX with previous dose level of 5-FU and one 
dose level reduction of oxaliplatin for all subsequent cycles. 
Neurotoxicity grade 
3 resolving to ≤ 
grade 2 between 
treatment cycles 
 
Continue FOLFOX with previous dose level of 5-FU and one 
dose level reduction of oxaliplatin for all subsequent cycles. 
Neurotoxicity grade 
3 persisting 
between treatment 
cycles 
 
Discontinue oxaliplatin. Continue 5-FU/leucovorin. Reassign 
to 5FUCMT if has not completed at least 5 cycles of 
FOLFOX. 
Neurotoxicity  
grade 4 
 
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 
 
Discontinue all study therapy. 
Cerebrovascular 
ischemia grade 3  
or 4 
 
Discontinue all study therapy. 
 
7.1.3.2 Oxaliplatin-Induced Pharyngolaryngeal Dysesthesia 
 
Oxaliplatin can induce an acute syndrome of pharyngolaryngeal dysesthesia (grades 3/4) 
characterized by subjective sensations of dysphagia or dyspnea, feeling of suffocation, without 
any evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or 
bronchospasm (no stridor or wheezing) occurs in 1-2% of the patients. 
 
If a patient develops this oxaliplatin-induced pharyngolaryngeal dysesthesia, proceed to evaluate 
the oxygen saturation with a pulse oximeter and if confirmed as normal, an anxiolytic agent may 
be given and the patient observed in clinic until the episode has resolved. The duration of the 
oxaliplatin infusion should be increased to six hours for all subsequent treatment cycles. 
 
 


 
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Pharyngolaryngeal dysesthesia may appear similar to a hypersensitivity reaction. The table below 
compares the two. 
 
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 
 
7.1.3.3 CAPOX 
 
The precise dose modification schema used and the symmetry of dose modification may be left to 
the discretion of the treating oncologist. The modification schema in Table Dose levels of CAPOX 
is a guideline.   
 
CAPOX Dose Levels for NON-neurologic toxicity: 
 
Dose Level* 
Oxaliplatin 
Capecitabine 
0 
130 mg/m2 
1000 mg/m
2 bid 
-1 
100 mg/m2 
750 mg/m
2 bid 
-2 
85 mg/m2 
500 mg/m
2 bid 
-3 
Discontinue Therapy 
Discontinue Therapy 
* Dose level 0 refers to the starting dose. 
 
 
 


 
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Suggested CAPOX Dose Modifications Based on Interval Adverse Events 
 
SYSTEM/ORGAN/
CLASS (SOC) 
ADVERSE 
EVENT 
AGENT 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT (Occurring before Day 11 -14 of Cycle) 
Blood and lymphatic 
Systemic disorders 
Neutropenia  
ANC (x 109/L) 
1000-1199 
Capecitabine 
Oxaliplatin 
If ANC less than 1.2 on Day 1 of cycle, hold treatment. 
Perform weekly CBC, maximum of 2 times. 
If ANC is greater than or equal to 1.2 within 2 weeks, proceed 
with treatment at the dose level noted across from the lowest 
ANC result of the delayed week(s). 
If ANC remains less than 1.2 after 2 weeks, discontinue 
treatment.  
ANC (x 109/L)  
 500 - 999 
Follow steps in first box above and if resumed, with one dose 
level reduction.  
ANC (x109/L)  
 less than 500 
Follow steps in first box above but resume with two dose level 
reduction.  
Platelets  
(x 109/L)  
50 – 74.9 
Capecitabine 
Oxaliplatin 
 
If platelets less than 75 on Day 1 of cycle, hold treatment. 
Perform weekly CBC, maximum of 2 times. 
If platelets greater than or equal to 75 within 2 weeks, proceed 
with treatment at the dose level noted across from the lowest 
platelets result of the delayed week(s). 
If platelets remain less than 75 after 2 weeks, discontinue 
treatment.  
Platelets  
(x 109/L)  
10 – 49.9 
Follow steps in first box above and if resumed, with one dose 
level reduction from the lowest platelets result of the delayed 
week(s). 
Platelets  
(x 109/L)  
Less than 10.0 
Follow steps in first box above but resume with two dose level 
reduction from the lowest platelets result of the delayed 
week(s).  
 
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  
 
7.1.4 
Duration of Therapy 
 
In the absence of unacceptable toxicities or disease progression, as defined in Section 10.1, or 
intolerable toxicity, chemotherapy will continue until completion of 6 cycles for FOLFOX and 4 
cycles for CAPOX. 
 
7.1.5 
Patient Compliance 
 
Trained medical personnel will administer protocol chemotherapy. Treatment compliance will be 
recorded in the patient’s medical record and case report form (CRF). 
 
Capecitabine treatment compliance will be monitored by review of the patient diary. 
 
 
 


 
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7.2 
Radiation Treatment Plan 
 
Pelvic radiation is recommended for patients when the excisional specimen demonstrates ypT3+ 
or N+ disease and requires radical TME surgery. Patients should be treated with standard 
preoperative chemoradiation or short course pelvic radiation according to standard institutional pre-
operative protocol.  
 
Optional preoperative pelvic radiation could be deliver as per institution standard to patients with 
pre-excision MRI reporting at least one of these findings: 
• 
cT3ab stage  
• 
node positive disease  
• 
not clear circumferential radial margin (CRM) 
 
Patients with yp staging as T1 (high risk) and T2 tumours do not require pre-operative pelvic 
radiation and should proceed directly to radical TME surgery. 
 
Patients who cannot tolerate six cycles of FOLFOX or those that require dose modification below 
dose level -2 (see Section 7.1.3.1) may receive preoperative 5FU chemoradiotherapy based on 
investigator decision. If chemoradiotherapy is given, it should be given according to local 
institutional guidelines for FOLFOX administration. 
 
7.3 
Surgical Treatment Plan  
 
Tumour excision should be performed within 2-5 weeks (FOLFOX) or 3-6 weeks (CAPOX) after 
first dose of last cycle of chemotherapy. 
 
Step/Indication 
Result 
Surgical Treatment Plan 
Pre-excision 
MRI/Endoscopy 
(post-chemotherapy) 
• Disease Progression OR 
• No Response demonstrated by at least one of these 
findings on pre-excision MRI 
- 
cT3ab stage 
- 
node positive disease 
- 
not clear circumferential radial margin (CRM) 
Total Mesorectal 
Excision (TME) or 
optional radiotherapy 
(per institution standard) 
followed by TME 
• No Disease Progression 
• Pre-excision MRI not meeting the “no response” 
criteria 
TAMIS/TEMS 
TEMS/TAMIS 
yp Staging :  
• ypN+ OR 
• ypT3 
Radiotherapy (per 
institution standard) 
followed by TME 
 
yp Staging:  
• ypT2 OR 
• ypT1 tumours with:  
- 
poorly differentiated histology and/or 
- 
lymphovascular invasion and/or 
- 
positive margin within < 1 mm 
TME 
 
yp Staging:  
• ypT0 N0 
• ypT1good N0 
Surveillance  
 
 


 
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Lesions that on pre-excision (post-chemotherapy) MRI and/or endoscopy show evidence of 
progression or no response to chemotherapy (see protocol section 8.2) should be treated with 
immediate TME surgery as progression of local disease in spite chemotherapy is an established 
poor prognostic factor. 
 
Local pathology ypstaging review determines subsequent therapy. Patients with ypstage 
T0/T1goodN0 tumours are treated with surveillance while patients with tumours with ypT2, N+ or 
ypT1 tumours with poor prognostic features or are treated with radical TME surgery within 6-8 
weeks after local excision. Poor prognostic features include poorly differentiated histology, 
lymphovascular invasion and/or positive margin within < 1 mm. ypT1good are those tumours that 
do not have poor prognostic factors. 
 
For information about retrospective ypstaging confirmation by central pathology review refer to 
section 11.1 of this protocol. 
 
Surgeons performing TEMS/TAMIS in this trial should have performed these procedures in at least 
20 previous rectal cancer cases [Stevenson 2015; Bonjer, 2015; Fleschman, 2015]. Each surgeon should 
submit an unedited video of a TEMS/TAMIS procedure with sutured defect closure for central 
review. A video of the 1st patient enrolled in CO.28 is acceptable. 
 
Surgeon trainees are not excluded from performing TME but their cases must be performed under 
supervision of a qualified surgeon and cancer-specific surgery must be ensured. 
 
As per protocol, transanal, endoscopic tumour excision is permitted for low rectal tumours that 
approach or involve the anal sphincter if complete excision is feasible. 
 
Lesions that on pre-excision (post-chemotherapy) MRI and/or endoscopy show evidence of 
progression or no response to chemotherapy (see protocol Section 8.2) should be treated with 
immediate TME surgery as progression of local disease in spite chemotherapy is an established 
poor prognostic factor. 
 
Prior to surgery, all patients will have pretreatment with mechanical bowel preparation, with the 
specific bowel cleansing regimen at the discretion of the treating surgeon. Patients will be usually 
admitted to hospital on the day of surgery. Appropriate antibiotics for gram positive, negative and 
anaerobic coverage, and taking patient allergies/sensitivities into considerations will be 
administered as per institutional guidelines preoperative or at the start of the procedure. Heparin 
will not be administered. 
 
The operating surgeon will use the minimally invasive transrectal platform of their choice. If the 
tumour encroaches into the anal canal, the surgeon can start the procedure using conventional 
transanal technique and complete the procedure with the transanal platform inserted using 
minimally invasive techniques. Where possible, the procedure will be video recorded. Excision of 
the tumour will include a minimum of 1 cm gross margin [Monson et al. 2013]. and a full thickness 
rectal excision, including a cuff of mesorectal fat. [Lezoche 2012]. After specimen extraction, 
vigorous irrigation with water will be recommended to minimize the risk of tumour implantation. 
The preferred management of the rectal defect will be sutured closure.  
 
If the tumour has progressed and is no long appropriate for local excision, the surgeon will 
photodocument the lesion and abandon the procedure. 
 
 


 
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The surgical specimen will be pinned to a cork board to prevent distortion of the orientation and 
photographed. The specimen will be reviewed by pathology for ypstaging. 
 
7.4 
Concomitant Therapy 
 
7.4.1 
Permitted 
 
Use of G-CSF (Gastrofil, Neulasta or Neupogen) is at the discretion of treating physicians but is 
not usually necessary. 
 
7.4.2 
Not Permitted 
 
Erythropoietin stimulating agents should not be administered at any point during this protocol. 


 
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8.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
8.1 
Definitions 
 
8.1.1 
Evaluable for Organ Preservation Rate 
 
All patients treated with FOLFOX or CAPOX and TEMS or TAMIS will be included in the organ 
preservation rate analysis as primary endpoint of this study. 
 
Organ preservation rate will additionally be calculated for all patients that have received protocol 
chemotherapy. 
 
8.1.2 
Evaluable for Rectal Cancer Control 
 
All patients treated with FOLFOX or CAPOX and TEMS or TAMIS will be evaluated for 
locoregional and distant relapse rate. 
 
Rectal cancer control will additionally be calculated for all patients that have received protocol 
chemotherapy. 
 
8.1.3 
Evaluable for Disease Free Survival 
 
All patients treated with FOLFOX or CAPOX and TEMS or TAMIS will be evaluable for 
assessment of disease free survival. 
 
Disease Free Survival will additionally be calculated for all patients that have received protocol 
chemotherapy. 
 
8.1.4 
Evaluable for Post-Operative Complications 
 
All patients treated with FOLFOX or CAPOX and tumour excision/surgery will be evaluable for 
post-operative complications. 
 
8.1.5 
Evaluable For Adverse Events 
 
All patients who have received at least one dose of protocol chemotherapy will be included in the 
safety analysis. 
 
8.1.6 
Evaluable for Quality of Life Assessment 
 
All patients who have completed a quality of life questionnaire are evaluable for quality of life. 
 
8.2 
Evidence of Disease Progression/No Response After Chemotherapy 
 
8.2.1 
Progression 
 
The diagnosis of progressive disease will be made by treating surgeon after review of the pre-
excision (post-chemotherapy) MRI and endoscopy. 
 
 


 
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8.2.2 
No Response 
 
No response to chemotherapy will be defined as meeting at least one of the criteria below: 
 
A. Pre-excision MRI reporting at least one of these findings: 
• 
cT3ab stage  
• 
node positive disease  
• 
not clear circumferential radial margin (CRM) 
 
OR 
 
B. Excision specimen reporting at least one of these findings:  
• 
node positive disease 
• 
ypT2 
• 
ypT1 tumours with: 
- 
poorly differentiated histology, and/or 
- 
lymphovascular invasion, and/or  
- 
positive margin within <1mm. 
 
8.3 
Organ Preservation Rate 
 
Organ preservation rate is defined as the proportion of patients who avoid TME. 
 
8.4 
Locoregional Relapse  
 
Locoregional relapse is defined as reappearance of a tumour within the rectum or pelvis. 
 
Evidence of Local Disease Recurrence: 
• 
Suspicious: Suspicious imaging requiring further confirmation. 
• 
Definite:  
Confirmation by cytology or histology OR Definitive imaging documenting local 
recurrence. 
 
Elevated CEA only or physical examination only are not sufficient as evidence of suspicious or 
definite local disease recurrence. 
 
Locoregional relapse is dated by the day of first evidence (clinical, radiological or pathological) of 
locoregional disease after complete tumour surgical excision date (with pathology results negative 
for malignant disease within 1 mm of surgical margins). It is strongly encouraged that suspicious 
or unequivocal evidence of first local relapse be confirmed definitively by either biopsy (preferred) 
or by repeat/confirmatory imaging. Where imaging evidence of first local relapse is, in the opinion 
of the investigator and radiologist, absolutely unequivocal and not requiring subsequent 
confirmation by either biopsy or follow-up imaging, this must be clearly indicated in supporting 
documentation. 
 
8.5 
Distant Disease  
 
Distant disease is defined as evidence of rectal cancer disease at sites remote from the rectum. 
 
Evidence of Distant Disease Recurrence: 
• 
Suspicious: Suspicious imaging requiring further confirmation. 
• 
Definite:  
Confirmation by cytology or histology OR Definitive imaging documenting 
distant recurrence. 
 
 


 
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8.6 
Dating of First Recurrence  
 
The diagnosis of recurrent disease by radiographs or scans should be dated from the date of the first 
suspicious record, even when the specific imaging abnormality requires subsequent confirmation 
by biopsy (required for confirmation of new primary malignancy) or is otherwise determined in 
retrospect (e.g. bone metastases that will never be biopsied but are definitively confirmed with 
subsequent imaging procedures). 
 
Initial dates of first recurrence should be made as they occur by those who are responsible for the 
care of the patient. Dates that are based on suspicion alone will be reviewed by the CCTG 
coordinating office in order to establish accuracy through subsequent clinical course. 
 
8.7 
Disease Free Survival 
 
Disease-Free Survival (DFS) is defined as the interval from complete tumour surgical excision date 
(with pathology results negative for malignant disease within 1 mm of surgical margins) to date of 
first occurrence of the events in the table below. 
 
Patients not meeting the criteria for failure by the analysis data cutoff date will be censored at their 
last disease assessment date. 
 
First Event 
Disease Free Survival 
None 
Censored 
Locoregional relapse 
Failure 
Distant disease 
Failure 
Non-protocol radiotherapy, chemotherapy or biologic therapy 
without documentation of the site of failure 
Failure 
Death due to any other reason 
Failure 
 
8.7.1 
Capture of Failures and Work-up at Detection of First Failure:  
 
Only the first event experienced will determine a patient’s failure status for DFS analysis. However, 
in order to fully capture the patterns of failure in this study population, a detailed work-up at the 
time of the first failure is required, and sites of failures should be documented in the CRF. 
 
For instance, if a patient first develops locoregional relapse, then a work-up for distant metastasis 
will be performed at the same time. If the distant metastatic work-up reveals the presence of distant 
metastasis, then all sites of failure will be documented, even though the time of the first detected 
failure event will be used to determine the disease free survival. Similarly, if a patient is first found 
to have distant metastasis, then a work-up for locoregional relapse should be performed at the same 
time. If the locoregional work-up does not reveal relapse at the same time, then this patient is 
considered to only have distant disease failure. 
 
8.8 
Management Following Relapse 
 
Management following relapse is at the discretion of the investigator. Survival and protocol 
chemotherapy or surgery related adverse events data should continue to be capture after first 
relapse. 
 
 


 
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9.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix III). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
9.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events, which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 9.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment) and at 
any time afterwards. 
• 
Unexpected adverse events are those, which are not consistent in either nature or severity with 
information contained in the product monograph. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
9.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the CO.28 section of the CCTG website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
 


 
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EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
CO.28 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533 2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application. 
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the CO.28 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application. 
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430). 
 
9.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting  
 
9.3.1 
Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 4.1.15. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy. 
 
9.3.2 
Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 6 months after the completion of 
study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 
 
Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
 


 
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If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
9.3.3 
Exposure Reporting (Non-study Participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. The investigator is 
responsible for determining significance, based on the agent to which the individual is exposed. 
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure using the CCTG Exposure Reporting Form available from the trial webpage. 
 
Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual for 30 days after the last dose/exposure. All follow-
up reports must be submitted to CCTG in a timely manner. A copy of the signed exposure follow-
up consent signature page must also be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or prolongation 
of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital 
anomaly/birth defect, then an SAE report must be additionally submitted as described above. 
 
9.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment cannot be ruled out). 
 
9.5 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) single reports or line listings) from other clinical trials that are 
reportable to regulatory authorities in Canada as reported to the CCTG. This includes all serious 
events that are unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. 
The reports will be posted to the CCTG trial CO.28 web-based safety monitoring utility. 
Investigators must review and document in the trial files proof of review of these events as per ICH 
GCP. 
 
 


 
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Investigators must notify their Research Ethics Boards (REBs) of events, which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes 
and any other event required by their REB. Safety reports that are not mandated by CCTG to be 
submitted to the REB are marked as ‘NR’ (not required) in the safety report monitoring utility. The 
date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial CO.28 
web based safety monitoring utility and documentation of REB submission must be retained in the 
study binder on site. The REB submission template provided by CCTG can be used to assist with 
tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 


 
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10.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
10.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 7.0. 
• 
Tumour progression as defined in Section 8.2. 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 7.0. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution. 
 
10.2 
Therapy After Protocol Treatment 
 
Supportive care therapy is recommended as per local standards. 
 
10.3 
Follow-up Off Protocol Treatment 
 
All patients will be seen 30 days after excision and then at months 6, 12, 18, 24, 30, 36, 48 and 
from the excision date (please refer to section 5.0 for more details). Phone contacts at months 48 
and 60 after excision will be acceptable. 


 
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11.0 
CENTRAL REVIEW PROCEDURES 
 
11.1 
Retrospective ypstaging Central Pathology Review 
 
There will be central pathology review for this study. Expert retrospective pathology review will 
be done for all patients to confirm ypstaging after excision. At least one disease site specialty 
pathologist with recognized diagnostic expertise for the tumour type will review the specimens and 
pathology report of each case. Another expert pathologist will be consulted to resolve significant 
diagnostic discordance if it arises. Results of the central pathology review will not be provided to 
the originating institution, the patient or patient record. Please consult CO.28 Correlative Studies 
Manual for additional details and timelines. 
 
11.2 
Central Surgery Review 
 
Surgeons performing TEMS/TAMIS in this trial should have performed these procedures in at least 
20 previous rectal cancer cases [Stevenson, 2015; Bonjer, 2015; Fleschman, 2015]. 
 
Each surgeon should submit an unedited video of a TEMS/TAMIS procedure with sutured defect 
closure for central review. A video of the 1st patient enrolled in CO.28 is acceptable. 
 
Please contact CO.28 CCTG Study Coordinator for additional details about video characteristics 
and its submission for central review. 


 
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12.0 
CORRELATIVE STUDIES 
 
A detailed Correlative Studies Manual will be provided on the CO.28 trial specific website, which 
will include details regarding sample preparation, handling and shipping. 
 
Specimens collected may be used by researchers now or in the future to better understand the nature 
of rectal cancer and how patients respond to treatment. Samples will be used for research purposes 
only and will not be sold. Patients will not be identified by name. The only identification of tissue 
will be by a patient study number assigned at the time of enrollment to the trial the surgical/ 
histology number and/or patient initials. Material issued to researchers will be anonymized and 
only identified by a coded number. 
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient. 
 
All patients on whom a diagnostic tumour block or slides are collected will be aware of this retrieval 
and will have given their consent. 
 
12.1 
Protocol-Mandated Correlative Studies 
 
Tumour Tissue Collection 
 
Consenting to submit representative tumour tissue of the diagnostic tumour tissue from a biopsy 
done prior to enrollment AND from the protocol excision that removes the primary tumour is 
mandatory for participation in this trial. 
 
One formalin fixed paraffin embedded (FFPE) block and one adjacent normal tissue block are 
requested from both the diagnostic tumour tissue from a biopsy done prior to enrollment AND from 
the protocol excision that removes the primary tumour. Where local centre regulations prohibit 
submission of tissue blocks, sites should request approval from the CCTG prior to local site 
activation to permit cores (2 x 2 mm cores of tumour) and slides (20 X 5 micron thick unstained 
slides from the block) to be submitted as an alternative to a block of tumour tissue. If, at any time, 
the submitting hospital requires the block or slides to be returned for medical or legal concerns, it 
will be returned by courier on request. 
 
Whole blood (for ctDNA), Whole Blood, Serum and Plasma Collection  
 
The submission of whole blood (for ctDNA), whole blood, serum and plasma is mandatory for 
participation in this trial. 
 
The CCTG is interested in exploring the use of surrogate tissues such as serum and plasma in 
evaluating potential prognostic or predictive biomarkers, or as evidence of pharmacodymanic 
effects. Whole blood, serum and plasma will be collected from all patients for planned studies for 
this trial. 
 
Planned priority assay:  
• 
Circulating tumour DNA 
 
Detailed instructions for whole blood (for ctDNA), whole blood, serum and plasma sample 
acquisition, preparation, and shipping are found in the CO.28 Correlative Studies Manual. 
 
 


 
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12.2 
Optional Banking of Samples 
 
Banking of Tumour Tissue 
 
Mandatory submission of tumour tissue has been described above. The subsequent banking of any 
remaining diagnostic tissue collected is not mandatory for participation in the study, but the 
participation of all centres is strongly encouraged. Blocks will be carefully banked as part of the 
CCTG tissue/tumour bank at Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 
 
Banking of Whole Blood, Serum and Plasma  
 
Mandatory submission of whole blood, serum and plasma has been described above. The 
subsequent banking of any remaining blood samples collected is not mandatory for participation in 
the study. Blood samples will be carefully banked as part of the CCTG tissue/tumour bank at 
Queen’s University in Kingston, Ontario. 
 
Proposals to use the banked specimens for the purposes of assessing markers involved in predicting 
treatment response and outcomes may be submitted to the bank. A scientific review process of any 
proposals to use the tissue will take place and any proposals approved will have undergone ethics 
approval. 


 
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13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
Objectives and Design 
 
This is a single-arm two-stage trial with the primary objective to determine the organ preservation 
rate in patients with early (cT1-3a,bN0) rectal cancer treated with neoadjuvant FOLFOX or 
CAPOX and TEMS or TEMIS. Secondary objectives include estimation of 3 year locoregional 
relapse rate, distant relapse rate, and disease free survival in patients treated with organ preservation 
and evaluation of toxicities and quality of life. 
 
13.2 
Endpoints and Analysis 
 
The primary endpoint of this study is the protocol specified organ preservation rate, defined as the 
proportion of patients with tumour downstaging to ypT0/T1good N0 and who avoid radical surgery. 
The 95% confidence interval for the organ preservation rate will be calculated. 
 
The 3 year locoregional relapse rate, distant relapse rate, and disease free survival will be estimated 
based on Kaplan-Meier method. 
 
13.3 
Sample Size and Duration of Study 
 
Prospective phase II studies have documented an organ preservation rate of 50-68% among patients 
with clinical T1-3N0 rectal tumours treated with chemoradiation and minimally invasive surgery. 
 
Based on these historic phase II data, the experimental treatment would be considered of no interest 
if the protocol specified organ preservation rate is 50% or lower (H0) and as promising if its 
avoidance rate is 65% or higher (H1). With an optimal two-stage minimax design, 22 patients 
would be accrued in the first stage. 
 
The trial would be stopped at the end of the first stage if the number of patients who avoided radical 
surgery is 10 or less. Otherwise the trial would proceed to the second stage to accrue 28 additional 
patients. The experimental procedure would be considered as promising if, out of the total patients 
accrued, 30 or more patients avoided radical surgery. The exact type I error rate and power of this 
design are respectively 0.1 and 0.8. The minimum and maximum sample sizes are respectively 22 
and 50 evaluable patients. Allowing for a 15% inevaluable rate, the total sample size is 58 patients. 
 
The interim analysis at 22 patients will also determine if the trial has recruited a proportional 
representation of T1/2 and T3 patients. If the interim analysis shows disproportionality between the 
number of T1/2 and T3 patients, the eligibility criteria and reasons limiting enrollment will be 
reviewed and the trial team will consider extending accrual of one or the other group if it is 
determined to be necessary. 
 
If the avoidance rate of the proposed procedure is 50% or lower, there is a 42% chance this study 
would be stopped. 
 
Based on CCTG previous survey results, the study potentially opening at 12 centres, each centre 
accruing 3 patients per year, the estimated minimum accrual time for 58 patients is 19 months. 
 
 


 
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13.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators’ meetings. 
 
13.5 
Interim Analysis 
 
Please refer to Section 13.3 for analysis after first stage (n=22). 
 
13.6 
Quality of Life Analysis 
 
The quality of life of patients will be assessed using EORTC-QLQ C30 with EORTC QLQ-CR29 
subscale. Scoring of the EORTC-QLQ C30 and CRC29 data will be completed following the 
procedures recommended by the EORTC Study Group on Quality of Life. For each domain or 
single item measure a linear transformation will be applied to standardize the raw score to range 
between 0 and 100. Questionnaire compliance rates will be ascertained at each measurement time 
point. Mean baseline scores for each subscale and summary scores will be calculated. 
 
Mean change scores from baseline at each assessment time and associated standard deviation will 
be calculated. Standard CCTG QOL Response Analysis categorizing patients as either having 
improved, stable, or worsened QOL will also be performed [Osoba 2005]. A change score of 10 
points from baseline is defined a priori as clinically relevant. For functional scales and global health 
status, patients will be considered to have QOL improvement if reporting a score 10-points or better 
than baseline at any time of QOL assessment. Conversely, patients will be considered worsened if 
reporting a score minus 10-points or worse than baseline at any time of QOL assessment without 
any improvement. Patients whose scores fall between 10-point changes from baseline at every QOL 
assessment will be considered as stable. In contrast to functional scales, for the determination of 
patient’s QOL response, classification of patients into improved and worsened categories will be 
reversed for symptom scales. QoL response rate and associated 95% confidence interval will be 
calculated for each domain and item. 
 
13.7 
Economic Analysis  
 
The purpose of the economic evaluation is to measure health utilities starting from baseline over 
time for patients who are treated with the protocol neoadjuvant chemotherapy. The health states of 
patients will be collected using the EQ-5D-5L questionnaire [Herdman 2011] and the health utilities 
of the health states will be obtained using the Canadian value sets [Xie 2016]. 
 
The prospective collection of health utilities directly from CO28 patients will enable the 
development of a model-based cost-effectiveness analysis to compare protocol treatment with the 
current standard treatment. Current standard therapy for T1-3 tumours includes radical surgery with 
Total Mesorectal Excision (TME), and preoperative chemoradiation for patients with T3 tumours 
or N1 tumours. 
 
A state-transition model will be constructed to conduct a cost-utility analysis of the neoadjuvant 
chemotherapy approach based on this protocol vs. the current standard approach from a government 
payer’s perspective, over a lifetime horizon with a 5% discounting for cost and effectiveness. The 
input of the model will be obtained by prospectively collecting efficacy data and health utilities in 
CO.28. Other efficacy data, utility data, resource utilization data and unit costs will be obtained 
from existing literature or retrospective chart reviews as needed. 
 
 


 
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The primary endpoint of the economic analysis will be incremental cost-utility ratio, which is the 
ratio of the incremental of cost between the two approaches to the incremental quality-adjusted life 
year gained between the two approaches. The incremental cost-effectiveness ratio will also be 
calculated, which is the ratio of the incremental cost between the two approaches to the incremental 
life-years gained between the two approaches. One way sensitivity analyses and probabilities 
sensitivity analysis will be conducted to assess for the robustness of the results and to examine the 
drivers of cost and effectiveness. 


 
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14.0 
PUBLICATION POLICY 
 
14.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
14.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
14.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
14.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
14.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 


 
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15.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
15.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
15.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrollment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 
 
 


 
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15.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study. 
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial. 
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject. 
 
15.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
 


 
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Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian. 
 
For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
15.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why. 
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
15.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP. 
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site. 
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained. 
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access. 
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained. 
 
For international participating regions, local regulatory guidance should be followed with respect 
to duration of records retention, unless otherwise contractually dictated. 
 
15.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
 


 
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15.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 


 
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16.0 
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APPENDIX I - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 


 
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APPENDIX II - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
All CO.28 chemotherapy drugs are commercially available and will not be supplied for this study. 
 
 
 


 
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APPENDIX III - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of enrollment and will apply to all eligible and ineligible 
patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data collection 
including SAE reporting (see Section 9.0 for details regarding SAE reporting). For details about accessing 
the EDC system and completing the on-line Case Report Forms, please refer to the Data Management 
Guidebook posted on the CO.28 area of the CCTG web-site (www.ctg.queensu.ca). 
 
The ELECTRONIC CRFs to be used in this trial are: 
 
Electronic Case Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be 
sent using Supporting Document 
Upload Tool* 
BASELINE REPORT 
Due within 2 weeks of patient enrollment.  
Copies of signature pages of 
main and optional consent 
forms; relevant pathology & 
radiology reports. 
CHEMOTHERAPY 
REPORT  
To be completed after each chemotherapy cycle. Due 
within 2 weeks of end of cycle. This report documents 
treatment, adverse events and investigations for each 
chemotherapy cycle. 
Relevant radiology reports. 
PRE-EXCISION VISIT 
REPORT 
To be complete within 2 weeks after pre-excision visit.  Relevant radiology reports. 
END OF TREATMENT 
REPORT 
To be complete within 4 weeks after final tumour 
excision  
 
SURGERY REPORT  
To be complete within 4 weeks after surgery (either 
TME or TEMS/TAMIS) 
Relevant pathology and 
surgery reports. 
CORRELATIVE 
STUDIES 
See Section 12 in this protocol. 
Relevant pathology reports. 
FOLLOW-UP REPORT 
Continued follow-up after chemotherapy, radiotherapy 
and/or protocol tumour excision(s) completed. Due 
within 2 weeks after contact with patient. 
Relevant pathology, 
radiology and surgery 
reports. 
RELAPSE REPORT  
To be completed at the time of disease relapse or 
failure. Due within 2 weeks after contact with patient. 
Relevant pathology, 
radiology and surgery 
reports. 
SHORT FOLLOW 
REPORT 
To be completed after disease relapse or failure and for 
patients that have no protocol tumour excision.  
 
DEATH REPORT** 
Required for all patients while study is open. Due 
within 2 weeks of knowledge of death. 
Autopsy report, if done. 
SERIOUS ADVERSE 
EVENT (SAE) REPORT 
All reportable serious adverse events must be reported 
as described in Section 9.0. Preliminary CCTG Serious 
Adverse Event Report due within 24 hours. Updated 
CCTG Serious Adverse Event Report due within 7 
days. 
All relevant test reports, 
admission, discharge 
summaries/notes. 
* Source documents other than those listed above may be requested to confirm eligibility, compliance, endpoints, and/or 
serious adverse events. Supporting documents should be uploaded immediately after the report they refer to has been 
submitted electronically. All supporting documents must have personal identifiers redacted. 
** It is the investigator's responsibility to investigate & report the date/cause of death of any patient who dies during this period. Any 
death that occurs during this protocol therapy or within 30 days after last dose that is considered as unexpected an related to protocol 
treatment must also be reported as a Serious Adverse Event as described in Section 9.0. 
 
 


 
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The collection of the following information will NOT be done through the EDC system. Instead submit as 
follows: 
 
Data  
Required at 
Collection /Submission 
Comments 
Quality of Life 
Questionnaire 
and EQ-5D  
Questionnaire 
To be completed within 30 
days prior to enrollment, at 
pre-excision visit, then at 
months 3, 6, 12, 24 and 36 
Patient to complete on paper; 
site CRA to enter data (as required) 
in the EDC system within 
corresponding folders 
Retain questionnaires 
at the site 
Capecitabine 
Patient Diary 
To be completed daily by the 
patient, if treated with 
Capecitabine 
To be collected and reviewed for 
compliance each cycle. Site CRA to 
enter data (as required) in the EDC 
system within corresponding folders 
Retain diary at the site 
 
 
 


 
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APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for Adverse Event (AE) reporting. 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: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


 
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APPENDIX V - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-enrollment (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 


 
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If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, as 
required by the schedule in the protocol. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that 
case, you may express sympathy that things are below par, but state that this is exactly the information we 
require if we are to understand more about how quality of life is affected. You may also remind them that 
it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . . 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 
 


 
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Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible. 
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion. 
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
cannot comprehend either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 


 
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8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 


 
 
Quality of Life Questionnaire – ENGLISH 
 
CCTG Trial: CO.28 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Within 30 days prior to enrollment 
 PRE-Excision 2-4 weeks (FOLFOX) or 3-5 weeks (CAPOX) after last cycle of chemotherapy  
 
 
After protocol excision. For patients who fail and go onto TME, these times are from TME date: 
 6 months      12 months      24 months      36 months 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy           mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 1 of 10 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (CO.28) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28. EORTC QLQ-C30 
Page 2 of 10 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 EORTC QLQ-C30 
Page 3 of 10 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
 
 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 4 of 10 
Please go on to the next page 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
Patients sometimes report that they have the following symptoms. Please indicate the extent to which 
you have experienced these symptoms during the past week. 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. Did you urinate frequently during the day? 
1 
2 
3 
4 
 
 
 
 
 
32. Did you urinate frequently during the night? 
1 
2 
3 
4 
 
 
 
 
 
33. Have you had any unintentional release (leakage) of 
urine? 
1 
2 
3 
4 
 
 
 
 
 
34. Did you have pain when you urinated? 
1 
2 
3 
4 
 
 
 
 
 
35. Did you have abdominal pain? 
1 
2 
3 
4 
 
 
 
 
 
36. Did you have pain in your buttocks/anal area/rectum? 
1 
2 
3 
4 
 
 
 
 
 
37. Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
 
 
 
 
 
38. Have you had blood in your stools? 
1 
2 
3 
4 
 
 
 
 
 
39. Have you had mucus in your stools? 
1 
2 
3 
4 
 
 
 
 
 
40. Did you have a dry mouth? 
1 
2 
3 
4 
 
 
 
 
 
41. Have you lost hair as a result of your treatment? 
1 
2 
3 
4 
 
 
 
 
 
42. Have you had problems with your sense of taste? 
1 
2 
3 
4 
 
 
 
 
 
43. Were you worried about your health in the future? 
1 
2 
3 
4 
 
 
 
 
 
44. Have you worried about your weight? 
1 
2 
3 
4 
 
 
 
 
 
45. Have you felt physically less attractive as a result of 
your disease or treatment? 
1 
2 
3 
4 
 
 
 
 
 
46. Have you been feeling less feminine/masculine as a 
result of your disease or treatment? 
1 
2 
3 
4 
 
 
 
 
 
47. Have you been dissatisfied with your body? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 5 of 10 
Please go on to the next page 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
48. Do you have a stoma bag (colostomy/ileostomy)?  
Yes  
No 
 
(please circle the correct answer) 
 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
Answer these questions ONLY IF YOU HAVE A STOMA BAG, if not please continue below: 
49. Have you had unintentional release of gas/flatulence 
from your stoma bag? 
1 
2 
3 
4 
 
 
 
 
 
50. Have you had leakage of stools from your stoma bag? 
1 
2 
3 
4 
 
 
 
 
 
51. Have you had sore skin around your stoma? 
1 
2 
3 
4 
 
 
 
 
 
52. Did frequent bag changes occur during the day? 
1 
2 
3 
4 
 
 
 
 
 
53. Did frequent bag changes occur during the night? 
1 
2 
3 
4 
 
 
 
 
 
54. Did you feel embarrassed because of your stoma? 
1 
2 
3 
4 
 
 
 
 
 
55. Did you have problems caring for your stoma? 
1 
2 
3 
4 
 
Answer these questions ONLY IF YOU DO NOT HAVE A STOMA BAG: 
 
 
 
49. Have you had unintentional release of gas/flatulence 
from your back passage? 
1 
2 
3 
4 
 
 
 
 
 
50. Have you had leakage of stools from your back 
passage? 
1 
2 
3 
4 
 
 
 
 
 
51. Have you had sore skin around your anal area? 
1 
2 
3 
4 
 
 
 
 
 
52. Did frequent bowel movements occur during the day? 
1 
2 
3 
4 
 
 
 
 
 
53. Did frequent bowel movements occur during the night? 
1 
2 
3 
4 
 
 
 
 
 
54. Did you feel embarrassed because of your bowel 
movement? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 6 of 10 
Please go on to the next page 
© QLQ-CR29 Copyright 2006 EORTC Quality of Life Group. All rights reserved. Version 2.1 
 
During the past 4 weeks: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
 
For MEN only: 
56. To what extent were you interested in sex? 
1 
2 
3 
4 
 
 
 
 
 
57. Did you have difficulty getting or maintaining an 
erection? 
1 
2 
3 
4 
 
For WOMEN only: 
58. To what extent were you interested in sex? 
1 
2 
3 
4 
 
 
 
 
 
59. Did you have pain or discomfort during intercourse? 
1 
2 
3 
4 
 
 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 7 of 10 
Please go on to the next page 
Fecal Incontinence Quality of Life Instrument 
 
Q 1: 
In general, would you say your health is: 
 
1   Excellent 
2   Very Good 
3    Good 
4   Fair 
5   Poor 
 
Q 2: 
For each of the items, please indicate how much of the time the issue is a concern for you due to accidental bowel 
leakage. 
 
Q2. Due to accidental bowel leakage: 
Most of 
the Time 
Some of 
The Time 
A Little of 
the Time 
None of 
the Time 
a. I am afraid to go out. 
1 
2 
3 
4 
b.  I avoid visiting friends. 
1 
2 
3 
4 
c.  I avoid staying overnight away from home. 
1 
2 
3 
4 
d.  It is difficult for me to get out and do things like 
going to a movie or to church. 
1 
2 
3 
4 
e.  I cut down on how much I eat before I go out. 
1 
2 
3 
4 
f.  Whenever I am away from home, I try to stay 
near a restroom as much as possible. 
1 
2 
3 
4 
g.  It is important to plan my schedule (daily 
activities) around my bowel pattern. 
1 
2 
3 
4 
h.  I avoid traveling. 
1 
2 
3 
4 
i.  I worry about not being able to get to the toilet in 
time. 
1 
2 
3 
4 
j.  I feel I have no control over my bowels. 
1 
2 
3 
4 
k.  I can’t hold my bowel movement long enough to 
get to the bathroom. 
1 
2 
3 
4 
l.  I leak stool without even knowing it. 
1 
2 
3 
4 
m.  I try to prevent bowel accidents by staying very 
near a bathroom. 
1 
2 
3 
4 
 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 8 of 10 
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Q 3: 
Due to accidental bowel leakage, indicate the extent to which you AGREE or DISAGREE with each of the 
following items. 
 
Q3. Due to accidental bowel leakage: 
Strongly 
Agree 
Somewhat 
Agree 
Somewhat 
Disagree 
Strongly 
Disagree 
a.  I feel ashamed. 
1 
2 
3 
4 
b.  I can not do many of things I want to do. 
1 
2 
3 
4 
c.  I worry about bowel accidents. 
1 
2 
3 
4 
d.  I feel depressed. 
1 
2 
3 
4 
e.  I worry about others smelling stool on me. 
1 
2 
3 
4 
f.  I feel like I am not a healthy person. 
1 
2 
3 
4 
g.  I enjoy life less. 
1 
2 
3 
4 
h.  I have sex less often than I would like to. 
1 
2 
3 
4 
i.  I feel different from other people. 
1 
2 
3 
4 
j.  The possibility of bowel accidents is always on 
my mind. 
1 
2 
3 
4 
k.  I am afraid to have sex. 
1 
2 
3 
4 
l.  I avoid traveling by plane or train. 
1 
2 
3 
4 
m.  I avoid going out to eat. 
1 
2 
3 
4 
n.  Whenever I go someplace new, I specifically 
locate where the bathrooms are. 
1 
2 
3 
4 
 
Q 4: 
During the past month, have you felt so sad, discouraged, hopeless, or had so many problems that you wondered if 
anything was worthwhile? 
 
1   Extremely So - To the point that I have just about given up 
2   Very Much So 
3   Quite a Bit 
4   Some - Enough to bother me 
5   A Little Bit 
6   Not At All 
 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 9 of 10 
Please go on to the next page 
Fecal Incontinence Severity Index 
 
Q 1: 
For each of the following, please indicate on average how often in the past month you experienced any 
amount of accidental bowel leakage: 
 
 
2 or More 
Times a Day 
(1) 
Once a 
Day 
(2) 
2 or More 
Times a 
Week 
(3) 
Once a 
Week 
(4) 
1 to 3 Times 
A Month 
(5) 
Never 
(6) 
a. Gas 
 
 
 
 
 
 
b. Mucus 
 
 
 
 
 
 
c. Liquid Stool 
 
 
 
 
 
 
d. Solid Stool 
 
 
 
 
 
 
  


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 10 of 10 
 
Low Anterior Resection Syndrome Score – LARS Score. English version 1.0 
 
Bowel function questionnaire  
  
The aim of this questionnaire is to assess your bowel function. 
Please tick only one box for each question. It may be difficult to select only one answer, as we know that for some 
patients symptoms vary from day to day. We would kindly ask you to choose one answer which best describes your 
daily life. If you have recently had an infection affecting your bowel function, please do not take this into account 
and focus on answering questions to reflect your usual daily bowel function. 
 
  
Do you ever have occasions when you cannot control your flatus (wind)?  
 No, never  
 Yes, less than once per week  
 Yes, at least once per week  
 
Do you ever have any accidental leakage of liquid stool?  
 No, never  
 Yes, less than once per week  
 Yes, at least once per week  
 
How often do you open your bowels?  
 More than 7 times per day (24 hours) 
 4-7 times per day (24 hours) 
 1-3 times per day (24 hours) 
 Less than once per day (24 hours) 
 
Do you ever have to open your bowels again within one hour of the last bowel opening?  
 No, never  
 Yes, less than once per week  
 Yes, at least once per week  
 
Do you ever have such a strong urge to open your bowels that you have to rush to the toilet?  
 No, never  
 Yes, less than once per week  
 Yes, at least once per week  
 
Translated March 2013 by Nick J. Battersby, Department of Colorectal Surgery, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK 
 
Please check to make sure you have answered all the questions. 
 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 


 
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CONFIDENTIAL 
77 
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APPENDIX VI - HEALTH UTILITIES ASSESSMENT 
 
Introduction 
 
The assessment of overall health benefits is complicated by the need for a measure that can combine various 
benefits, such as overall survival, disease free survival, and quality of life into a single measure of benefit. 
Patients may value particular benefits differently. There is no obvious way to add together independently 
collected benefits for an individual or for a trial to yield a measure of overall benefit. Health utilities are a 
measure of how people value particular health outcomes. They provide a common denominator that can be 
combined with survival to form a measure of overall health benefits. 
 
Such a measure of overall health benefit can then be used as part of a health economic analysis. Health 
economic analyses assess the benefits and costs of an intervention, for consideration whether the 
intervention may be worth its "costs" -- including financial, toxicity, and social costs. 
 
The collection of information about health utilities is becoming more common in clinical protocols. In 
clinical trials, health utilities are most often collected using a patient self-reported questionnaire (similar to 
the collection of quality of life data). 
 
Health utility and quality of life assessments provide different but complementary information. 
• 
Health utility is a measure of preference for a given health state that acknowledges the risk and 
uncertainty of outcomes in choices patients face and in clinical decision-making. 
• 
They can be used as a weighting factor to adjust survival by quality of life. 
• 
Depending on whether a disease-specific or generic quality of life instrument is used, often only utility 
assessments may be able to compare patient groups with different diseases. 
• 
Only utilities provide a single meaningful measure that can be incorporated in health policy and health 
economic analyses. 
 
Health utilities data can be used in a variety of ways: 
• 
to try and achieve the best possible outcome for patients and populations 
• 
to evaluate the extent of change in health benefits of an individual, group, or population across time 
• 
to evaluate new treatments, technologies, and patient management strategies 
• 
to support approval of new drug applications or patient management strategies 
• 
to try to provide the best value for health care dollars within and across diseases and health 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of new therapies or patient management strategies will most likely be based on a 
combination of health benefit and cost data. This may be formally done using health utilities as part of a 
health economic analysis. 
 
Instructions for Administration of a Health Utilities Questionnaire 
The instructions below are intended as a guide for the administration of the Health Utilities Questionnaire 
 
1. Preamble 
 
Health utilities data are collected for research purposes, and will not be used for the patient’s individual 
medical care. The assessment is in the form of a self report questionnaire. Therefore, it must be 
completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 


 
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78 
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The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pre-treatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, eg: psychological distress, social disruption, symptoms, 
side-effects, et cetera. 
 
The Clinical Research Associate (CRA) should collect the questionnaire as soon as it has been 
completed, check to see that each question has been answered and gently remind the patient to answer 
any inadvertently omitted questions. If a patient states that s/he prefers not to answer some questions 
and gives a reason(s), the reason(s) should be noted on the questionnaire. If a specific reason is not 
given, this also should be noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment, as required by the schedule in the protocol (not required during treatment for this 
trial). 
 
4. Assessments During Follow-up 
 
The health utilities questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they 
feel unwell. In that case, you may express sympathy that things are below par, but 
state that this is exactly the information we require if we are to understand more 
about how overall health is affected. You may also remind them that it takes only a 
few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels 
better! 
 
5. What If… 
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 


 
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CCTG TRIAL: CO.28 
 
 
CONFIDENTIAL 
79 
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There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Four situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. 
The patient leaves the clinic before the questionnaire could be administered, or someone forgets 
to give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the 
phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. 
The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible.  
 
C. 
The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient's wishes is likely to result in the questionnaire not being 
completed at all, then the patient may take the questionnaire home with instructions that it is to 
be completed the same day. When the questionnaire is returned, the date on which the 
questionnaire was completed should be noted and a comment made on the questionnaire as to 
why the patient took it away from the clinic before completion. 
 
D. 
The patient is no longer attending clinic during the scheduled follow-up period. 
 
Should the patient no longer be attending clinic, he/she should be contacted by phone to ask 
him/her to complete the questionnaire and mail it to the clinic. In order to facilitate this, ensure 
that after randomization all patients are provided with 2 blank questionnaires and 2 clinic-
addressed stamped envelopes. When the questionnaire is returned, the date on which the 
questionnaire was received should be recorded on the questionnaire. The date on which the 
questionnaire was completed should be noted on the appropriate case report form, as well as 
where and why the patient completed the questionnaire outside of the clinic. 


 
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6. Inability to Complete Health Utilities Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the EQ-5D assessment in the clinic, the 
questionnaire should be read to them and the answers recorded by a health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social 
worker who is familiar with the instructions for administering the questionnaires would be acceptable). 
If the patient is completing the questionnaire at home, and a telephone interview by the clinical research 
associate is not possible, then a spouse or friend may read the questions to the patient and record the 
answers. However, this method should be a last resort, and the spouse or friend should be instructed to 
not coach or suggest answers to the patient. Whichever method is used, it should be recorded on the 
questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 


 
 
Health Utilities Questionnaire – ENGLISH 
 
CCTG Trial: CO.28 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Within 30 days prior to enrollment 
 After 3 cycles of FOLFOX or after 2 cycles of CAPOX 
 
 PRE-Excision 2-4 weeks (FOLFOX) or 3-5 weeks (CAPOX) after last cycle of chemotherapy  
 
After protocol excision. For patients who fail and go onto TME, these times are from TME date: 
 30 days     6 months      12 months     24 months     36 months 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
______________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 
 
 


This box to be completed by the clinical research associate:   Pt. Serial #: _____________   Pt. Initials: ____ ____ ____ 
 
CCTG Trial CO.28 
Page 1 of 2 
Please go on to the next page 
 
© 2009 EuroQol Group EQ-5D™ 
EQ-5D Questionnaire 
 
CCTG: CO.28 
 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 


 
CCTG Trial CO.28 
Page 2 of 2 
 
© 2009 EuroQol Group EQ-5D™ 
The worst health 
you can imagine 
 
• 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please check to make sure you have answered all questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you. 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100 
5
15
25
35
45
55
75
65
85
95
The best health you 
can imagine 


 
PROTOCOLADMINISTRATIVE UPDATE #3: 2020-JAN-21 
 
CCTG TRIAL: CO.28 
 
 
CONFIDENTIAL 
84 
CONFIDENTIAL 
APPENDIX VII - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate 
this process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org). These staging criteria should be used for new trials. 
 


 
PROTOCOLADMINISTRATIVE UPDATE #3: 2020-JAN-21 
 
CCTG TRIAL: CO.28 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
LIST OF CONTACTS 
 
PATIENT ENROLLMENT 
All patients must be registered with CCTG before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
ELECTRONIC DATA  
CAPTURE (EDC) AND RIPPLE 
(technical support) 
CCTG Home Page (Toolbox): 
https://scooby.ctg.queensu.ca 
Email Support Staff at: 
support@ctg.queensu.ca 
 
 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Alexander Montenegro  
Study Coordinator, CCTG 
Email: amontenegro@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CO-CHAIRS 
Dr. Hagen Kennecke 
Study Co-Chair 
Email: hkennecke@bccancer.bc.ca 
or: 
Dr. Carl Brown 
Study Co-Chair 
Email: cbrown@providencehealth.bc.ca 
 
 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 9.0 for 
details of reportable events. 
Alexander Montenegro  
Study Coordinator, CCTG 
Email: amontenegro@ctg.queensu.ca 
613-533-6430 
613-533-2941 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN for 
 
NEOADJUVANT CHEMOTHERAPY, EXCISION AND OBSERVATION FOR 
EARLY RECTAL CANCER: The NEO Trial. 
 
CCTG Protocol Number: CO.28 
 
Prepared by: 
Signature 
Date 
 
CCTG/Queen’s Statistician 
 
 
 
            
 
 
 
 
  
 
 
 
Dongsheng Tu 
 
 
Reviewed by: 
Signature 
Date 
 
CCTG/Queen’s 
Senior Investigator       
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
Chris O’Callaghan 
 
 
 
 
 
 
July 2, 2020 


ABBREVIATIONS 
 
AE  
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
ANC 
 
Absolute Neutrophil Count 
 
BSA 
 
Body Surface Area 
CAPOX 
Chemotherapy with Capecitabine and Oxaliplatin 
CCTG  
Canadian Cancer Trials Group 
CEA 
 
Carcinoembryonic Antigen 
CI  
 
Confidence Interval 
CRM 
 
Clear Circumferential Radial Margin 
CRF 
 
Case Report Form 
CTCAE  
Common Toxicity Criteria for Adverse Events 
DFS 
 
Disease Free Survival 
DRR 
 
Distant Relapse Rate 
DSMC  
Data and Safety Monitoring Committee 
ECOG  
Eastern Cooperative Cancer Group 
EORTC  
European Organization for Research and Treatment of Cancer 
FOLFOX 
Chemotherapy with Oxaliplatin, Leucovorin, and Fluorouracil 
FIQL 
 
Fecal Incontinence Quality of Life 
INR 
 
International Normalized Ratio 
LARS  
Low Anterior Resection Syndrome 
LKA 
 
Last day the patient is Known Alive 
MAX 
 
Maximum 
MIN 
 
Minimum 
LRR 
 
Locoregional Relapse Rate 
MPV 
 
Major Protocol Violation 
MRI 
 
Magnetic Resonance Imaging 
NA  
 
Not Assessed or Not Applicable 
NCI 
 
National Cancer Institute 
NR  
 
Not Reported 
PT  
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
QLQ 
 
Quality of Life Questionnaire  
QoL 
 
Quality of Life 
SAS 
 
Statistical Analysis System 
STD 
 
Standard Deviation 
TAMIS  
Transanal Minimally Invasive Surgery 
TME 
 
Total Mesorectal Excision 
TEMS  
Transanal Endoscopic Microsurgery 
UNL 
 
Upper Normal Limit 


TABLE OF CONTENTS 
 
1. 
Introduction ___________________________________________________ 6 
2. 
Study Description _______________________________________________ 6 
2.1 
Background _______________________________________________________ 6 
2.2 
Study Design ______________________________________________________ 6 
3. 
Objectives _____________________________________________________ 7 
3.1 
Primary __________________________________________________________ 7 
3.2 
Secondary _________________________________________________________ 7 
3.3 
Tertiary __________________________________________________________ 7 
4. 
Endpoints _____________________________________________________ 7 
4.1 
Primary Efficacy ___________________________________________________ 7 
4.2 
Secondary Efficacy _________________________________________________ 7 
4.3 
Safety ____________________________________________________________ 8 
5. 
Sample Size and Power __________________________________________ 8 
6. 
Data Set Descriptions ____________________________________________ 8 
7. 
Statistical Analysis ______________________________________________ 8 
7.1 
General Methods ___________________________________________________ 8 
7.2 
Study Conduct _____________________________________________________ 9 
7.2.1 
Patient Disposition and Follow-up _________________________________________ 9 
7.2.2 
Accrual Patterns _______________________________________________________ 9 
7.2.3 
Eligibility Violations/Protocol Deviations ___________________________________ 9 
7.3 
Study Population __________________________________________________ 10 
7.3.1 
Patient Pretreatment Characteristics _______________________________________ 10 
7.3.2 
Baseline Pathology Results _____________________________________________ 10 
7.3.3 
Baseline Exams ______________________________________________________ 11 
7.3.4 
Concomitant Medications and Major Medical Problems at Baseline ______________ 11 
7.4 
Extent of Neoadjuvant Chemotherapy Exposure ________________________ 11 
7.4.1 
Duration of Chemotherapy ______________________________________________ 11 
7.4.2 
Modifications of Neoadjuvant Chemotherapy _______________________________ 12 
7.4.3 
Cumulative dose, dose intensity and relative dose intensity _____________________ 12 
7.4.4 
Off Neoadjuvant Chemotherapy __________________________________________ 13 
7.5 
Surgical Treatments _______________________________________________ 13 
7.5.1 
Pre-excision Characteristics and MRI results ________________________________ 13 
7.5.2 
Pre-excision Exam ____________________________________________________ 13 
7.5.3 
Pre-excision Extent of Disease ___________________________________________ 13 
7.5.4 
Plan of Surgical Treatment ______________________________________________ 13 
7.5.5 
Surgical Treatment ____________________________________________________ 13 
7.5.6 
Pathology Results after surgical treatment __________________________________ 14 
7.6 
Radiation Treatments ______________________________________________ 14 
7.7 
Efficacy __________________________________________________________ 14 
7.7.1 
Organ Preservation Rate ________________________________________________ 14 
7.7.2 
3 Year Loco-Regional Relapse Rate _______________________________________ 15 
7.7.3 
3 Year Distant Relapse Rate _____________________________________________ 15 


7.7.4 
3 year Disease Free Survival ____________________________________________ 16 
7.8 
Safety ___________________________________________________________ 16 
7.8.1 
Adverse Events _______________________________________________________ 16 
7.8.2 
Laboratory Evaluations ________________________________________________ 17 
7.8.2.1 
Hematology _______________________________________________________ 17 
7.8.2.2 
Biochemistry ______________________________________________________ 17 
7.8.2.3 
Other laboratory evaluations __________________________________________ 17 
7.8.3 
Post-operative complications ____________________________________________ 17 
7.8.3.1 
Reoperation _______________________________________________________ 17 
7.8.3.2 
Blood loss/transfusion _______________________________________________ 17 
7.8.3.3 
Intraoperative injury _________________________________________________ 17 
7.8.3.4 
Hospitalization _____________________________________________________ 18 
7.8.4 
Deaths on Study/Adverse Events Leading to Discontinuations due to Toxicity _____ 18 
7.8.5 
Other safety _________________________________________________________ 18 
7.8.5.1 
Sigmoidoscopy/colonoscopy __________________________________________ 18 
7.8.5.2 
Other radiologic investigations _________________________________________ 18 
7.8.5.3 
Transfusions _______________________________________________________ 18 
7.8.5.4 
Major medical problems ______________________________________________ 19 
7.9 
Concomitant Medications and Other Anti-Cancer Treatments ____________ 19 
7.10 
Quality of Life __________________________________________________ 19 
7.10.1 
Scoring Algorithms ___________________________________________________ 19 
7.10.1.1 
EORTC QLQ-C30 __________________________________________________ 19 
7.10.1.2 
EORTC QLQ-CR29 _________________________________________________ 20 
7.10.1.3 
Low Anterior Resection Syndrome (LARS) Score _________________________ 21 
7.10.1.4 
Fecal Incontinence Quality of Life (FIQL) Instrument ______________________ 21 
7.10.2 
Data Sets ____________________________________________________________ 22 
7.10.3 
Compliance __________________________________________________________ 22 
7.10.4 
Analyses of QOL _____________________________________________________ 22 
7.10.4.1 
Baseline and Change Score Analysis __________________________________ 22 
7.10.4.2 
Proportions of Deterioration and Improving or Stable for EORTC QLQ-C30 and 
CR29 at Post-Baseline Assessment _____________________________________________ 22 
7.10.4.3 
Proportions of LARS Severity Group at Baseline and Post-baseline Assessment 22 
8. 
Appendices ___________________________________________________ 23 
Appendix 1: Tables and Figures ___________________________________________ 23 
 
 
Tables 
Table 1. Patient Disposition .................................................................................................................. 23 
Table 2: Follow-up of Patients .............................................................................................................. 23 
Table 3: Accrual by Center ................................................................................................................... 23 
Table 4: Eligibility and Reasons for Ineligibility and Major Protocol Violations ................................ 24 
Table 5: Pre-treatment Characteristics at Baseline .............................................................................. 25 
Table 6: Baseline Pathology Results ..................................................................................................... 26 
Table 7: Baseline Sigmoidoscopy/Colonoscopy and Other Radiology Investigations .......................... 27 
Table 8: Baseline Hematology .............................................................................................................. 28 
Table 9: Baseline Biochemistry ............................................................................................................. 29 
Table 10: Baseline Coagulation ............................................................................................................ 30 
Table 11: Baseline Symptoms Status ..................................................................................................... 30 
Table 12: Prior Concomitant Medications (Baseline) .......................................................................... 31 
Table 13: Past or Current Major Medical Problems ............................................................................ 31 
Table 14: Tobacco Smoking History at Baseline .................................................................................. 32 
Table 15: Number of Patients by Cycle of Chemotherapy .................................................................... 33 
Table 16: Number of Cycles of Chemotherapy per Patient ................................................................... 33 
Table 17: Total Duration of Chemotherapy .......................................................................................... 33 
Table 18: Number of Patients with Modifications of Chemotherapy .................................................... 33 


Table 19: Cumulative Dose ................................................................................................................... 34 
Table 20: Actual Dose Intensity ............................................................................................................ 34 
Table 21: Relative Dose Intensity .......................................................................................................... 34 
Table 22: Off Neoadjuvant Chemotherapy Summary ............................................................................ 35 
Table 23: Pre-excision Characteristics and MRI results ...................................................................... 36 
Table 24: Pre-excision Sigmoidoscopy/Colonoscopy and Other Radiology Investigations .................. 36 
Table 25: Pre-excision Extent of Disease .............................................................................................. 37 
Table 26: Plan of surgical Treatment ................................................................................................... 38 
Table 27: Surgery Summary .................................................................................................................. 38 
Table 28: Pathology Results After Surgical Treatment ......................................................................... 39 
Table 29: Radiotherapy Treatment ....................................................................................................... 40 
Table 30: Summary of Organ Preservation .......................................................................................... 41 
Table 31: Summary of Disease Outcomes ............................................................................................. 42 
Table 32: Acute Non-Hematologic Adverse Events ............................................................................... 43 
Table 33: Severe Acute Non-Hematologic Adverse Events ................................................................... 43 
Table 34: Acute (On-treatment) Adverse Events Related to Oxaliplatin for Patients on FOLFOX ...... 44 
Table 35: Severe Delayed Non-Hematologic Adverse Events ............................................................... 44 
Table 36: Hematology: Worst Grade per Patient ................................................................................. 45 
Table 37: Biochemistry: Worst Grade per Patient ................................................................................ 46 
Table 38: Other Laboratory Investigations ........................................................................................... 47 
Table 39: Surgery and Post-operative Complications .......................................................................... 48 
Table 40: All Deaths ............................................................................................................................. 49 
Table 41: Deaths Before Surgery .......................................................................................................... 49 
Table 42: Adverse Event leading to Discontinuation of Neoadjuvant Chemotherapy .......................... 49 
Table 43: Sigmoidoscopy/Colonoscopy and Other Radiology Investigations ....................................... 50 
Table 45: Major Medical Problems ...................................................................................................... 51 
Table 46: Concomitant Medication ....................................................................................................... 51 
Table 47: Anti-Cancer Treatment ......................................................................................................... 52 
Table 48: Compliance Rate with QoL Assessment ................................................................................ 53 
Table 49: QoL: Summary Baseline Scores ............................................................................................ 54 
Table 50: Summary QOL Change Scores from Baseline for Scale/Domain/Item at Each Time Period*
 ............................................................................................................................................................... 55 
Table 51: Proportion of Patients with Deterioration, Improvement or Stable EORTC QLQ-C30 and 
CR29 domains/items and Global QLQ scales* ..................................................................................... 56 
Table 52: Proportion of Patients in LARS Severity Groups .................................................................. 56 
 
 
Figures 
Figure 1: Accrual by Calendar Time .................................................................................................... 24 
Figure 2: Kaplan-Meier Curve for Locoregional Relapse Free Survival ............................................. 42 
Figure 3: Kaplan-Meier Curve for Distant Relapse Free Survival ....................................................... 42 
Figure 4: Kaplan-Meier Curve for Disease Free Survival.................................................................... 42 
 
 
 
 
 
 
 
 
 


1. Introduction 
This analysis plan describes the final analysis performed by the Canadian Cancer Trials 
Group (CCTG) for the CO.28 trial. It will be used for the writing of the Canadian 
Cancer Trials Group study report. 
2. Study Description 
2.1 Background 
Current standard therapy for patients with T1-3 rectal tumours includes radical surgery 
with Total Mesorectal Excision (TME), and preoperative chemoradiation for patients 
with T3 tumours or N1 tumours. Although the locoregional relapse rates with modern 
adjuvant therapy are low (generally 5%), in patients treated with radical resection, 
ongoing issues with bowel function, incontinence, sexual function and depression 
persist. These are significantly worse in patients treated with neoadjuvant or adjuvant 
radiotherapy. 
Multiple single arm and randomized phase II studies have explored the use of pelvic 
chemoradiation followed by Transanal Endoscopic Microsurgery (TEMS) or Transanal 
Minimally Invasive Surgery (TAMIS) as a means to increase rectal organ preservation 
for patients with early rectal cancer but neoadjuvant radiation significantly increases 
wound-healing complications and adversely affects sphincter and sexual function.  
Population based studies have documented an increasing use of local excision/ 
minimally invasive surgery in the treatment of T1N0 or T2N0 rectal tumours but a 
significant proportion of clinical T1-2N0 tumours are pathologically node positive and 
the literature demonstrates an increased rate of local relapse with local excision versus 
surgical resection. Neoadjuvant chemotherapy is a potential approach to reduce local 
and distant relapse for rectal tumours treated with excision alone since it has been 
shown to reduce locoregional recurrence in stage II/III rectal cancer but without the 
toxicities of pelvic radiation. There is, however, virtually no prospective experience of 
neoadjuvant chemotherapy and excision/surgery for early rectal tumours. This phase II 
trial was designed to determine the outcomes of the patients with stage 1-2 rectal 
tumours treated with chemotherapy (FOLFOX or CAPOX) followed by minimally 
invasive surgery (TEMS or TAMIS). The primary endpoint of the study is the rate of 
organ preservation. 
2.2 Study Design 
CO.28 is a single arm, two-stage phase II clinical study of FOLFOX/CAPOX as a 
neoadjuvant treatment for patients with stage I-II (cT1-3ab/N0) rectal cancer. The study 
is being conducted by the Canadian Cancer Trials Group.  
A total of 50 evaluable patients would be enrolled, in a two-stage minimax design with 
22 patients accrued in the first stage. The trial would be stopped at the end of the first 
stage if the number of patients who avoided radical surgery is 10 or less. Otherwise the 
trial would proceed to the second stage to accrue 28 additional patients. Allowing for a 
15% inevaluable rate, the total sample size would be 58 patients. 
This study opened to accrue patients on August 22, 2017. On April 19, 2019, 11 of the 
19 patients enrolled in the first stage were found to have avoid radical surgery. It was 
decided the study would processed to continue accrual of patients to full sample size. 
The trial was closed to further accrual on May 19, 2020 after 58 patients were accrued. 


A final analysis will be performed on a database which will be locked after all patients 
completed their treatments and all data observed from the patients are cleaned. This 
plan describes the details of this final analysis. 
The CCTG Data and Safety Monitoring Committee (DSMC) has been reviewing safety 
data annually and as otherwise required. These analyses have been prepared by a 
CCTG/Queen’s Senior Biostatistician.   
3. Objectives 
3.1 Primary 
The primary objective of this study is to determine the organ preservation rate in 
patients with early (cT1-3a,bN0) rectal cancer treated with neoadjuvant FOLFOX or 
CAPOX and TEMS or TAMIS. 
3.2 Secondary 
Secondary objectives are: 
• To describe the 3-year Locoregional Relapse Rate (LRR) in patients treated with 
organ preservation.  
• To describe the 3-year Distant Relapse Rate (DRR) in patients treated with organ 
preservation.  
• To describe the 3-year Disease Free Survival (DFS) rate in patients treated with 
organ preservation.  
• To evaluate the rate of post-operative complications following neoadjuvant 
FOLFOX/CAPOX and tumour excision/surgery.  
• To evaluate nature, severity and frequency of acute and long term toxicities in all 
patients.  
• To evaluate Quality of Life (QoL) in all patients.  
• To evaluate the cost-effectiveness of the neo-adjuvant chemotherapy approach vs. 
the current standard approach.  
3.3 Tertiary 
The tertiary objectives of this study are to evaluate the prognostic value of baseline 
ctDNA as an independent prognostic value in addition to ypstage and histology. 
(Note: The plan to address the last of the secondary objectives, i.e., the cost-
effectiveness analysis, and the tertiary objectives will be developed separately later.) 
4. Endpoints 
4.1 Primary Efficacy 
The primary efficacy endpoint is the protocol specified organ preservation rate. 
4.2 Secondary Efficacy 
The secondary efficacy endpoints are: 
• 3 year locoregional relapse rate 
• 3 year distant relapse rate 
• 3 year disease free survival  
• Quality of life 


4.3 Safety 
The safety endpoints are post-operative complication rate, serious and non-serious 
adverse events (clinical and laboratory), laboratory parameters, dosing data (including 
dose interruptions, total delivered dose and dose modifications) and reasons off 
treatment.  
5. Sample Size and Power 
The expected organ preservation rate is 50-68% among patients with clinical T1-3N0 
rectal tumours treated with chemoradiation and minimally invasive surgery. Based on 
these historic phase II data, the experimental treatment would be considered of no 
interest if the protocol specified organ preservation rate is 50% or lower (H0) and as 
promising if its avoidance rate is 65% or higher (H1).  
An optimal two-stage minimax design would be used to test the above hypotheses, 
which would accrual 22 evaluable patients in the first stage. The trial would be stopped 
at the end of the first stage if the number of patients who avoided radical surgery is 10 
or less. Otherwise the trial would proceed to the second stage to accrue 28 additional 
evaluable patients. The experimental procedure would be considered as promising if, 
out of the total patients accrued, 30 or more patients avoided radical surgery. The exact 
type I error rate and power of this design are respectively 0.1 and 0.8. Allowing for a 
15% inevaluable rate, the total sample size would be 58 patients.  
6. Data Set Descriptions 
Five types of analysis samples will be used: 
1. All Accrued Patients: 
All patients accrued in the study. 
2. All Chemotherapy Treated Patients: 
All patients who have received at least one dose of FOLFOX or CAPOX.  
3. All Chemotherapy & Excision Treated Patients 
All patients who have received at least one dose of FOLFOX or CAPOX and TEMS 
or TAMIS.  
4. All Chemotherapy & Excision/Surgery Treated Patients 
All patients who have received at least one dose of FOLFOX or CAPOX and 
excision (TEMS or TAMIS) or surgery (TME). 
5. All Quality of Life Evaluable Patients 
All patients who have completed at least one quality of life questionnaire. 
7. Statistical Analysis 
7.1 General Methods 
Continuous and ordinal categorical variables are summarized using the mean, median, 
standard error, minimum and maximum values.  All confidence intervals are 
computed based on normal approximations except those for rates, which will be 
computed based on the exact method. 


Percentages given in the summary tables will be rounded and may therefore not always 
add up to exactly 100%. Listings, tabulations, and statistical analyses will be carried 
out using the SAS (Statistical Analysis System, SAS Institute, North Carolina, USA) 
software. 
Baseline evaluations will be those collected on CRF Eligibility Worksheet and Baseline 
Report and closest to, but no later than, the first day of study medication for treated 
subjects and closest to, but no later than, the date of enrollment, for subjects who were 
enrolled but who never received any treatment. 
Laboratory results, adverse events, and other symptoms are coded and graded using the 
NCI CTCAE when available.  
When converting a number of days to other units, the following conversion factors will 
be used: 
1 year = 365.25 days 
1 month = 30.4375 days 
When either day or month of a date is missing, the missing day and/or month will be 
imputed by the midpoint within the smallest known interval. For example, if the day of 
the month is missing for any date used in a calculation, the 15th of the month will be 
used to replace the missing day.  If the month and day of the year are missing for any 
date used in a calculation, the first of July of the year will be used to replace the missing 
date. 
7.2 Study Conduct 
All accrued patients are included in the analysis of study conduct.  
7.2.1 
Patient Disposition and Follow-up 
• Number of patients accrued, treated (on study, off study), never treated (Table 
1) 
• Number of alive patients (Table 2) 
• Median (estimated by Kaplan-Meier method) and range (minimum and 
maximum) (Table 2) of the follow-up time (months) defined as time from the 
day of accrual to the last day the patient is known alive (LKA) as the latest of 
dates of enrollment, day 1 of reporting period on CRF Chemotherapy Report, 
date of attendance on CRF Pre-Excision Report, date of surgery or date 
definitive decision was made on CRF Surgery Report, and attendance/last 
contact on CRF Follow-up Report and CRF Short Follow-up Report or censored 
at the time of death and calculated as  
 
[(date of death or LKA − date of accrual) + 1)]/30.4375. 
7.2.2 
Accrual Patterns 
• Number of patients accrued by center (Table 3) 
• Accrual of patients by calendar time (Figure 1) 
7.2.3 
Eligibility Violations/Protocol Deviations 
Eligibility violations of inclusion or exclusion criteria are centrally reviewed by CCTG; 
a field (y/n) for eligibility status and reason for ineligibility is entered in the database.  


A major protocol violation (MPV) is defined as a deviation from the protocol, initiated 
by the center or the investigator, serious enough to mean that the patient's data 
contributes little, if any, information on the efficacy or toxicity of the regimen under 
study. MPVs are coded by CCTG based on its standard codes.  
• Number of patients eligible, not eligible (Table 4) 
• Reasons for ineligibility (Table 4) 
• Major protocol violations: % for each type of violations (Table 4) 
7.3 Study Population 
All accrued patients are included in the study population analyses. 
7.3.1 
Patient Pretreatment Characteristics  
• Gender: male, female (Table 5) 
• Age: median, minimum, maximum values; <65, ≥65 (Table 5) 
• Race: White, Black or African American, Native Hawaiian or other Pacific 
Islander, Asian, Not reported (or refused), Unknown (Table 5) 
• Height: median, minimum, maximum values (Table 5) 
• Weight: median, minimum, maximum values (Table 5) 
• BSA: median, minimum, maximum values (Table 5) 
• ECOG Performance Status: 0, 1 (Table 5) 
• Months from first histological diagnosis of colorectal cancer to enrollment: 
median, minimum, maximum values (Table 5) 
• Tumour Invasion based on pelvic MRI: submucosa, muscularis propia, 
muscularis propia no more than 5 mm into the subserosa/perirectal tissue, 
muscularis propia more than 5 mm into the subserosa/perirectal tissue, not 
visible on pelvic MRI (Table 5) 
• cT-stage: T1, T2, T3a, T3b (Table 5) 
• Tumour Height from anal verge (cm): median, minimum, maximum values 
(Table 5) 
7.3.2 
Baseline Pathology Results 
• Longest dimension of Invasive Carcinoma: median, minimum, maximum 
values (Table 6) 
• Histology: adeno-carcinoma, etc. (Table 6) 
• Histologic grade: well differentiated, moderately differentiation, not stated in 
report (Table 6) 
• Deepest layer of invasion: Mucosa, Lamina Propia, Muscularis mucosa, 
Submucosa, Muscularis propia, Serosa, Perirectal tissue, Subserosa, Not Stated 
in Report (Table 6) 
• Depth of invasion into subserosa: median, min-max (Table 6) 
• Deep margin: positive for invasive carcinoma, negative, not stated in report, not 
applicable; median, minimum, maximum values (Table 6) 
• Mucosal margin: positive for invasive carcinoma, negative, not stated in report, 
not applicable; median, minimum, maximum values (Table 6) 
• Pathologic T stage: T0, T1, T2, T3, unknown (Table 6) 
• Number of nodes examined: median, minimum, maximum values (Table 6) 
• Number of nodes with tumour: median, minimum, maximum values (Table 6) 


• Tumour deposits: yes, no (Table 6) 
7.3.3 
Baseline Exams 
• Sigmoidoscopy/colonoscopy: normal, abnormal non-malignant, abnormal 
malignant ((Table 7) 
• Other radiology investigations: normal, abnormal non-malignant, abnormal 
malignant (Table 7) 
• Hematology: Hemoglobin, WBC, absolute neutrophil count (ANC), neutrophils, 
platelets, lymphocytes, basophils, monocytes, eosinophils (Table 8)  
• Biochemistry: serum creatinine, total bilirubin, ALT, creatinine clearance (Table 
9) 
• 
Coagulation: PT, INR, PTT (Table 10) 
• Baseline symptom status (Table 11) 
7.3.4 
Concomitant Medications and Major Medical Problems at Baseline 
• Number of patients with concomitant Medication (Table 12) 
• Number of patients with other past and current major medical problems ongoing 
at baseline (Table 13) 
7.3.5 
Tobacco Smoking History at Baseline 
• Ever smoked any tobacco product: Yes, No, Unknown (Table 14) 
• Currently smoking: Yes, No (Table 14) 
• Current average number of cigarettes per day: median, minimum, maximum 
(Table 14) 
• Years from quitting smoking to enrollment: median, minimum, maximum 
(Table 14) 
• Years from beginning smoking cigarettes to enrollment: median, minimum, 
maximum (Table 14) 
• Total number of years of smoking cigarettes: median, minimum, maximum 
(Table 14) 
• Average number of cigarettes smoked per day: median, minimum, maximum 
(Table 14) 
• 
Average pack years of cigarettes smoked: median, minimum, maximum (Table 
14) 
7.4 
Extent of Neoadjuvant Chemotherapy Exposure 
Patients included are those who received at least one dose of FOLFOX or CAPOX as 
defined in Section 6. 
7.4.1 
Duration of Chemotherapy 
During protocol treatment, the patients are planned to receive either FOLFOX infusion 
on a 14 day cycle (IV oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 over 2 hours on 
day 1 and bolus fluorouracil 400 mg/m2 over 5 - 15 minutes and continuous infusion 
of fluorouracil 2400 mg/m2 over 46 to 48 hours on days 1-2) for a total of 6 cycles or 
CAPOX on a 21 day cycle (IV oxaliplatin 130 mg/m2 over 2 hours on day 1 and 1000 
mg/m2 capecitabine orally twice daily for 14 days from day 1) for a total of 4 cycles. 
 
Duration of a neoadjuvant chemotherapy treatment (in weeks) during the study is 


defined as follows: 
• For patients on FOLFOX: 
[last date of the treatment− first date of the treatment+ 14]/7, 
• For patients on CAPOX: 
[last date of the treatment− first date of the treatment+ 21]/7 
 
where the first and last date of the treatment are taken from respective treatment 
administration section of CRF Chemotherapy Report.  
The following variables will be summarized using the data set of all chemotherapy 
treated patients: 
• 
Number of patients by cycle of chemotherapy (Table 15) 
• 
Total number of cycles of chemotherapy per patient (Table 16) 
• 
Total treatment duration (weeks) per patient (Table 17) 
7.4.2 
 Modifications of Neoadjuvant Chemotherapy  
The administration of a neoadjuvant chemotherapy drug in a cycle may be modified 
(given early, delayed, omitted, reduced, interrupted, discontinued, increased, or the 
infusion rate was increased or decreased) because of toxicity or other reasons. For each 
drug, the following variables will be summarized using the data set of all chemotherapy 
treated patients: 
• 
Number of patients with at least one cycle with modifications to 
administration (Table 18) 
• 
Number of patients with modifications to administration by cycle (Table 18) 
• 
Reason for these modifications (Table 18) 
7.4.3 
Cumulative dose, dose intensity and relative dose intensity  
The cumulative dose (mg/m2) per patient for capecitabine, oxaliplatin, leucovorin and 
fluorouracil (bolus and continuous) is defined as the sum over all cycles of the total 
actual dose received divided by the BSA in a given cycle. 
The actual dose intensity (mg/m2/week) per patient for capecitabine, oxaliplatin, 
leucovorin and fluorouracil (bolus and continuous) is defined as the cumulative dose 
(mg/m2) divided by “treatment duration” (in weeks), where “treatment duration” per 
patient is defined as the duration from first day of drug administration to the last day 
of drug administration plus 14 days (for patients on FOLFOX) or 21 days (for patients 
on CAPOX) over all cycles in which the given drug is prescribed.   
The median and range of cumulative dose and actual dose intensity will be summarized 
in respectively Table 19 and Table 20.   
The relative dose intensity per patient is defined as the actual dose intensity 
(mg/m2/week) divided by the planned weekly dose as assigned in the protocol (42.5 
mg/m2/week for oxaliplatin, 200 mg/m2/week for leucovorin, 200 mg/m2/week for 
bolus fluorouracil, and 1200 mg/m2/week for continuous fluorouracil for patients on 
FOLFOX; 43.3 mg/m2/week for oxaliplatin and 9333.3 mg/m2/week for capecitabine 
for patients on CAPOX). The patient relative dose intensities will be grouped according 


to the following categories: < 60%,  ≥ 60% - <80%, ≥ 80% - < 90%, ≥ 90% (Table 
21). 
7.4.4 
Off Neoadjuvant Chemotherapy 
The reason for off neoadjuvant chemotherapy will be taken from Off Neoadjuvant 
Chemotherapy Section of CRF Chemotherapy Report. 
The following information will be summarized (Table 22): 
• Number of patients off neoadjuvant chemotherapy 
• Reason off neoadjuvant chemotherapy 
7.5 
Surgical Treatments 
Tumour excision are performed within 2-5 weeks (for patients on FOLFOX) or 3-6 
weeks (for patients on CAPOX) after first dose of last cycle of chemotherapy after a 
pre-excision visit performed within 2 weeks after the first dose of the last cycle (cycle 
6) of FOLFOX therapy or within 3 weeks after the first dose of the last cycle (cycle 4) 
of CAPOX. Information from pre-excision visit and on the surgical treatment will be 
taken respectively from the CRF Pre-Excision Report and CRF Surgery Report. 
7.5.1 
Pre-excision Characteristics and MRI results 
• Weight: median, minimum, maximum values (Table 23) 
• BSA: median, minimum, maximum values (Table 23) 
• ECOG Performance Status: 0, 1 (Table 23) 
• cT-stage: T0, Tis, T1, T2, T3a, T3b, T3c, T3d, T4a, T4b, Tx (Table 23) 
• Node positive disease: Yes, No (Table 23) 
• Clear circumferential radial margin (CRM): Yes, No (Table 23) 
• Progressive Disease: Yes, No (Table 23) 
7.5.2 
Pre-excision Exam 
• Sigmoidoscopy/colonoscopy: normal, abnormal but non-malignant, abnormal 
and malignant (Table 24) 
• Other radiology investigations: normal, abnormal but non-malignant, abnormal 
and malignant (Table 24) 
7.5.3 
Pre-excision Extent of Disease 
• 
Number of patients with disease assessment, number of patients with disease 
progression, site of diseases, number of disease sites, largest measure (Table 25) 
• 
Number of patients with new lesions, site of new lesions, number of new 
lesions (Table 25) 
7.5.4 
Plan of Surgical Treatment 
Based on the results of pre-excision assessments, a plan of surgical treatment is 
developed by the investigator. The following information will be summarized (Table 
26): 
• Number of patients with each choice of surgical treatment 
7.5.5 
Surgical Treatment 
The following information on the surgeries performed will be summarized: 


• Number of patients who received tumour excision (Table 27) 
o Procedure performed: TEMS, TAMIS, TME, other (Table 27) 
o Time in operating room: median, minimum, maximum (Table 27) 
o Resection margins: R0, R1, R2 (Table 27) 
o Mesorectal excision: Total/complete, incomplete, unknown (Table 27) 
o Subsequent surgery recommended: Not applicable, Yes but declined by 
patient, No because complete tumour resection and ypT0 or ypT1good, 
No other (Table 27) 
• Number of patients with definitive decision not to have tumour (Table 27) 
o Reasons for definitive decision not to have tumour excision (Table 27) 
7.5.6 
Pathology Results after surgical treatment 
• Site of the tumor: rectum, nodes, other (Table 28) 
• Longest dimension of Invasive Carcinoma: median, minimum, maximum 
values (Table 28) 
• Lymphatic invasion: Yes, No (Table 28) 
• Vascular invasion: Yes, No (Table 28) 
• Histology: adeno-carcinoma, etc. (Table 28)  
• Histologic grade: well differentiated, moderately differentiation, not stated in 
report (Table 28) 
• Deepest layer of invasion: Mucosa, Lamina Propia, Muscularis mucosa, 
Submucosa, Muscularis propia, Serosa, Perirectal tissue, Subserosa, Not Stated 
in Report (Table 28) 
• Depth of invasion into subserosa: median, min-max (Table 28) 
• Deep margin: positive for invasive carcinoma, negative, not stated in report, not 
applicable; median, minimum, maximum values (Table 28) 
• Mucosal margin: positive for invasive carcinoma, negative, not stated in report, 
not applicable; median, minimum, maximum values (Table 28) 
• Pathologic T stage: T0, T1, T2, T3, unknown (Table 28) 
• Number of nodes examined: median, minimum, maximum values (Table 28) 
• Number of nodes with tumour: median, minimum, maximum values (Table 28) 
• Tumour deposits: yes, no (Table 28) 
7.6 
Radiation Treatments 
Pelvic radiation is recommended for patients when the excisional specimen 
demonstrates ypT3+ or N+ disease and requires radical TME surgery. The following 
information will be summarized for patients who received any pelvic radiation therapy 
prior to TME surgery: 
• Site of Radiotherapy: Rectum, Sigmoid colon, Anus (Table 29) 
• Duration of Radiotherapy (days): median, minimum, maximum (Table 29) 
• Total dose of radiation: median, minimum, maximum (Table 29) 
7.7 
Efficacy 
7.7.1 
Organ Preservation Rate 
After completion of neoadjuvant chemotherapy, the protocol requires that patients with 
lesions that on pre-excision (post-chemotherapy) MRI and/or endoscopy showing 
evidence of progression or no response to chemotherapy to be treated with immediately 


the radical TME surgery. Other patients will be treated with local excision TEMS or 
TAMIS. Patients with ypstage T0/T1goodN0 tumours based on local pathology 
ypstaging review after TEMS or TAMIS are treated with surveillance while patients 
with tumours with ypT2, N+ or ypT1 tumours with poor prognostic features are treated 
with radical TME surgery within 6-8 weeks after local excision. The numbers of 
enrolled patients who were treated with respectively neoadjuvant chemotherapy, TME 
and TEMS or TAMIS immediately after completion of neoadjuvant chemotherapy, and 
TME or surveillance after TEMS or TAMIS will be summarized (Table 30). 
Organ preservation rate, the primary endpoint of this study, is defined as the proportion 
of patients with tumour downstaging to ypT0/T1good N0 who avoid radical surgery 
(TME) among all patients treated with FOLFOX or CAPOX and TEMS or TAMIS. 
The 95% confidence interval for the organ preservation rate will be calculated (Table 
30). 
Organ preservation rate will additionally be calculated among all patients that have 
received neoadjuvant chemotherapy. 
7.7.2 
3 Year Loco-Regional Relapse Rate 
Locoregional relapse is defined as reappearance of a tumour within the rectum or pelvis. 
The number of patients with each site (rectum, pelvis, pelvic lymph nodes, and others) 
of locaregional relapse will be summarized (Table 31).  
Locoregional relapse free survival is calculated as time from complete tumour surgical 
excision date (with pathology results negative for malignant disease within 1 mm of 
surgical margins) to the first date of definitive evidence (clinical, radiological or 
pathological) of locoregional relapses. Patients with distant relapse only, died, loss to 
follow up, or alive at clinical cut-off will be censored at respectively last date of distant 
relapses, date of death, date of lost to follow-up, and last disease assessment date 
calculated as the last of dates of attendance/last contact on Follow-up Report.  
Kaplan-Meier method (Figure 2) will be used to estimate the 3 year loco-regional 
relapse rate and associated 95% confidence interval first among all patients treated with 
FOLFOX or CAPOX and TEMS or TAMIS (Table 31) and additionally among all 
patients that have received neoadjuvant chemotherapy. 
7.7.3 
3 Year Distant Relapse Rate 
Distant relapse is defined as appearance of rectal cancer disease at sites remote from 
the rectum. The number of patients with each site of distant relapse (Lung, Liver, Brain, 
Distant lymph nodes, Bone, Skin, Ascites, Pleural effusion, Adrenal glands, Other) will 
be summarized (Table 31).  
Distant relapse free survival is calculated as time from complete tumour surgical 
excision date (with pathology results negative for malignant disease within 1 mm of 
surgical margins) to the first date of definitive evidence (clinical, radiological or 
pathological) of distant relapses. Patients died, loss to follow up, or alive at clinical cut-
off will be censored at respectively date of death, date of lost to follow-up, and last 
disease assessment date calculated as the last of dates of attendance/last contact on 
CRD Follow-up Report.  
Kaplan-Meier method (Figure 3) will be used to estimate the 3 year distant relapse rate 
and associated 95% confidence interval first among all patients treated with FOLFOX 


or CAPOX and TEMS or TAMIS (Table 31) and additionally among all patients that 
have received neoadjuvant chemotherapy. 
7.7.4 
3 year Disease Free Survival 
Disease-Free Survival (DFS) is defined as the interval from complete tumour surgical 
excision date (with pathology results negative for malignant disease within 1 mm of 
surgical margins) to date of first occurrence of the events in the below.  
• Locoregional relapse reported in CRF Relapse Report 
• Distant disease reported in CRF Relapse Report 
• Non-protocol radiotherapy, chemotherapy, or biologic therapy without 
documentation of the site of failure and reported in CRF Chemotherapy Report, 
Pre-Excision Report, and Surgery Report 
• Death due to any other reason reported in CRF Death Report 
Patients who are alive without locoregional or distant relapse or receiving non-protocol 
radiotherapy, chemotherapy, or biologic therapy without documentation of the site of 
failure at the analysis data cutoff date will be censored at their last disease assessment 
date calculated as the last of dates of attendance/last contact on Follow-up Report. 
A frequency table will be provided describing DFS events and censorings as follows: 
• Number of patients who had a DFS event (Relapse (locoregional, distant), non-
protocol therapy, death (due to any other reason) (Table 31) 
• Number of patients censored with reasons of censoring (alive at the clinical cut-
off, lost to follow-up) (Table 31) 
Kaplan-Meier method (Figure 4) will be used to estimate the 3 year DFS rate and 
associated 95% confidence interval first among all patients treated with FOLFOX or 
CAPOX and TEMS or TAMIS (Table 31) and additionally among all patients that have 
received neoadjuvant chemotherapy. 
7.8 
Safety 
The safety analyses will based on the Chemotherapy Treated population defined in 
Section 6 unless otherwise specified. Adverse events and laboratories are graded and 
categorized using the NCI CTCAE except where CTCAE grades are not available. 
7.8.1 
Adverse Events 
Adverse events (AEs) are recorded in the Adverse Events (AE) sections of CRF 
Chemotherapy Report, CRF Pre-Excision Report, CRF Surgery Report, CRF Follow 
Up Report (only AEs thought to be related to protocol treatment), and CRF Short 
Follow Up Report (ongoing or new grade 3 or higher AEs which are thought to be 
related to protocol treatment).  Severity grade 5 will be combined with grade 4 for the 
purpose of this report. Adverse events reported during study treatment (in AE sections 
of CRF Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report) 
are defined as acute (on treatment) adverse events. Adverse events reported in AE 
section of CRF Follow Up Report and CRF Short Follow Up Report will be defined as 
delayed (long term) AEs.  
Treatment (capecitabine, oxaliplatin, leucovorin, surgery, and radiotherpy) related 
adverse events are those events with a relation to protocol therapy of 3=possible, 


4=probable or 5=definite. 
Severe adverse events are those events reported with a NCI CTCAE Grade of 3 or 
higher. 
The following variables are summarized: 
• 
Acute adverse events: worst CTCAE grade per patient (Table 32) 
• 
Severe acute adverse events: worst CTCAE grade per patient (Table 33) 
• 
Treatment related acute adverse events: worst CTCAE grade per patient 
(Table 34) 
• 
Delayed severe adverse events: worst CTCAE grade per patient (Table 35) 
7.8.2 
Laboratory Evaluations 
Laboratory evaluations, except coagulation and CEA, reported on CRF Chemotherapy 
Report and CRF Pre-Excision Report will be included in the calculation laboratory 
adverse events.  Coagulation is only reported on CRF Pre-Excision Report and CEA 
on CRF Pre-Excision Report and of CRF Follow Up Report, which will be summarized 
individually. Laboratory results will be classified according to the NCI CTCAE when 
available. 
7.8.2.1 Hematology 
• Hemoglobin, WBC, absolute neutrophil count (ANC), neutrophils, platelets, 
lymphocytes, basophils, monocytes, eosinophils: worst CTCAE grade per 
patient (Table 36) 
7.8.2.2 Biochemistry 
• 
Serum creatinine, total bilirubin, ALT, creatinine clearance: worst CTCAE 
grade per patient (Table 37) 
7.8.2.3 Other laboratory evaluations 
• Pre-excision Coagulation: CTCAE grade of PT, INR, PTT (Table 38) 
• 
Serum CEA: The mean and standard deviation of baseline CEA levels and the 
change of CEA levels from baseline at pre-excision and each follow-up visits 
(Table 38) 
7.8.3 
Post-operative complications 
For patients with a tumour excision attempted, the following post-operative 
complications reported on CRF Surgery Report will be summarized (Table 39): 
7.8.3.1 Reoperation 
• Patients requiring reoperation: Yes, No 
• Reoperation procedure performed: debridement, incision and drainage, 
diverting ostomy, other 
7.8.3.2 Blood loss/transfusion 
• Estimated amount (cc) of blood loss during surgery: median, minimum, 
maximum 
• Any transfusions or blood products during surgery: Yes, no 
• Type of Transfusion: Red cell concentrates, Platelets, Other 
7.8.3.3 Intraoperative injury 
• Any intraoperative injury: Yes, no 


• Site of injury: Bladder, Ureter, Vein, Artery, Large Bowel, Small Bowel, Nerve, 
Other 
7.8.3.4 Hospitalization 
• Any time in intensive care: Yes, No 
• Days in intensive care: median, minimum, maximum 
• Ongoing hospitalization: Yes, no 
• Days from admission to hospital for the tumour excision to discharge: median, 
minimum, maximum 
• Discharge destination: Home, Assisted living (non-medical), Skilled nursing 
home, Hospice, Chronic care hospital, Rehabilitation facility, Died, Transfer to 
other hospital, Other 
7.8.4 
Deaths on Study/Adverse Events Leading to Discontinuations due to 
Toxicity 
• 
All Deaths: number of patients who died and cause of death from CRF Death 
Report (Table 40) 
• 
Deaths before surgery: number of patients who died and cause of death from 
CRF Death Report (Table 41) 
• 
Adverse events leading to discontinuations of neoadjuvant: number of patients 
with adverse events leading to discontinuations of treatment as identified from 
CRF Chemothrapy Report (Table 42)  
7.8.5 
Other safety 
7.8.5.1 Sigmoidoscopy/colonoscopy 
• Sigmoidoscopy/colonoscopy during protocol treatment (reported on CRF 
Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report): 
all normal, at least one abnormal but all non-malignant, all abnormal and 
malignant (Table 43) 
• Sigmoidoscopy/colonoscopy during follow-up (reported on CRF Follow Up all 
normal, at least one abnormal but all non-malignant, all abnormal and malignant 
(Table 43) 
7.8.5.2 Other radiologic investigations 
• Other radiologic investigations during protocol treatment (reported on CRF 
Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report): 
all normal, at least one abnormal but all non-malignant, all abnormal and 
malignant (Table 43) 
• Other radiologic investigationsy during follow-up (reported on CRF Follow-up 
REPORT): all normal, at least one abnormal but all non-malignant, all abnormal 
and malignant (Table 43) 
7.8.5.3 Transfusions 
• Number of patients who received any blood transfusions (red blood cells, 
platelets, and/or other) during protocol treatment (reported on CRF 
Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report)  
(Table 44)  
• Number of patients who received any blood transfusions (red blood cells, 
platelets, and/or other) during follow-up (reported on CRF Follow-Up Report)  
(Table 44)  


7.8.5.4 Major medical problems 
• Number of patients with each type of medical problems during protocol 
treatment (reported on Chemotherapy Report, CRF Pre-Excision Report, and 
CRF Surgery Report)  (Table 45)  
• Number of patients with each type of medical problems during follow-up 
(reported on CRF Follow-Up Report)  (Table 45)  
7.9 
Concomitant Medications and Other Anti-Cancer Treatments 
Concomitant medication is defined as medication, other than protocol therapy, which 
is taken by patients any time on treatment or after end of treatment. Patients may also 
receive any other anti-cancer treatment during or after being taken off protocol 
treatment. 
• Concomitant medications for patients during protocol treatment (reported on 
Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report) 
(Table 46) 
• Concomitant medications for patients 30 days after excision (reported on CRF 
Follow-Up Report) (Table 46) 
• Anti-cancer treatments for patients during protocol treatment (reported on 
Chemotherapy Report, CRF Pre-Excision Report, and CRF Surgery Report)  
(Table 47) 
• Anti-cancer treatments for patients after protocol treatment but before relapse 
(reported on Follow-Up Report) (Table 47) 
• Anti-cancer treatments for patients after relapse (reported on Short Follow-Up 
Report) (Table 47) 
7.10 
Quality of Life 
The quality of life of patients in this study is assessed by using EORTC QLQ-C30 
(version 3.0), QLQ-CR29, Low Anterior Resection Syndrome Score (LARS), and the 
Fecal Incontinence Quality of Life (FIQL) Instrument at baseline, pre-excision (2 
weeks (FOLFOX) or 3 weeks (CAPOX) after last injection in last cycle of 
chemotherapy), after excision (months 6, 12, 24, and 36). The following are the scoring 
algorithms for each of these four QoL instruments.  
7.10.1 Scoring Algorithms  
7.10.1.1 EORTC QLQ-C30 
The EORTC core questionnaire, QLQ-C30 (version 3.0), consists of five Functional 
Scales, Global Health Status, and nine Symptoms Scales. Each scale in the 
questionnaire will be scored (0 to 100) according to the EORTC recommendations in 
the EORTC QLQ-C30 Scoring Manual.  The scoring method for EORTC QLQ-C30 
is summarized below.  In this summary Qi refers to the i-th question on the QLQ-C30. 
Functional scale’s scores: 
• Physical functioning: 
 
(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
• Role functioning: 
 
 
(1 - ((Q6+Q7)/2-1)/3) * 100 
• Emotional functioning:  
(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
• Cognitive functioning: 
 
(1 - ((Q20+Q25)/2-1)/3) * 100 
• Social functioning:  
 
(1 - ((Q26+Q27)/2-1)/3) * 100 


Global health status score: 
• Global QOL: 
((Q29+Q30)/2-1)/6 * 100 
Symptom scale’s scores: 
• Fatigue: 
 
 
 
 
((Q10+Q12+Q18)/3-1)/3 * 100 
• Nausea and vomiting: 
 
((Q14+Q15)/2-1)/3 * 100 
• Pain: 
 
 
 
 
 
((Q9+Q19)/2-1)/3 * 100 
• Dyspnea: 
 
 
 
 
((Q8-1)/3 * 100 
• Insomnia:  
 
 
 
(Q11-1)/3 * 100 
• Appetite loss: 
 
 
 
(Q13-1)/3 * 100 
• Constipation: 
 
 
 
(Q16-1)/3 * 100 
• Diarrhea: 
 
 
 
 
(Q17-1)/3 * 100 
• Financial difficulties: 
 
(Q28-1)/3 * 100 
7.10.1.2 EORTC QLQ-CR29 
QLQ-CR29 is a colon and rectum cancer site-specific supplemental module to the 
EORTC core questionnaire, which consists of five Functional Scales, 18 Symptoms 
Scales as well as stoma status. Each scale in the questionnaire will be scored (0 to 100) 
according to the EORTC recommendations in the EORTC QLQ-CR29 Scoring 
Manual.  The scoring method for EORTC QLQ-CR29 is summarized below.  In this 
summary Qi refers to the i-th question on the QLQ-CR29. 
Functional scale’s scores: 
• Body image: 
• Anxiety: 
• Weight:  
• Sexual Interest (men):  
• Sexual Interest (women): 
(1 - ((Q45+Q46+Q47)/3 -1)/3) * 100 
(1 - (Q43)-1)/3) * 100 
(1 - (Q44-1)/3) * 100 
(1 - (Q56-1)/3) * 100 
(1 - (Q58-1)/3) * 100 
Symptom scale’s scores: 
• Urinary frequency 
((Q31+Q32)/2-1)/3 * 100 
• Blood and mucus in stool 
((Q38+Q39)/2-1)/3 * 100 
• Stool frequency 
((Q52+Q53)/2-1)/3 * 100 
• Urinary incontinence 
(Q33-1)/3 * 100 
• Dysuria 
(Q34-1)/3 * 100 
• Abdominal pain 
(Q35-1)/3 * 100 
• Buttock pain 
(Q36-1)/3 * 100 
• Bloating 
(Q37-1)/3 * 100 
• Dry mouth 
(Q40-1)/3 * 100 
• Hair loss 
(Q41-1)/3 * 100 
• Taste 
(Q42-1)/3 * 100 
• Flatulence 
(Q49-1)/3 * 100 
• Fecal incontinence 
(Q50-1)/3 * 100 
• Sore skin 
(Q50-1)/3 * 100 
• Embarrassment 
(Q54-1)/3 * 100 
• Stoma care problems 
(Q55-1)/3 * 100 
• Impotence 
(Q57-1)/3 * 100 
• Dyspareunia  
(Q59-1)/3 * 100 
• Stoma status 
(Q48-1) * 100 


7.10.1.3 Low Anterior Resection Syndrome (LARS) Score 
Low Anterior Resection Syndrome (LARS) Score is a scoring system for bowel 
dysfunction after low anterior resection (LAR) for rectal cancer.  It consists of 5 
questions and the answers to them are assigned a score based on the following 
algorithm:  
Question 1: Do you ever have occasions when you cannot control your flatus 
(wind)?  
• No, never   
 
 
 
 
 
 
 
0 
• Yes, less than once per week   
 
 
 
4 
• Yes, at least once per week   
 
 
 
7 
Question 2: Do you ever have any accidental leakage of liquid stool?  
• No, never   
 
 
 
 
 
 
 
0 
• Yes, less than once per week  
 
 
 
3 
• Yes, at least once per week   
 
 
 
3 
Question 3: How often do you open your bowels?   
• More than 7 times per day (24 hours)  
 
4 
• 4-7 times per day (24 hours)  
 
 
 
2 
• 1-3 times per day (24 hours)  
 
 
 
0 
• Less than once per day (24 hours)  
 
 
5 
Question 4: Do you ever have to open your bowels again within one hour of the 
last bowel opening?  
• No, never   
 
 
 
 
 
 
 
0 
• Yes, less than once per week  
 
 
 
9 
• Yes, at least once per week   
 
 
 
11 
Question 5: Do you ever have such a strong urge to open your bowels that you 
have to rush to the toilet?  
• No, never   
 
 
 
 
 
 
 
0 
• Yes, less than once per week  
 
 
 
11 
• Yes, at least once per week 
 
 
 
 
16 
LARS total score is defined as the sum of scores to these 5 questions. 
7.10.1.4 Fecal Incontinence Quality of Life (FIQL) Instrument 
The Fecal Incontinence Quality Of Life (FIQL) Instrument is a disease-specific tool 
designed to evaluate the impact of Fecal Incontinence (FI).  It consists of four scales. 
Each scale in the instrument will be scored (1 to 4), where 1 is very affected and 4 is 
not affected, based on the scoring method summarized below.  In this summary, Qi 
refers to the i-th question on the FIQL instrument:  
FIQL scale’s scores: 
• Lifestyle: 
(Q2A+Q2B+Q2C+Q2D+Q2E+Q2G+Q2H+ 
Q3B+Q3L+Q3M)/10 
• Coping/Behavior: 
(Q2F+Q2I+Q2J+Q2K+Q2M+Q3C+Q3H+ 
Q3J+Q3N)/9 
• Depression/Self Perception: (Q1+Q3D+Q3FJ+Q3G+Q3I+Q3K+Q4)/7 
  
 
 
 
 
 
 
(Question 1 is reverse coded first) 


• Embarrassment:  
 
 
(Q2L+Q3A+Q3E)/3) 
For all of questionnaires/instruments, missing items in a scale will be handled by the 
following methods: Values will be imputed for missing items by “assuming that the 
missing items have values equal to the average of those items which are present” for 
any scale in which at least half the items are completed.  A scale in which less than 
half of the items are completed will be treated as missing. 
7.10.2 Data Sets 
The analyses of quality of life data will be restricted to accrued patients who have 
completed at least one QoL questionnaire. 
7.10.3 Compliance 
Compliance will be described, by time of evaluation, by the number and percentage of 
subjects who filled out a questionnaire (per subject, at least one question answered) in 
that period of evaluation. The denominator used in calculating the percentage for 
baseline will be all accrued subjects (Table 48). 
7.10.4 Analyses of QOL 
7.10.4.1 Baseline and Change Score Analysis 
For each scale of EORTC QOL-C30 and CR29 and FIQL instrument and total score of 
LARS, descriptive statistics (mean, standard deviation) will be presented at baseline. 
The same statistics will be generated for change score from baseline at each time of 
post-baseline evaluation. (Table 49 and Table 50) 
7.10.4.2 Proportions of Deterioration and Improving or Stable for EORTC QLQ-C30 
and CR29 at Post-Baseline Assessment 
The deterioration is defined as a change score from baseline which is –10 points or 
lower. The proportions of patients who had improving (defined as change score from 
baseline of 10 points or higher) or stable (defined as change score from baseline of 
between –10 and 10 points) (Table 51). QoL response rate and associated 95% 
confidence interval will be calculated for each scale and item. 
7.10.4.3 Proportions of LARS Severity Group at Baseline and Post-baseline 
Assessment 
Based on the LARS total score of LARS, a patient can be classified into one of the 
following 4 groups: 0 to 20 (no LARS), 21 to 29 (minor LARS), and 30 to 42 (major 
LARS). Proportions of patients in each of these four groups and associated 95% 
confidence interval will be calculated at baseline and each time of post-baseline 
assessments (Table 52). 
 
 


8. Appendices 
Appendix 1: Tables and Figures 
 
Table 1. Patient Disposition 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Accrued 
** (**) 
 
 
Treated 
** (**) 
  On study 
** (**) 
  Off study (1)   
** (**) 
 
 
Never Treated 
** (**) 
(1) Off all study therapy 
 
Table 2: Follow-up of Patients 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Number of patients alive 
*** (%) 
 
 
Fellow-up (months) 
 
 
median 
** 
  
Minimum-maximum      
**-** 
 
Table 3: Accrual by Center 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Center #1 
** (**) 
Center #2 
** (**) 
Center #3 
** (**) 
... 
** (**) 
 
 
 


Figure 1: Accrual by Calendar Time 
 
 
 
 
Table 4: Eligibility and Reasons for Ineligibility and Major Protocol Violations 
Data set:  All Accrued Patients 
 
Number of Patients (%) 
N=** 
Eligible 
** (**) 
Not Eligible 
** (**) 
Reason for ineligibility  
 
 
<Reason 1> 
** 
 
<Reason 2> 
** 
 
... 
** 
Major protocol violation 
 
<violation type 1> 
 
<violation type 2> 
 
… 
 
** 
** 
 
 
0
10
20
30
40
50
60
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Accrued Paients
Time


Table 5: Pre-treatment Characteristics at Baseline 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Gender  
 
  Female 
** (**) 
  Male 
** (**) 
Age (years) 
 
  N 
  Median 
  Min - Max 
** 
** 
** - ** 
  < 65 
  ≥ 65 
** (**) 
** (**) 
Race 
 
White 
** (**) 
Black or African American 
** (**) 
Native Hawaiian or Pacific Islander 
** (**) 
Asian 
** (**) 
Not reported (or refused) 
** (**) 
Unknown 
** (**) 
Height 
 
 
N 
**  
Median 
** 
Min-Max 
** - ** 
Weight 
 
 
N 
**  
Median 
** 
Min-Max 
** - ** 
BSA  
 
N 
**  
Median 
** 
Min-Max 
** - ** 
ECOG Performance Status 
 
  0 
** (**) 
  1 
** (**) 
Months from First Histological Diagnosis to enrollment 
 
N 
** 
Median 
** 
Min – Max 
** - ** 
Tumour Invasion based on pelvic MRI 
Submucosa 
Muscularis propia 
Muscularis propia no more than 5 mm into the subserosa/perirectal tissue 
Muscularis propia more than 5 mm into the subserosa/perirectal tissue 
Not visible on pelvic MRI 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
cT-stage (based on pelvic MRI) 
T1 
T2 
T3a 
T3b 
 
**(**) 
**(**) 
**(**) 
**(**) 
Tumour Height from anal verge (cm)  
 
N 
** 
Median 
** 
Min – Max 
** - ** 
 
 
 


 
Table 6: Baseline Pathology Results  
Dataset :All Accrued Patients 
 
Number of patients (%) 
N=** 
Longest dimension of Invasive Carcinoma 
  N 
 
Median 
 
Min – Max 
 
** 
** 
** - ** 
Histology  
 
Adeno-carcinoma 
 
Squamous  
 
Other 
 
** (**) 
** (**) 
** (**) 
Histologic Grade 
 
Well -Differentiated 
Moderately Differentiated 
Not stated in report 
** (**) 
** (**) 
** (**) 
** (**)
Deepest Layer of Invasion  
Mucosa 
Lamina Propia 
Muscularis mucosa 
Submucosa 
Muscularis propia 
Serosa 
Perirectal tissue 
Subserosa 
 
 Depth of invasion into subserosa 
Median 
Min-max 
Not Stated in Report 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
** 
**-** 
** (**)
Deep Margin 
Positive for invasive carcinoma 
Median 
Min-Max 
Negative 
Not stated in Report 
Not Applicable 
Mucosal Margin 
Positive for invasive carcinoma 
Median 
Min-Max 
Negative 
Not stated in Report 
Not Applicable 
 
**(**) 
** 
**-** 
**(**) 
**(**) 
**(**) 
 
**(**) 
** 
**-** 
**(**) 
**(**) 
**(**)
Pathologic T Stage 
**(**) 
T0 
T1 
T2 
T3 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Tumour deposits 
 
 
  Yes 
**(**) 
 
  No 
**(**) 
 
 
 


Table 7: Baseline Sigmoidoscopy/Colonoscopy and Other Radiology 
Investigations 
 
Data set:  All Accrued Patients 
 
Number of Patients (%) 
N=** 
Sigmoidoscopy 
 
Normal 
** (**) 
 
Abnormal, Non-malignant 
** (**) 
 
Abnormal, malignant 
** (**) 
Colonoscopy 
 
 
Normal 
** (**) 
 
Abnormal, Non-malignant 
** (**) 
 
Abnormal, malignant 
** (**) 
Other Radiology 1 
 
 
Result 1 
** (**) 
 
… 
** (**) 
… 
 
 
 


Table 8: Baseline Hematology 
Data set:  All Accrued Patients 
 
Number of Patients (%) 
N=** 
Hemoglobin 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
WBC 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Absolute neutrophil count (ANC) 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Platelet 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Lymphocytes 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Basophils 
 
 
Normal 
** (**) 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
 
Not reported (1) 
** (**) 
Monocytes 
 
 
Normal 
** (**) 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
 
Not reported (1) 
** (**) 
 
 


Eosinophils 
 
 
Normal 
** (**) 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
 
Not reported (1) 
** (**) 
 
Table 9: Baseline Biochemistry 
Data set:  All Accrued Patients 
 
Number of Patients (%) 
 
Total 
N=** 
Serum Creatinine 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Total bilirubin 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
ALT 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
Creatinine Clearance 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
(1) Not done or outside the 30-day window prior to enrollment 
 
 


Table 10: Baseline Coagulation 
Data set:  All Accrued Patients 
 
Number of Patients (%) 
 
Total 
N=** 
PT 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
INR 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
PTT 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Not reported (1) 
** (**) 
(1) Not done or outside the 30-day window prior to enrollment 
Table 11: Baseline Symptoms Status 
Data set:  All Accrued Patients  
 
Number of patients (%) 
N=** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
Patients with any symptom/ 
finding at baseline 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients 
with 
particular 
symptom/finding, 
within 
body system:  
Body System 1(1) 
Event 1 
Event 2 
Event 3 
...  
Body System 2(1) 
Event 1  
...  
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a body system 
 
 
 


Table 12: Prior Concomitant Medications (Baseline) 
Data set:  All Accrued Patients 
 
Number of patients (%) 
 
N=** 
Any prior concomitant medication (1)  
 
    No 
** (**) 
    Yes 
** (**) 
Drug Name 1                 
 
** (**)           
Drug Name 2 
** (**) 
.... 
 
Table 13: Past or Current Major Medical Problems 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Patients Reporting at least one past or current major 
medical problem at baseline 
** (**) 
Medical Problem(1) 
 
... 
** (**) 
(1) patients may report more than one medical problem reported 
 
 
 


Table 14: Tobacco Smoking History at Baseline 
 
Data set:  All Accrued Patients 
 
Number of patients (%) 
N=** 
Ever smoked any tobacco product  
 
    Yes 
** (**) 
 
No 
 
Unknown 
** (**) 
** (**) 
Currently smoking 
 
    Yes 
** (**) 
 
No 
** (**) 
Current Average number of cigarettes per day 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
Years from quitting smoking to enrollment 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
Years from beginning smoking cigarettes to 
 
enrollment 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
Total number of years of smoking cigarettes 
 
N 
    Median 
    Min - Max 
 
 
** 
** 
**
**
Average number of cigarettes smoked per day 
 
N 
    Median 
    Min - Max 
 
 
** 
** 
Average pack years of cigarettes smoked  
 
N 
    Median 
    Min - Max 
 
 
** 
** 
** - ** 
 
 
 
 
 


 
Table 15: Number of Patients by Cycle of Chemotherapy 
Data Set: All Chemotherapy Treated Patients  
 
Number of Patients (%) 
 
FOLFOX 
N=** 
CAPOX 
N=** 
Cycle 
1 
** (**) 
** (**) 
 
 
2 
** (**) 
** (**) 
 
 
3 
** (**) 
** (**) 
 
 
... 
 
 
 
 
 
 
Table 16: Number of Cycles of Chemotherapy per Patient 
Data Set: All Chemotherapy Treated Patients 
 
FOLFOX 
CAPOX 
Number of Cycles: 
 
 
 
N 
** 
** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
 
 
 
 
Table 17: Total Duration of Chemotherapy 
Data Set: All Chemotherapy Treated Patients 
 
FOLFOX 
CAPOX 
Duration in weeks: 
 
 
 
N 
** 
** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
 
 
 
 
Table 18: Number of Patients with Modifications of Chemotherapy  
Data Set: All Chemotherapy Treated Patients 
 
FOLFOX 
CAPOX 
 
Oxaliplatin 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Oxaliplatin 
Capecitabine 
Patients with at least one 
cycle with (type of 
modification) over all cycles 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
Reason for (type of 
modification) 
 
 
 
 
 
 
 
Reason 1 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
… 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
Dose reduction by cycle 
 
 
 
 
 
 
 
Cycle 
1 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
2 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
... 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 


Table 19: Cumulative Dose 
Data Set: All Chemotherapy Treated Patients 
 
FOLFOX 
CAPOX 
 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Oxaliplatin 
Capecitabine 
Cumulative dose per 
patient (<unit>) 
 
 
 
 
 
 
 
N 
*** 
*** 
*** 
*** 
*** 
*** 
 
Mean (STD) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
Median 
** 
** 
** 
** 
** 
** 
 
Min-Max 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
 
Table 20: Actual Dose Intensity 
Data Set: All Chemotherapy Treated Patients 
 
FOLFOX 
CAPOX 
 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Oxaliplatin 
Capecitabine 
Dose intensity 
 
 
 
 
 
 
 
N 
*** 
*** 
*** 
*** 
*** 
*** 
 
Mean (STD) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
Median 
** 
** 
** 
** 
** 
** 
 
Min-Max 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
 
Table 21: Relative Dose Intensity 
Data Set: All Chemotherapy Treated Patients 
 
 
FOLFOX 
CAPOX 
 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Oxaliplatin 
Capecitabine 
Relative Dose intensity  
 
 
 
 
 
 
 
 
 
 
 
 
 
 ≥ 90% planned intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 80% - < 90% planned intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 60% - < 80% planned intensity 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 < 60% planned intensity   
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
 
 


 
Table 22: Off Neoadjuvant Chemotherapy Summary 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
Patients off Chemotherapy 
 
** (**) 
 
Reason off protocol therapy 
 
 
Treatment Completed 
 
 
Progressive Disease (objective) 
 
 
Symptomatic Progression 
 
 
Intercurrent Illness – adverse events unrelated to  
 
 
 
protocol treatment 
Adverse events related to protocol therapy 
Patient Refusal (not related to adverse event) 
Death 
Other Reason 
 
 
** 
** 
** 
** 
** 
 
** 
** 
** 
** 
** 
 
 
 
 


Table 23: Pre-excision Characteristics and MRI results 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
Weight 
 
 
N 
**  
Median 
** 
Min-Max 
** - ** 
BSA  
 
N 
**  
Median 
** 
Min-Max 
** - ** 
ECOG Performance Status 
 
  0 
** (**) 
  1 
** (**) 
cT-stage (based on pelvic MRI) 
T0 
Tis 
T1 
T2 
T3a 
T3b 
T3c 
T3d 
T4a 
T4b 
Tx 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
Node positive disease  
 
Yes 
** (**) 
No 
** (**) 
Clear circuferential radial margin (CRM) 
 
Yes 
 
No 
 
** (**) 
** (**) 
Progressive disease 
 
Yes 
 
No 
 
** (**) 
** (**) 
 
 
Table 24: Pre-excision Sigmoidoscopy/Colonoscopy and Other Radiology 
Investigations 
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients (%) 
N=** 
Sigmoidoscopy 
 
Normal 
** (**) 
 
Abnormal, Non-malignant 
** (**) 
 
Abnormal, malignant 
** (**) 
Colonoscopy 
 
 
Normal 
** (**) 
 
Abnormal, Non-malignant 
** (**) 
 
Abnormal, malignant 
** (**) 
Other Radiology Investigation 1 
 
 
Result 1 
** (**) 
 
… 
** (**) 
… 
 


 
Table 25: Pre-excision Extent of Disease 
Data set:  All Chemotherapy Treated Patients 
 
Number of 
patients (%) 
N=** 
Patients with disease assessment 
** (**) 
 
 
Patients with disease progression 
** (**) 
 
 
Number of Disease sites 
 
              1 
** (**) 
              2 
** (**) 
              3 
** (**) 
              4 
** (**) 
              ≥5 
** (**) 
 
 
Longest Diameter in mm 
 
              < 2 
** (**) 
              2-5 
** (**) 
              > 5-10 
** (**) 
              > 10 
** (**) 
 
 
 Site of Disease(1) 
 
 
Abdomen 
** (**) 
 
Adrenals 
** (**) 
 
Bone 
** (**) 
 
Brain 
** (**) 
 
Liver 
** (**) 
 
Lung 
** (**) 
 
Nodes 
** (**) 
 
Subcutaneous Tissue 
** (**) 
              .... 
** (**) 
 
 
Patients with new lesions 
** (**) 
 
 
Number of new lesions 
 
              1 
** (**) 
              2 
** (**) 
              3 
** (**) 
              4 
** (**) 
              ≥5 
** (**) 
 
 
 Site of Disease(1) 
 
 
Abdomen 
** (**) 
 
Adrenals 
** (**) 
 
Bone 
** (**) 
 
Brain 
** (**) 
 
Liver 
** (**) 
 
Lung 
** (**) 
 
Nodes 
** (**) 
 
Pleura 
** (**) 
 
Skin 
** (**) 
 
Subcutaneous Tissue 
** (**) 
              .... 
** (**) 


 
Table 26: Plan of surgical Treatment  
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients (%) 
N=** 
TAMIS/TEMS 
** (**) 
Mesorectal Excision (TME) 
** (**) 
No Surgery Planned (Patient Refusal) 
** (**) 
No Surgery Planned (Tumour excision not appropriate) 
** (**) 
Other 
** (**) 
 
Table 27: Surgery Summary 
 
Data set:  All Chemotherapy Treated Patients 
 
 
Patients received tumour excision 
 
 
Procedure Performed 
TEMS 
TAMIS 
TME  
Other  
 
 
Time in operating room (minutes) 
 
Median 
 
Min-max 
 
Resection margins 
R0 
R1 
R2 
 
Mesorectal excision 
Total/complete 
Incomplete 
Unknown  
 
Subsequent Surgery Recommended 
Not applicable (TME performed) 
Yes 
Yes, but declined by patient 
No, complete tumour resection and ypT0 or ypT1good 
 
Other  
 
Patients with definitive decision not to have tumour excision  
 
 
Reason for definitive decision not to have tumour excision 
 
 Intercurrent Illness 
 
 Progressive Disease 
 
 Patient Refusal 
 
 Death 
 
 Other 
Number of patients (%) 
N=** 
** (**) 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
** 
**_** 
 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
** (**) 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 


Table 28: Pathology Results After Surgical Treatment 
Dataset: All Chemotherapy and Excision/Surgery Treated Patients 
 
Number of patients (%) 
N=**
Site of tumor 
 
Rectum 
 
Nodes  
 
Other 
 
** (**) 
** (**) 
** (**) 
Longest dimension of Invasive Carcinoma 
  N 
 
Median 
 
Min – Max 
 
** 
** 
** - ** 
Lymphatic invasion  
 
Yes 
 
No  
 
Not stated in the report 
 
** (**) 
** (**) 
** (**) 
Vascular invasion 
 
 
Yes 
 
No  
 
Not stated in the report 
 
** (**) 
** (**) 
** (**) 
Histology  
 
Adeno-carcinoma 
 
Squamous  
 
Other 
 
** (**) 
** (**) 
** (**) 
Histologic Grade 
 
Well -differentiated 
Moderately differentiated 
Poorly differentiated 
Undifferentiated, anaplastic 
Grade cannot be assessed 
Not stated in report 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Deepest Layer of Invasion  
Mucosa 
Lamina Propia 
Muscularis mucosa 
Submucosa 
Muscularis propia 
Serosa 
Perirectal tissue 
Subserosa 
 
 Depth of invasion into subserosa 
Median 
Min-max 
Not Stated in Report 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
** 
**-** 


Deep Margin 
Positive for invasive carcinoma 
Median 
Min-Max 
Negative 
Not stated in Report 
Not Applicable 
Mucosal Margin 
Positive for invasive carcinoma 
Median 
Min-Max 
Negative 
Not stated in Report 
Not Applicable 
 
**(**) 
** 
**-** 
**(**) 
**(**) 
**(**) 
 
**(**) 
** 
**-** 
**(**) 
**(**) 
**(**)
Pathologic T Stage 
**(**) 
T0 
T1 
T2 
T3 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Number of Nodes examined 
N 
Median 
Min-Max 
Number of nodes with tumour 
N 
Median 
Min-Max 
 
** 
** 
** - ** 
 
** 
** 
** - ** 
Tumour deposits 
 
 
  Yes 
**(**) 
 
  No 
**(**) 
 
 
Table 29: Radiotherapy Treatment 
 
Data set:  All Chemotherapy & Excision Treated Patients 
 
 
Number of Patients with Radiation treatment  
 
Site of Radiotherapy 
Rectum  
Sigmoid colon 
Anus  
 
Duration of Radiotherapy 
 
Median 
 
Min-max 
 
Total Dose of radiation (cGy) 
Median 
Min-max  
Number of patients (%) 
N=** 
 
** (**) 
 
 
** (**) 
** (**) 
** (**) 
 
 
**  
** - ** 
 
 
** 
** - ** 
 
 
 


Table 30: Summary of Organ Preservation 
Dataset: All Accrued Patients 
 
Number of Patients (%) 
N=** 
Patients received neoadjuvant chemotherapy 
No 
Yes 
Disease Progression or no response 
 
Yes 
 
 
Disease Progression 
 
 
No Response based on Pre-excision MRI 
 
 
cT3ab stage  
 
 
node positive disease  
 
 
not clear circumferential radial margin (CRM) 
 
No response based on excision specimen 
 
 
node positive disease 
  
 
ypT2 
 
 
ypT1 tumours with: 
 
 
 
- poorly differentiated histology 
 
 
 
- lymphovascular invasion 
 
 
 
- positive margin within <1mm 
 
 
 
 
 
Treated with TME 
 
No 
 
 
Treated with TEMS/TAMIS 
 
 
Ypstage T0/T1 goodN0 
 
 
 
No 
 
 
 
Subsequent TME 
 
Yes 
 
Organ Preservation Rate (%) (95% CI)  
 
Over All Chemotherapy and Excision Treated Patients 
 
Over All Chemotherapy Treated Patients 
 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
**(**) 
** (**) 
** (**) 
** (**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
** (**) 
 
** (**) 
 
** (**) 
 
** (**) 
** (**) 
** (**) 
 
 
** (**-**) 
** (**-**) 
 
 
 


Table 31: Summary of Disease Outcomes 
Data set:  All Chemotherapy & Excision Treated Patients 
 
Number of Patients (%) 
N=** 
 
 
Patients who had Disease free survival (DFS) event 
** (**) 
 
 
 
Locoregional Relapse 
Site of Disease 
Rectum 
Pelvis 
Pelvic Lymph nodes 
Other 
 
**(**) 
 
**(**) 
**(**) 
**(**) 
**(**) 
 
 
Distant Disease 
Site of Disease 
Lung 
Liver 
Brain 
Distant lymph nodes 
Skin 
Ascites 
Pleural effusion 
Adrenal glands 
other 
 
Non-protocol therapy without documentation of site of failure 
Radiotherapy 
Chemotherapy 
Biologic therapy 
**(**) 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
** (**) 
** (**) 
**(**) 
 
 
 
 
Death (due to any other reason) 
 
**(**) 
 
 
Patients who were censored 
**(**) 
 
Reason Censored 
 
 
 
Alive at the clinical cut-off 
 
Lost to follow-up 
 
3 year locoregional relapse rate (%) (95% CI) 
 
3 year distant relapse rate (%) (95% CI) 
 
3 year Disease free survival rate (%) (95% CI) 
**(**) 
**(**) 
 
**(**-**) 
 
**(**-**) 
 
**(**-**) 
 
 
Figure 2: Kaplan-Meier Curve for Locoregional Relapse Free Survival 
 
Figure 3: Kaplan-Meier Curve for Distant Relapse Free Survival 
 
Figure 4: Kaplan-Meier Curve for Disease Free Survival 
 
Note: Same table and figures will be made for all chemotherapy treated patients. 
 


Table 32: Acute Non-Hematologic Adverse Events  
 
Data set:  All Chemotherapy Treated Patients  
 
Number of patients (%) 
N=** 
 
Worst grade 
Any 
grade 
 
NR 
1 
2 
3 
4 
5 
 
Patients with any AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
 
 
Table 33: Severe Acute Non-Hematologic Adverse Events  
 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
 
Worst grade 
Any grade 3 
or higher AE 
 
 
 
 
3 
4 
5 
 
Patients with any AE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
 
 
 


Table 34: Acute (On-treatment) Adverse Events Related to Oxaliplatin for 
Patients on FOLFOX  
 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
 
Worst grade 
Any 
grade 
 
NR 
1 
2 
3 
4 
5 
 
Patients 
with 
any 
drug 
related AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 (1) Patients may have more than one event within a category. 
 
NOTE:  Same type of table to be made on adverse events related to leucovorin 
and 5FU for patients on FOLFOX, to oxaliplatin and capecitabine for patients on 
CAPOX, to surgery for patients who received surgery, and to radiotherapy for 
patients who received radiotherapy. 
  
Table 35: Severe Delayed Non-Hematologic Adverse Events   
 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
 
Worst grade 
Any grade 3 
or higher AE 
 
 
 
 
3 
4 
5 
 
Patients with any AE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 


 
Table 36: Hematology: Worst Grade per Patient 
Data set:  All Chemotherapy Patients 
 
Number of Patients (%) 
N=** 
Hemoglobin 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
WBC 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Absolute neutrophil count (ANC) 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Platelet 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Lymphocytes 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Basophils 
 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
Monocytes 
 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
Eosinophils 
 
 
>1-1.5xULN 
** (**) 
 
>1.5-2.0xULN 
** (**) 
 
>2.0-5.0xULN 
** (**) 
 
>5.0xULN 
** (**) 
 
 


Table 37: Biochemistry: Worst Grade per Patient 
Data set:  All Chemotherapy Patients 
 
Number of Patients (%) 
 
Total 
N=** 
Serum Creatinine 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Total bilirubin 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
ALT 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
Creatinine Clearance 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
 
 


Table 38: Other Laboratory Investigations 
 
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients (%) 
 
Total 
N=** 
Pre-excision coagulation 
 
 
PT 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
INR 
 
 
Grade 0 
** (**) 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
PTT 
 
 
 
Grade 1 
** (**) 
 
Grade 2 
** (**) 
 
Grade 3 
** (**) 
 
Grade 4 
** (**) 
 
Serum CEA 
 
 
At Baseline 
 
 
N 
** 
 
 
Mean 
** 
 
 
Standard deviation 
** 
 
Change at pre-excision visit from baseline 
 
 
 
N 
** 
 
 
Mean 
** 
 
 
Standard deviation 
** 
 
Change at Month 6 follow-up visit from baseline 
 
 
 
N 
** 
 
 
Mean 
** 
 
 
Standard deviation 
** 
 
… 
 
 
 


Table 39: Surgery and Post-operative Complications 
Data set:  All Chemotherapy & Excision/Surgery Treated Patients 
 
 
Patients Requiring Reoperation 
 
Reoperation procedure performed  
 
 
Debridement 
 
 
Incision and drainage 
 
 
Diverting Ostomy 
 
 
Other 
 
Blood loss/transfusion 
 
Estimated amount (cc) of blood loss during surgery 
N 
Median 
Min-max 
 
Any transfusions or blood products during surgery 
 
Type of transfusion 
 
  
Red cell concentrates 
 
  
Platelets 
 
  
Other 
 
Patients with Intraoperative injury  
Site of Injury 
Bladder 
Ureter 
Vein 
Artery 
Large bowel 
Small bowel 
Nerve injury 
Other  
 
Hospitalization 
Any time in intensive care 
  
No 
  
Yes 
  
 
Days in intensive care 
 
 
N 
 
 
Median 
 
 
Min-max 
Ongoing hospitalization 
  
Yes 
  
No 
 Days from admission for tumor excision to discharge 
  
N 
  
Median 
  
Min-Max 
 Discharge destination 
 
 
 
Home 
 
 
 
Assisted living (non-medical) 
 
 
 
Skilled nursing home 
 
 
 
Hospice 
 
 
 
Chronic care hospital 
 
 
 
Rehabilitation facility 
 
 
 
Died 
 
 
 
Transfer to other hospital 
 
 
 
Other 
Number of patients (%) 
N=** 
** (**) 
 
** 
** 
** 
** 
 
 
 
** 
** 
**-** 
** (**) 
 
** 
** 
** 
 
** (**) 
 
** 
** 
** 
** 
** 
** 
** 
** 
 
 
 
** (**) 
** (**) 
 
** 
** 
**-** 
 
** (**) 
** (**) 
 
** 
** 
**-** 
 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 


Table 40: All Deaths 
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients 
(%) 
N=** 
Number of Patients who died 
** (**) 
 
 
Cause of Death 
 
 
Study-specific malignant disease only 
** 
 
Adverse event possibly, probably or definitely related to  protocol treatment 
** 
 
Complication from a non-protocol treatment for this malignancy  
** 
 
Other primary malignancy 
** 
 
Other condition or circumstance 
** 
 
Table 41: Deaths Before Surgery 
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients (%) 
N=** 
Number of Patients who died before surgery 
** (**) 
 
 
Cause of Death 
 
 
Study-specific malignant disease only 
** 
 
Adverse event possibly, probably or definitely related to  protocol treatment 
** 
 
Complication from a non-protocol treatment for this malignancy  
** 
 
Other primary malignancy 
** 
 
Other condition or circumstance 
** 
 
 
Table 42: Adverse Event leading to Discontinuation of Neoadjuvant 
Chemotherapy 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
N=** 
Number discontinued neoadjuvant chemotherapy from adverse events 
 
      <Adverse event 1>(a) 
      <Adverse event 2> 
      .... 
 
** (**) 
 
** 
** 
(a): one patient may have more than one adverse event 
 


Table 43: Sigmoidoscopy/Colonoscopy and Other Radiology Investigations 
Data set:  All Chemotherapy Treated Patients 
 
Number of Patients (%) 
N=** 
Sigmoidoscopy/colonoscopy during protocol treatment 
 
All Normal 
** (**) 
 
At least one abnormal but all non-malignant 
** (**) 
 
All Abnormal and malignant 
** (**) 
Sigmoidoscopy/colonoscopy during follow-up 
 
 
All Normal 
** (**) 
 
At least one Abnormal but all non-malignant 
** (**) 
 
All Abnormal and malignant 
** (**) 
Other Radiology investigations during protocol treatment 
 
All Normal 
** (**) 
 
At least one abnormal but all non-malignant 
** (**) 
 
All Abnormal and malignant 
** (**) 
Other Radiology investigations during follow-up 
 
All Normal 
** (**) 
 
At least one abnormal but all non-malignant 
** (**) 
 
All Abnormal and malignant 
** (**) 
 
 
Table 44: Transfusion 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients 
(%) 
 
N=** 
Number (%) of patients transfused during protocol treatment 
** (**) 
 
 
 
Type of transfusion 
 
 
Number of patients received Red Blood Cells 
** 
 
Number of patients received Platelets 
** 
 
Number of patients received Other Transfusions 
** 
 
 
Number (%) of patients transfused during follow-up 
** (**) 
 
 
 
Type of transfusion 
 
 
Number of patients received Red Blood Cells 
** 
 
Number of patients received Platelets 
** 
 
Number of patients received Other Transfusions 
** 
 
 


Table 45: Major Medical Problems 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
 
N = *** 
Any major medical problem during protocol treatment 
 No 
 Yes 
 
** (**) 
** (**) 
 
Type of medical problem during protocol treatment* 
 
 
Medical problem A 
 
 
… 
 
** (**) 
** (**) 
Any major medical problem during follow-up 
 
 
No 
 
 
Yes 
 
** (**) 
** (**) 
 
Type of major medical problem during follow-up* 
 
 
Medical Problem A 
 
 
… 
 
** (**) 
** (**) 
* one patient may have more than one medical problem 
 
Table 46: Concomitant Medication 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
 
N = *** 
Any concomitant medication during protocol treatment 
 No 
 Yes 
 
** (**) 
** (**) 
 
Type of concomitant medications during protocol treatment* 
 
 
Medication A 
 
 
… 
 
** (**) 
** (**) 
Any concomitant medication 30 days after excision 
 
 
No 
 
 
Yes 
 
** (**) 
** (**) 
 
Type of concomitant medications 30 days after excision * 
 
 
Medication A 
 
 
… 
 
** (**) 
** (**) 
* one patient may have more than one medication. 
 
 
 


Table 47: Anti-Cancer Treatment 
Data set:  All Chemotherapy Treated Patients 
 
Number of patients (%) 
 
N = *** 
Number of patients with any other anti-cancer treatment during 
protocol treatment  
** (**) 
 
Chemotherapy (1) 
 
 
Drug 1 … 
 
Radiotherapy (1) 
 
Hormonal therapy (1) 
 
 
Drug 1 … 
 
Immunotherapy (1) 
 
 
Drug 1 … 
 
Other (1) 
 
 
Drug 1 … 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Number of patients with any anti-cancer treatment during follow-up 
but before relapse 
** (**) 
 
Chemotherapy (1) 
 
 
Drug 1 … 
 
Radiotherapy (1) 
 
Hormonal therapy (1) 
 
 
Drug 1 … 
 
Immunotherapy (1) 
 
 
Drug 1 … 
 
Other (1) 
 
 
Drug 1 … 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Number of patients with any anti-cancer treatment during after relapse 
** (**) 
 
Chemotherapy (1) 
 
 
Drug 1 … 
 
Radiotherapy (1) 
 
Hormonal therapy (1) 
 
 
Drug 1 … 
 
Immunotherapy (1) 
 
 
Drug 1 … 
 
Other (1) 
 
 
Drug 1 … 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
(1) Patients could have more than one type of anti-cancer treatment. 
 
 
 
 


Table 48: Compliance Rate with QoL Assessment  
Dataset: All Quality of Life Evaluable Patients 
 
N = ** 
 
N 
received (%) 
Baseline 
** 
** (**) 
Pre-Excision 
** 
** (**) 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
** 
** 
** 
** 
 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 


Table 49: QoL: Summary Baseline Scores 
Dataset: All Quality of Life Evaluable Patients 
EORTC QLQ-C30 
 
Functional scales 
 
 
Physical 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
... 
... 
EORTC QLQ-C30  
 
Global QOL 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
EORTC QLQ-C30 
 
Symptom scales 
 
 
Fatigue 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
… 
… 
EORTC QLQ-CR29 
 
Functional scales 
 
 
Body Immage 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
... 
... 
EORTC QLQ-CR29  
 
Stoma status 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
EORTC QLQ-C29 
 
Symptom scales 
 
 
Urinary frequency 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
… 
… 
 
 
LARS Score  
 
Total score 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
 
 
FIQL Instrument 
 
Scales 
 
 
Lifestyle 
 
 
 
N 
*** 
 
 
Mean 
*** 
 
 
STD 
*** 
 
… 
… 
 


Table 50: Summary QOL Change Scores from Baseline for Scale/Domain/Item 
at Each Time Period* 
Dataset: All Quality of Life Evaluable Patients 
 
 
Scale/Domain/Item 
Change Score 
Pre-Excision 
 
 
N 
** 
 
Mean 
** 
 
STD 
** 
Post-Excision 
Month 6 
N 
Mean 
STD  
Month 12 
N 
Mean 
STD 
Month 24 
N 
Mean 
STD 
Month 36 
N 
Mean 
STD 
 
 
 
** 
** 
 
 
** 
** 
 
 
** 
** 
 
 
** 
** 
* Table will be provided for each of EORTC QLQ-C30/CR29 and FIQL instrument scale/domain/item 
and LARS total score. 
 
 
 


Table 51: Proportion of Patients with Deterioration, Improvement or Stable 
EORTC QLQ-C30 and CR29 domains/items and Global QLQ scales* 
All Quality of Life Evaluable Patients 
 
N(%) 
Deterioration 
 
   Physical function 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**) 
Improvement 
 
   Physical function 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**) 
Stable 
 
   Physical function 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**) 
* Table will be provided for each EORTC QLQ-C30/CR29 scale/domain/item 
 
Table 52: Proportion of Patients in LARS Severity Groups 
Dataset: All Quality of Life Evaluable Patients 
 
N(%) 
No LARS 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**) 
Minor LARS 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**) 
Major LARS 
 
 
Pre-Excision 
**(**) 
 
Post-Excision 
Month 6 
Month 12 
Month 24 
Month 36 
 
**(**) 
**(**) 
**(**) 
**(**)