Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait. A Multi-center Prospective Randomized Controlled Trial. (CCHOWW)
Phase: NA
Conditions: Rectal Cancer, Consolidation
Sponsor: Hospital Alemão Oswaldo Cruz

 
 
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OSWALDO CRUZ 
HOSPITAL ALEMÃO 
INTERNATIONAL RESEARCH SITE 
 
 
 
Chemoradiotherapy and consolidation chemotherapy with or 
without oxaliplatin for distal rectal cancer and Watch and Wait. 
(CCHOWW) 
 
 
 
 
 
 
Clinical trials - NCT: 05000697 
 
 
 
 
 
 
Version 3.0 
23/January/2024 
 
 
 
 
 
 
This document is confidential and its use, reproduction, disclosure, and publication 
are restricted to primary investigators and the sponsor 
 

 
 
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OSWALDO CRUZ 
HOSPITAL ALEMÃO 
INTERNATIONAL RESEARCH SITE 
 
 
 
 
Chemoradiotherapy and consolidation chemotherapy with or 
without oxaliplatin for distal rectal cancer and Watch and Wait. 
(CCHOWW) 
 
 
 
 
 
Clinical trials - NCT: 05000697 
 
 
 
 
 
 
 
Version 3.0 
23/January/2024 
 
 
 
 
 
 
This document is confidential and its use, reproduction, disclosure, and publication 
are restricted to primary investigators and the sponsor 
 

 
 
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LIST OF ABBREVIATIONS 
nCRT: Neoadjuvant Chemoradiotherapy 
Ccr: Complete Clinical Response 
WW: Watch and Wait (Strict Surveillance Program) 
TME: Total Mesorectal Excision. 
APR: Abdominal Perineal Amputations 
ISR: Intersphincteric Resections 
pCR: Complete Pathological Response 
CRT: Chemoradiation 
5-FU: Fluorouracil 
TNT: Total Neoadjuvant Therapy 
RT: Radiotherapy 
IMRT: Modulated Intensity Radiotherapy 
ICRU: International Commission on Radiation Units and Measurements SIB-IMRT: 
Modulated Intensity Technique With Integrated Reinforcement 
BED: Biological Effective Dose 
CTV: Clinical Target Volume 
GTV: Macroscopic tumor volume 
PTV: Target Planning 
ITV: Internal Target Volume 
RM: Magnetic Resonance Imaging 
T2 - Thoracic 
CIP: International Research Site 
HAOC: Hospital Alemão Oswaldo Cruz 
CONEP: National Research Ethics Committee 
Postal code: Institutional Review Board or Ethics Committee 
CRF [Regional Pharmacy Council]: Case Report Form 
ICF: Informed Consent Form 
 
 

 
 
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LIST OF TABLES 
Table 1: Administration of Radiotherapy ................................................................... 20 
Table 2: Subject’s flowchart detailing pre- and post-randomization activities, as well 
as follow-up and assessment periods. ...................................................................... 29 
Table 3: Interruption rules for radiotherapy during chemoradiation. ......................... 33 
Table 4. Estimated budget for Research costs. ........................................................ 42 
 
 
 
 

 
 
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Compliance Statement 
This document is a protocol for a research project. This study will be conducted 
in compliance with all the stipulations of this protocol, the current IRC/CONEP rules, 
and the guidelines established by the Documento das Américas and the Good Clinical 
Practice Guide (E6/R2) of the ICH- International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use. 
 
 

 
 
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SUMMARY 
1. TRIAL INFORMATION ........................................................................................... 8 
1.1 PROTOCOL SYNOPSIS ...................................................................................... 8 
1.2 Protocol Background .......................................................................................... 12 
1.3 Contributions ...................................................................................................... 12 
1.4 Sponsorship ........................................................................................................ 13 
2. INTRODUCTION .................................................................................................. 14 
3. RATIONALE ......................................................................................................... 18 
4. OBJECTIVES ....................................................................................................... 19 
5. STUDY DESIGN ................................................................................................... 19 
5.1 Treatment ........................................................................................................... 19 
5.2 Radiotherapy ...................................................................................................... 19 
5.2.1 Target volume: ................................................................................................. 20 
5.2.2 Boost GTV: ...................................................................................................... 21 
5.2.3 Target Planning ............................................................................................... 21 
5.3 Chemotherapy .................................................................................................... 21 
5.3.1 Concomitant chemotherapy: ............................................................................ 21 
5.3.2 Consolidation chemotherapy: .......................................................................... 21 
6. Clinical Response Assessment ......................................................................... 22 
6.1 Definition of Complete Clinical Response: .......................................................... 22 
6.2 Definition of Near Complete Response............................................................... 22 
6.3 Suggested protocol for Clinical Response Assessment ..................................... 23 
6.4 Suggested Complete or Nearly Complete Clinical Response Follow-up Protocol 
(“Watch & Wait”) ....................................................................................................... 24 
6.5 Central Response Assessment Committee ........................................................ 24 
7. METHODOLOGY ................................................................................................. 24 
7.1 Type of study ...................................................................................................... 24 

 
 
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7.2 Screening Participating and Co-Participating Sites ............................................ 24 
7.3 Patients ............................................................................................................... 25 
7.4 Inclusion Criteria ................................................................................................. 26 
7.6 Randomization .................................................................................................... 27 
7.7 Data Collection ................................................................................................... 27 
7.8 Statistical Analysis .............................................................................................. 28 
7.9 Flowchart ............................................................................................................ 29 
8. ETHICAL ASPECTS ............................................................................................ 30 
9. POTENTIAL RISKS AND BENEFITS .................................................................. 31 
9.1 Chemotherapy toxicity and dose adjustment: ..................................................... 31 
9.2 Radiotherapy toxicity and discontinuation rules .................................................. 32 
10. SUBJECT DISCONTINUATION ........................................................................ 33 
11. ADVERSE EVENTS ........................................................................................... 34 
11.1 Classification of adverse events. ...................................................................... 34 
11.2 Follow-up of adverse event reports. ................................................................. 39 
12 
PROCEDURES AND SPECIAL INSTRUCTIONS ......................................... 39 
12.1 Changes to Protocol ......................................................................................... 39 
12.2 Discontinuation of Subjects and Study Interruption .......................................... 40 
13. CONFIDENTIALITY ........................................................................................... 40 
14. CLINICAL ENDPOINTS ..................................................................................... 40 
14.1 Primary endpoint .............................................................................................. 40 
14.2 Secondary endpoints: ....................................................................................... 41 
15. SCHEDULE ........................................................................................................ 41 
16. INTERIM ANALYSIS .......................................................................................... 41 
17. BUDGET ............................................................................................................ 42 
18. BIBLIOGRAPHY ................................................................................................ 44 
 

 
 
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1. TRIAL INFORMATION 
1.1 
PROTOCOL SYNOPSIS 
Data Category 
Information 
Main Sponsor 
Hospital Alemão Oswaldo Cruz 
Contact for public queries 
+55 11 -3549-0729 / +55 11 -98159-
4568 
dvilanova@haoc.com.br 
Contact for scientific queries 
roperez@haoc.com.br 
Public title 
Chemoradiotherapy and consolidation 
chemotherapy with or without oxaliplatin 
for distal rectal cancer and Watch and 
Wait. (CCHOWW) 
Health condition(s) or problem(s) studied 
Distal Rectal Cancer 
Inclusion Criteria 
1. Age ≥18 years; 
2. ECOG 0-2 or KPS≥70; 
3. Primary rectum adenocarcinoma 
(biopsy-confirmed) accessible on 
digital rectal examination (at least 
the lower border) by the assistant 
colorectal surgeon; 
4. Endoscopic documentation of the 
primary lesion; 
5. Chest CT scan and contrast-
enhanced CT or abdomen magnetic 
resonance without evidence of 
metastatic disease; 

 
 
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6. High-resolution magnetic resonance 
imaging performed on a 1.5T or 
3.0T system using a surface coil 
with: sagittal T2-weighted images 
including the anal margin and 
sacrum; T2-weighted oblique axial 
images acquired in a perpendicular 
plane to the long axis of rectal wall 
guided by the sagittal images; 
coronal images acquired parallel to 
the anal canal plane. Small FOV 
(field of view) (16-18cm), section 
thickness of 3mm, matrix size 
increased so that the voxel is from 
1.0 to 1.5mm3) and number of 
excitations increased to get a 
satisfactory signal; 
7. Radiological criteria (centralized):  
a. Inferior border of tumor ≤1cm 
(including tumors at or below) 
the anorectal ring defined in 
sagittal or coronal views by 
magnetic resonance imaging; 
b. mrT2, mrT3 (any subclass) 
c. mrN0 or mrN1; 
d. mrEMVI: any status 
e. mrCRM: any status 

 
 
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Exclusion Criteria 
1. Pregnancy 
2. ECOG ≥3 or KPS<70 
3. mrT4 
4. mrN2 
5. Not consenting to participation 
6. Metastatic 
disease 
(any 
type; 
internal iliac and obturator lymph 
node involvement are considered 
local disease and not metastatic 
disease, 
so 
not 
considered 
exclusion criteria) 
7. Prior pelvic radiotherapy 
8. Underlying neuropathy 
9. Receiving treatment with another 
anticancer drug or method 
10. Presence 
of 
uncontrolled 
life-
threatening illnesses. 
Study Type 
Randomized prospective clinical trial 
Sample size 
216 subjects (108 per group) 
Purposes 
To compare the results of consolidation 
chemotherapy 
with 
fluoropirimidine 
alone or fluoropirimidine + oxaliplatin in 
reaching a cCR after nCRT in the context 
of a randomized prospective clinical trial. 
Clinical endpoints 
Primary endpoints: 
• 
To reach a complete or nearly 
complete clinical response achieved at 
18 weeks from the end of the last day of 
radiotherapy using clinical (rectal digital), 
endoscopic and 
radiological 
exams 
(mrTRG 
classification). 

 
 
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Endoscopy 
and 
radiology 
will 
be 
assessed by the Central Committee of 
Response Assessment. 
Secondary endpoints: 
• 
Surgery-free survival in 3 years 
• 
TME-free survival in 3 years 
• 
Metastasis-free survival in 3 
years 
• 
Regrowth-free 
survival in 3 
years 
• 
Colostomy-free survival in 3 
years 
Treatment 
1- 
Consolidation group with 1 drug: 
RT (54Gy) with daily capecitabine 
825mg/m2 twice daily, followed by 
capecitabine 1000mg/m2 twice daily for 
14 days in a 21-day cycle for 4 cycles (12 
weeks), starting 1 to 2 weeks after the 
end of radiotherapy; 
2- 
Consolidation group with 2 drugs: 
RT (54Gy) plus daily capecitabine 
825mg/m2 twice daily, followed by 
mFOLFOX6, XELOX for 6 cycles (12 
weeks), starting 1 to 2 weeks after the 
end of radiotherapy. 
Length of Study 
The study lasts 4 years. 
If the arm with 2 drugs shows response 
rate ≥25% after 72 patients, the study will 
be stopped (efficacy).  

 
 
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If the 2-drug arm shows a response rate 
of less than 5% after 72 patients, the 
study will be stopped. 
Ethical Aspects 
The study will be conducted according to 
Resolutions no. 466/12 and 251/97 of 
the National Health Council - Ministry of 
Health, 
Declaration 
of 
Helsinki's 
principles and International Conference 
of Harmonisation (ICH) Good Clinical 
Practices/Good 
Clinical 
Practices: 
Document of Americas, as well as the 
local legislation. 
1.2 Protocol Background 
Protocol 
Version 
Final date 
1 
10/Nov/2021 
2.0 
22/Jun/2023 
1.3 Contributions 
Author Name 
Function 
Angelita Habr-Gama 
Conception, Project writing, 
Rodrigo Oliva Perez 
Conception, Project writing, Initial 
assessment of patients (central 
endoscopic review); Final assessment of 
patients (central endoscopic review - 
related to the primary clinical endpoint) 
Guilherme Pagin São Julião 
Conception, Project writing, Initial 
assessment of patients (central 
endoscopic review); Final assessment of 
patients (central endoscopic review - 
related to the primary clinical endpoint) 

 
 
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Bruna Borba Vailati 
Conception, Project writing, Initial 
assessment of patients (central 
endoscopic review); Final assessment of 
patients (central endoscopic review - 
related to the primary clinical endpoint) 
Cinthia Denise Ortega 
Conception, Project writing, Initial 
assessment of patients (central 
radiological review); Final assessment of 
patients (central radiological review - 
related to the primary clinical endpoint) 
Thiago Jorge 
Conception, Project writing 
Renata D’Alpino 
Conception, Project writing 
Jorge Sabbaga 
Conception, Project writing 
Patricia Bailão Aguilar 
Conception, Project writing 
Fabio Roberto Kater 
Conception, Project writing 
1.4 Sponsorship 
Hospital Alemão Oswaldo Cruz (HAOC) will assume the responsibilities 
regarding RDC No. 09/2015 related to ICH E6 (R2), ethical submission and project 
follow-up. This trial will not be financially supported by an external institution. 
 
 

 
 
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2. INTRODUCTION 
The significant response to neoadjuvant chemoradiotherapy (nCRT) has 
resulted in a dramatic change in the treatment of distal rectal cancer.1 The observation 
that some patients have an near complete and complete tumor response to treatment 
has led experts to consider organ preservation strategies to avoid the need for radical 
surgery. 2-5 Patients who developed a complete clinical response (cCR) defined by 
clinical, endoscopic and radiological criteria were followed up without immediate 
surgery and enrolled in a strict surveillance program (Watch and Wait - WW) with 
oncological results comparable to those of radical surgery. 6-9 Ultimately, these patients 
would avoid the risk of immediate postoperative morbidity and mortality, in addition to 
the potential negative consequences on urinary, sexual, and anorectal function often 
observed after total mesorectal excision (TME).10-12 In addition, patients treated using 
the WW strategy would avoid the need for a temporary/permanent stoma - a 
particularly relevant aspect among patients with distal tumors. 13 In this group of 
patients, abdominoperineal amputations (APR) with a definitive ostomy or 
intersphincteric resection (ISR) with poor postoperative anorectal function are the only 
radical surgical alternatives available. 14.15 
On the other hand, patients treated without immediate surgery after reaching 
a cCR remain at risk of local regrowth of the primary tumor. Recent evaluation of large 
international databases suggests that the 3-year risk of local regrowth is nearly 25%. 
5,16 Local regrowths are often restricted to the intestinal wall and usually amenable to 
salvage resection with proper long term local disease control. 17-19 Furthermore, 
patients reaching a cCR are still at risk of developing distant metastases. Comparison 
between patients with cCR treated by WW and patients with pathological complete 
response (pCR) treated by radical surgery shows similar rates of distant metastases. 
9,20 However, patients with initial cCR followed by local regrowth appear to have a 
higher risk of metastatic disease development.20 These latter patients may represent 
a distinct group of patients, because full pathologic response was never actually 
reached. It is still controversial whether immediate radical surgery in this specific 
subgroup of patients would have prevented the development of distant metastases 
observed after the diagnosis of local regrowth.21 
 
 

 
 
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Ultimately, organ preservation has become an attractive alternative for 
patients with distal rectal cancer when the surgical alternatives are APR or ISR. Most 
studies until the present moment have reported cCR rates of nearly 25% in sites 
practicing WW and using standard CRT regimens similar to the experimental arm of 
the German study (2 cycles of 5FU-based chemotherapy).9 In this scenario, several 
alternatives were suggested to increase the chances of reaching a complete clinical 
response and allow the opportunity for an organ preservation strategy.22 
Several particularities of neoadjuvant treatment can affect tumor regression 
rates in rectal cancer.23-25 Studies suggest that specific characteristics of the 
radiotherapy and chemotherapy regimen can influence complete response rates. Data 
provided by several studies using different doses of radiation in rectal cancer suggest 
that there is an increase in complete response rates as total doses increase.24 
Radiosensitizing chemotherapy may also affect response rates to neoadjuvant 
treatment. Additional incorporated chemotherapy after completion of radiotherapy 
(consolidation chemotherapy) also significantly increased clinical and pathological 
complete response rates.22,25-27 Early retrospective studies (before the introduction of 
total neoadjuvant therapy concept - TNT) suggested that including additional 
chemotherapeutic agents (beyond 5FU / fluoropirimidines concomitantly used with RT) 
in nCRT regimens would significantly increase pCR rates. Oxaliplatin was the most 
commonly chemotherapeutic agent used with 5FU. Unfortunately, subsequent 
randomized controlled trials have failed to demonstrate significant increases in pCR 
rates when oxaliplatin is added to standard nCRT regimens. Instead, a significant 
increase in treatment-related toxicity was observed. 28 
A single phase 2 study was performed using additional 5FU bolus cycles with 
the purpose of improving cCR rates (rather than pCR). This study included 4 additional 
cycles of bolus infusion of 5FU (for the usual 2 cycles) to be administered during RT 
but also during the “washout” period. Surprisingly, cCR rates were nearly 50% of all 
treated patients, including tumors with initial stage T2/T3.  
 
 

 
 
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While the increase in cCR rates could have been attributed to the increase in 
the number of chemotherapy cycles dosed during and after completion of RT 
("consolidation" chemotherapy, although not named as such at that moment), an 
additional change in regimen could also have contributed to the increase in cCR rates: 
the RT dose escalation that was also incorporated into this nCRT regimen (50.4Gy to 
54Gy).27,29 Therefore, it was not possible to establish a direct cause-effect relationship 
between rates of cCR and consolidation chemotherapy or dose escalation of RT. 
Regardless of the difficulty of establishing the relationship between cause and effect, 
this “new” nCRT regimen with consolidation chemotherapy using fluoropirimidine alone 
started to be used as the choice regimen (standard) in some institutions after seeing 
such very promising preliminary results and minimal negative impact on treatment 
toxicity. 
Another non-randomized prospective study also suggested the potential 
effects of consolidation chemotherapy on treatment response. The clinical trial known 
as the “Timing Trial” included patients with locally advanced disease in 4 different arms 
(sequentially, non-randomized).26 The main purpose of the trial was to investigate 
progressively longer interval periods between the completion of RT and surgery in 
response rate: 6, 12, 18 and 24 weeks. However, patients included in 12, 18 and 24 
received consolidation chemotherapy with 2 drugs (fluoroprimidine and oxaliplatin - 
mFOLFOX for 2, 4 or 6 cycles, respectively). A significant increase in pCR rates was 
observed the higher the number of chemotherapy cycles with 2 consolidation drugs 
(pCR 25%, 30% and 38%, respectively) compared to lack of consolidation 
chemotherapy in patients who went on surgery at 6 weeks (pCR 18 %).26 Once again, 
although the increase in pCR rates could have been attributed to the increase in the 
number of chemotherapy cycles (consolidation), the effect of longer intervals in time 
could also have contributed to this observation. 
Finally, with the introduction of the TNT concept in which adjuvant 
chemotherapy is administered immediately before nCRT (induction) or after nCRT 
(consolidation), early experiences (using regimens with 2 or 3 drugs) have shown an 
increase in complete response and chances of organ preservation in these patients. 
30.31  
 
 

 
 
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Both studies using consolidation (RAPIDO) and induction (PRODIGE) 
compared to the “conventional” nCRT regimen demonstrated significantly higher rates 
of complete pathologic response. Even though there was no possibility of organ 
preservation in either study, the higher rates of pathological complete response in the 
experimental arms of both trials suggest the potential impact of consolidation/induction 
with additional chemotherapy in increasing the possibility of organ preservation.31 
(Conroy et al. Lancet Oncol 2021 in press) A prospective randomized trial (OPRA) 
showed preliminary results of the comparison between induction and consolidation 
chemotherapy (FOLFOX). Although there was no difference in disease-free survival 
rates in 3 years between arms, organ preservation rates were significantly better for 
consolidation chemotherapy compared to induction chemotherapy. 
In summary, there is evidence to support that consolidation chemotherapy can 
contribute to increased response rates in rectal cancer after nCRT. Both 5FU and 
5FU/oxaliplatin-based chemotherapy consolidation regimens have shown promising 
results. 
Although the single-drug consolidation regimen had already been incorporated 
into the services routine for more than a decade, consolidation chemotherapy including 
oxaliplatin has been reaching significant space in different sites in Brazil and in the 
world, and its regular use in neoadjuvant therapy is already widely adopted. However, 
no studies have addressed the benefit of oxaliplatin during consolidation to improve 
response rates compared to consolidation with 5FU alone. Although prior studies 
including oxaliplatin were negative and associated with increased toxicity, all of these 
trials used oxaliplatin concurrently with RT and we do not have the real dimension of 
benefit that oxaliplatin can add in the context of consolidation chemotherapy. Both 
strategies (consolidation with 5FU alone or 5FU/oxaliplatin) are already widely used, 
however, no study has directly compared these two types of treatment. The addition 
of oxaliplatin may be associated with higher response rates, but it may also simply add 
higher rates of morbidity/toxicity without a significant increase in response. 
 
 

 
 
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3. RATIONALE 
Patients with rectal cancer near the anus often require delicate and time-
consuming surgery to treat the disease. This surgery can result in some important 
consequences such as difficulties in urinating, difficulties to have sexual intercourse 
(in men with difficulty in penis erection) and use of a feces collection bag in the belly 
(colostomy/ileostomy). Despite this, in patients treated with radiotherapy and 
chemotherapy before this surgery, near to one in three patients have complete tumor 
elimination. 
In some specialized centers for the cancer treatment, such patients have been 
followed up with periodic exams, without the immediate need for surgery. In these 
cases, surgery would only be performed if exams show that the tumor has grown or 
appeared again. Several researches studied different combinations and doses of 
radiotherapy and chemotherapy to try increasing the chances of the tumor 
disappearance and, therefore, to avoid surgery in a larger number of patients. 
In general, the treatment is performed with radiotherapy and chemotherapy 
together (for approximately 6 weeks) and then a second part with chemotherapy alone. 
However, it is unknown if combining chemotherapy with 2 drugs leads to a greater 
chance of tumor disappearance than chemotherapy with one drug. Many hospitals 
have used both treatment methods (with one or two drugs in this phase of treatment). 
But if the combination of two drugs increases the chances of tumor disappearance was 
not studied yet. 
 
 

 
 
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4. OBJECTIVES 
To compare the results of consolidation chemotherapy with fluoropyrimidine 
alone or fluoropirimidine + oxaliplatin in reaching a complete or near-complete clinical 
response after neoadjuvant chemoradiotherapy (nCRT). 
5. STUDY DESIGN 
5.1 Treatment 
1) 
Consolidation group with 1 drug: RT (54Gy) with daily capecitabine 825mg/m2 
twice daily, followed by capecitabine 1000mg/m2 twice daily for 14 days in a 21-day 
cycle for 4 cycles (12 weeks), starting 1 to 2 weeks after the end of radiotherapy; 
(Alternative consolidation regimens will include infusion or bolus FU); 
2) 
Consolidation group with 2 drugs: RT (54Gy) plus daily capecitabine 
825mg/m2 twice daily, followed by mFOLFOX6, XELOX for 6 cycles (12 weeks), 
starting 1 to 2 weeks after the end of radiotherapy. 
Figure 1. Study design 
 
 
 
5.2 Radiotherapy 
Preoperative radiotherapy will be administered on a linear accelerator in the 
prone or supine position, preferably with a full bladder. The use of an abdominal board 
is allowed.  
 

 
 
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Three or four isocentric fields as well as the IMRT technique are allowed as long as all 
bundles are treated daily. Dose distribution and calculation should be performed on 
CT or RM and specified according to ICRU 50 guidelines. 
Dose specification: All patients will receive 25 daily fractions of 1.8 Gy up to a 
total dose of 45 Gy in the pelvic field, including the tumor bed with a margin and the 
regional lymph nodes. A field reduction after 45 Gy is recommended up to 54 Gy. The 
last 5 fractions will then be delivered to the tumor bed with a margin. 
Alternatively, radiotherapy can be administered using the intensity modulated 
technique with integrated reinforcement (SIB-IMRT). The prescribed dose for regional 
lymph nodes and areas at risk for microscopic disease will be 45Gy in 25 fractions (1.8 
Gy per fraction); while the 'raw' tumor (i.e., primary tumor and enlarged/metabolically 
active lymph nodes) is primed with a higher dose of 52.5Gy in 25 fractions (2.1 Gy per 
fraction). The entire SIB-IMRT course will be administered once a day, 5 fractions per 
week for 5 weeks. 
Table 1: Administration of Radiotherapy 
change 
30 
Total Dose 
BED=63. 
BED=62.1 
native 1 
x 1.8Gy 
54Gy 
72Gy10 
0Gy12 
change 
25 
Total Dose 
BED=63. 
BED=61.6 
native 2 
x 2.1Gy 
52.5Gy 
53Gy10 
9Gy12 
 
5.2.1 Target volume: 
pelvic CTV 
• 
Primary tumor 
• 
mesorectum: Distally, only lymph nodes or tumor deposits up to 4cm are 
included. For tumors in the lower rectum, this means that the entire mesorectum area 
up to the pelvic floor is included. 
• 
Pre-sacral ganglia and ganglia throughout the superior rectal artery: As local 
recurrences are very uncommon above S1 - S2, lymph nodes above this level should 
not be included unless there are signs of pathological presacral lymph nodes. In this 
case, the cranial limit of the CTV must be at least 1 cm above the most cranial 
pathological lymph node. 
 
 

 
 
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• 
Lateral pelvic lymph nodes: until they reach the level of the obturator canal, 
internal iliac artery to the bifurcation of external iliac artery. The CTV cranial border is, 
in most cases, just below the bifurcation of internal and external iliac arteries. In most 
patients, it occurs at the level of S1 - S2. 
• 
Ischiorectal fossa and anal canal: Included in pelvic CTV only if the tumor 
grows into the levators or down into the anal canal. 
• 
Lymph nodes along the external iliac artery: Included if tumor grows in anterior 
organs such as prostate, urinary bladder, cervix, vagina or uterus to such an extent 
that external lymph nodes are at risk of metastases. 
5.2.2 Boost GTV: 
GTV is the visible primary tumor and visible pathological lymph nodes. 
The GTV boost plus a 2 cm margin within the same anatomical compartment 
where the tumor is, for the 45-Gy dose, also around the radiologically compromised 
lymph nodes. 
5.2.3 Target Planning 
Target Planning (PTV) should normally be defined and includes CTV and 
internal target volume (ITV) and a required margin for the configuration. Such margins 
depend on several factors related to the equipment of each radiotherapy center. 
5.3 Chemotherapy 
5.3.1 Concomitant chemotherapy: 
Capecitabine: 825mg/m2 twice daily on radiotherapy days 
5.3.2 Consolidation chemotherapy: 
Consolidation capecitabine: 1000mg/m2 bid, for 14 days, in 3-week cycles, for 
4 cycles. 
Consolidation options with oxaliplatin: 
➢ 
mFOLFOX6: Oxaliplatin 85mg/m2 plus Leucovorin 400mg/m2 in 2-hour 
infusion. 5FU 400mg/m2 bolus infusion, followed by 5FU 2400mg/m2 as a 46-hour 
infusion Q2W for 6 cycles 
 
 

 
 
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➢ 
CAPOX: Oxaliplatin 130mg/m2 in 2-hour infusion. Capecitabine 1000mg/m2 
bid for 14 days, starting on the night of oxaliplatin infusion. Repeating Q3W for 4 cycles. 
6. Clinical Response Assessment 
Response assessment will be performed at 12 weeks (and 18 weeks from the 
last date of radiotherapy if cCR or near complete response is detected at 12 weeks). 
All patients will perform endoscopic reassessment, digital rectal examination and high-
resolution MRI. Endoscopic biopsies will be at the discretion of the research 
site/institution responsible for the patient, not as a part of the trial. 
Patients with complete or near complete clinical response at 12 weeks 
(assessed by the trial’s Central Committee) will be suggested to perform a new 
reassessment after 18 weeks of the last dose/day of RT. The decision regarding the 
definitive treatment of the patient 18 weeks after the end of treatment will be entirely 
responsibility of each patient’s institution, regardless the result and evaluated by the 
trial’s Central Committee. 
6.1 Definition of Complete Clinical Response: 
• 
Endoscopic: whitish scar, telangiectasias, no masses or ulcerations6 
• 
Clinical: no irregularities or hardened areas6 
• 
Radiological: mrTRG1: fibrosis with low signal seen on images 
T2-weighted replacing the primary tumor; no diffusion restriction on diffusion-weighted 
images; no lymph nodes with border irregularity or mixed signal intensity; without 
extramural vascular invasion32-35 
6.2 Definition of Near Complete Response 
• 
Endoscopic: residual tumor ≤2cm (or ≥70% reduction in original tumor 
volume/size) 4,36,37 
• 
Clinical: Superficial ulceration or small (questionable) irregularity of mucosa, 
rectal wall 
 
 

 
 
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• 
Radiologic: mrTRG2 with predominantly low-signal fibrosis with foci of tumor 
signal in intermediate intensity seen on T2-weighted images with or without diffusion 
restriction; mrTRG1: fibrosis with low signal intensity seen on T2-weighted images 
replacing primary tumor with diffusion restriction; no lymph nodes with border 
irregularity or mixed signal intensity; without extramural vascular invasion 36 
The decision to undergo a surgery or not after 12 or 18 weeks is entirely at the 
discretion of each assisting surgeon/institution and subject. Such a decision does not 
interfere in any way with the primary clinical endpoint of the trial regarding the response 
assessment. 
Only those patients with an near complete/complete response at the time of 
response assessment at 12 weeks will be recommended for a second response 
assessment at 18 weeks after the end of treatment. Patients with incomplete response 
(poor response) at 12 weeks will be recommended for surgery at that moment. 
The definition of complete radiological response, described below 
(centralized), as well as the clinical and endoscopic findings will be discussed by the 
central evaluation committee. The meetings for findings validation will be by means of 
regular virtual meetings of the central committee along with the surgeon and radiologist 
assistant of each patient. 
6.3 Suggested protocol for Clinical Response Assessment 
• 
Suggested magnetic resonance imaging assessment: 
➢ 
1.5T - FRFSE; TR/TE: 3300/120 (ms); cut thickness/interval: 3.0/0; matrix: 256 
x 256; NSA 8) 
➢ 
3.0T - FRFSE; TR/TE: 8000/150 (ms); cut thickness/interval: 3.0/0; matrix: 288 
x 288; NSA 5) Diffusion (DWI) -inclusion of a high b-value of at least 800. 
• 
Suggested Endoscopic Assessment: 
Endoscopic assessment with flexible endoscope (preferably gastroscope for 
retroflexion); direct endoscopic view and retroflexion of the primary tumor/scar. 
Endoscopic biopsies will be at the discretion of the participating site and will not be 
part of the trial. 
 
 

 
 
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6.4 Suggested Complete or Nearly Complete Clinical Response Follow-up 
Protocol (“Watch & Wait”) 
As it is a controversial strategy in the medical literature, the decision to under 
a surgery or not in patients with complete or near complete clinical response at 12 and 
18 weeks after the end of radiotherapy will be entirely optional and the decision of each 
participating institution and the subject. The use or not of the follow-up scheme without 
surgery (Watch & Wait) will not interfere with the primary clinical endpoint and will not 
be recommended by the trial. For this reason, the exact protocol for clinical, 
endoscopic and radiological follow-up of patients included in this therapeutic strategy 
will not be suggested by the trial and will be the sole responsibility of the participating 
institution. Therefore, the trial will not be responsible for the costs, organization or 
follow-up of forms outside the standard of care of each institution. 
6.5 Central Response Assessment Committee 
The definition of complete radiological response, described previously 
(centralized), as well as the clinical and endoscopic findings will be discussed by the 
central evaluation committee. Meetings of findings validation will regularly occur (every 
2 weeks) by virtual meetings of the central committee. As indicated in the list of authors 
of the paperwork and their respective contributions, the central committee for response 
assessment will include 1 radiologist and 3 surgeons. 
7. METHODOLOGY 
7.1 Type of study 
Randomized prospective clinical trial with two parallel groups. 
7.2 Screening Participating and Co-Participating Sites 
The International Research Site (CIP) - HAOC team will identify and invite the 
sites to take part in the trial. Sites will be identified according to experience, 
recommendation and capacity to conduct the trial (population, site structure, 
availability of site staff and handling cases of distal rectal cancer). The site will be 
approved for the trial, if it includes: 
 
 

 
 
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• Structure to assist potential patients for this trial; 
• Experience in conducting clinical trials; 
• Potential to screen subjects; 
• Team with availability to conduct the trial activities; 
All selected participating institutions have their own infrastructure, sufficient 
and adequate to offer the same conditions and include subjects in the trial. No 
intervention, method or examination is foreseen that is not already an integral part of 
the routine treatment and evaluation of patients diagnosed with rectal cancer. 
All institutions are aware that all procedures, treatments and clinical follow-up 
of the subjects included in the trial will be defined and will be the responsibility of each 
institution, and not of the clinical trial or the coordinating site. And aware that there will 
be no funding and/or sponsorship for any of the treatment/follow-up arms/parts already 
routinely employed in the treatment of patients with rectal cancer. 
The sites will receive the regulatory package after inclusion in the Plataforma 
Brasil and approval of the study by CONEP to start submission to the local ethics 
committee. 
The team responsible for performing the trial in each selected site shall include 
at least: 1 Clinical Oncologist, 1 Radiologist, 1 Endoscopist, 1 Trial Coordinator, 1 
Biomedical and 1 Regulatory Affairs Analyst. 
7.3 Patients 
Patients with distal rectal cancer will be screened for the trial after initial 
clinical, endoscopic and radiological assessment. Initial staging will define eligible 
patients to take part in the trial. These patients must agree with the randomization and 
sign the informed consent form before inclusion in the research protocol.  
Enrolled patients will be randomized to the one-drug group or the two-drug group. 

 
 
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7.4 Inclusion Criteria 
01. Age ≥18 years; 
02. ECOG 0-2 or KPS≥70; 
03. Primary rectum adenocarcinoma (biopsy-confirmed) accessible on digital rectal 
examination (at least the lower border) by the assistant colorectal surgeon; 
04. Endoscopic documentation of the primary lesion; 
05. Chest CT scan and contrast-enhanced CT or abdomen magnetic resonance 
without evidence of metastatic disease; 
06. High-resolution magnetic resonance imaging performed on a 1.5T or 3.0T system 
using a surface coil with: sagittal T2-weighted images including the anal margin and 
sacrum; T2-weighted oblique axial images acquired in a perpendicular plane to the 
long axis of rectal wall guided by the sagittal images; coronal images acquired parallel 
to the anal canal plane. Small FOV (field of view) (16-18cm), section thickness of 3mm, 
matrix size increased so that the voxel is from 1.0 to 1.5mm3) and number of excitations 
increased to get a satisfactory signal; 
07. Radiological criteria (centralized): 
a. 
Inferior border of tumor ≤1cm (including tumors at level or below) of the 
anorectal ring defined in the sagittal or coronal section by magnetic resonance 
imaging; 
b. 
mrT2, mrT3 (any subclass) 
c. 
mrN0 or mrN1; 
d. 
mrEMVI: any status 
e. 
mrCRM: any status 
7.5 
Exclusion Criteria 
01. 
Pregnancy 
02. 
ECOG ≥3 or KPS<70 
03. 
mrT4 
04. 
mrN2 
05. 
Not consenting to participation 
06. 
Metastatic disease (any type; internal iliac and obturator lymph node 
involvement are considered local disease and not metastatic disease, so not 
considered exclusion criteria) 
 
 

 
 
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07. 
Prior pelvic radiotherapy 
08. 
Underlying neuropathy 
09.  
Receiving treatment with another anticancer drug or method  
10.  
Presence of uncontrolled life-threatening illnesses. 
7.6 Randomization 
Subjects will be randomized and designated in the ratio 1: 1 in both groups 
(consolidation with 1 or 2 drugs) according to the randomization method by 
permutation of blocks of size 4. 
7.7 Data Collection 
The study data collection form is the electronic case report form (electronic 
CRF) via internet. The data will be entered into the system by the site staff. Training 
and support for system use will be made available to investigators by the coordinating 
site. The data collection and management system is validated and has safety and 
reliability for the study. System functionalities include: patient registration, 
randomization with data entry, data cleaning and export for statistical analysis. 
We will use data collected directly from the patient and/or family member for 
24-hour allocation confidentiality. Several procedures will ensure data quality, 
including: 
1) All researchers will participate in a training session prior to the study start to ensure 
consistency of study procedures, including data collection; 
2) Investigators will be able to call the study Coordinating Site to resolve questions 
or issues that may arise; 
 
 

 
 
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3) Data cleaning for identifying inconsistencies will be conducted periodically 
(approximately every fifteen days). Sites will be notified about the inconsistencies to 
provide correction; 
4) Statistical techniques for identifying fraud will be performed throughout the study; 
5) The Coordinating/Sponsor Site will monthly review detailed reports on data 
screening, inclusion, follow-up, consistencies and completeness. It will immediately 
take action to resolve potential issues. 
7.8 Statistical Analysis 
The primary endpoint (WW decision due to cCR / nearly complete) was seen 
in 55% and 85% at 12 weeks among patients with early cT3 and cT2 rectal cancer, 
respectively. In this study, there was a distribution of 66% cT3 and 33% cT2. Therefore, 
response rates are highly dependent on the exact T-stage distribution. Considering the 
inclusion of more advanced disease (late mrT3 or even mrT4 rectal cancer), we would 
expect 40% cCR/near-CR in one-drug arm. In this scenario, if the results in the 2-drug 
group are ≥60% cCR / near-CR, the study will be considered POSITIVE. Incorporation 
of oxaliplatin into a CRT consolidation regimen that results in ≥20% increase in cCR / 
near complete exceeds the potential drawbacks of treatment-related toxicity. 
We assumed that the primary endpoint would occur in 40% of subjects in the 
one-drug group and 60% in the two-drug group, which corresponds to an absolute 
difference of 20% between proportions. It is estimated that a sample of 194 (97 per 
group ) provides statistical power of 80% to detect this difference between proportions 
at the 5% significance level using chi-squared test and assuming two-sided hypothesis 
and considering 1:1 allocation ratio. The estimated rate of loss to follow-up (“drop-out” 
rate) is 10% in each group. Thus, the sample size calculation determines 216 subjects, 
with 108 subjects per group. Sample size calculation was performed using SAS 9.4 
(PROC POWER procedure). 
 
 

 
 
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7.9 Flowchart 
Table 2: Subject’s flowchart detailing pre- and post-randomization activities, as 
well as follow-up and assessment periods. 
Procedures 
V1 
Treatment 
Range 1 
Treatment 
V2  
12 WEEKS2 
V3  
18 WEEKS3 
Clinical 
assessment 
X 
 
 
 
 
 
Inclusion / 
Exclusion Criteria 
X 
 
 
 
 
 
Signature of the 
Informed Consent 
Form 
X 
 
 
 
 
 
Registration of 
previous and 
concurrent drugs 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
Administration of 
therapies: 
Consolidation 
groups with 1 or 2 
drugs 
X 
X 
 
X 
 
 
Response 
Assessment: 
Magnetic 
Resonance 
imaging, Rectal 
Touch and 
Endoscopic 
Evaluation. 
X 
 
 
 
X 
X 
Discontinuation 
Criteria 
X 
X 
X 
X 
X 
X 
Assessment of 
adverse events 
X 
X 
X 
X 
X 
X 
Clinical 
Endpoints4,5 
 
 
 
 
X 
X 
1- 1- to 2-weeks interval. 
2- Response Assessment after 12 weeks. Patients with incomplete response (poor response) 
at 12 weeks will be recommended for surgery at that moment. Only those patients with a near 
complete/complete response at the time of the response assessment at 12 weeks should be 
submitted to response assessment at 18 weeks after the end of treatment. 
 
 

 
 
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3- Response Assessment after 18 weeks. 
4- To reach a complete or nearly complete clinical response achieved at 12 and 18 weeks 
from the end of the last day of radiotherapy using clinical (rectal digital), endoscopic and 
radiological (mrTRG classification) criteria, the last two parameters being evaluated by a 
central committee. (positive clinical endpoint) 
5- Patients with an incomplete response (at 12 or 18 weeks) will be considered a negative 
clinical endpoint. 
8. Ethical Aspects 
The study will be conducted according to the principles of the Declaration of 
Helsinki and International Conference of Harmonisation’s Good Clinical Practices 
guidelines/Good Clinical Practices: Document of the Americas. The study protocol and 
other relevant documents will be submitted to the Independent Ethics Committee for 
collegiate evaluation and approval. All subjects or, when applicable, their legal 
representatives, should sign and initialize the ICF together with a member of the team 
responsible for explaining the document. Subjects shall be informed that the study 
participation is entirely voluntary and that the consent to participate in the study may 
be withdrawn at any time without affecting the subject’s treatment or the relationship 
with the physician. 
The study database will be created without information on the study subjects’ 
identity; therefore, all analyses will be conducted anonymously and with ensured 
privacy of the subjects enrolled in the research. The information collected will be solely 
used for the study purpose and the results found will be published in scientific journals 
of this field. Every individual invited to participate in the research will be informed in 
written about the research purpose and procedures involved, and they can only be 
enrolled in the study after agreeing to participate. No study evaluation or procedure 
should be made prior to the obtainment of the subjects’ informed consent. The 
Principal Investigator is responsible for ensuring that the ICF obtainment procedure is 
conducted according to the specifications of Good Clinical Practices. 
 
 

 
 
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9. POTENTIAL RISKS AND BENEFITS 
9.1 Chemotherapy toxicity and dose adjustment: 
Dose reduction is planned in case of severe hematological and/or non-
hematological toxicity. Dose adjustments should be made according to the system 
showing the greatest degree of toxicity. Toxicities will be assessed using the NCI CTC, 
version 5.0. Treatment will be delayed until: neutrophils ≥1.5 x 109 / L and platelets 
≥75 x 109 / L. 
• 
5FU dose modification: 
Recovery from mucositis, diarrhea. If 5-FU treatment is delayed, the 
associated oxaliplatin dose should also be delayed. If 5-FU is permanently 
discontinued, oxaliplatin should also be discontinued. If toxicity requires a dosing delay 
of more than four weeks, the patient will be permanently withdrawn from study 
treatment due to toxicity. Dose modifications for hematological or GI toxicity will be 
based on the worst toxicity observed during the previous cycle. Upon recovery, 
standard dose adjustments for 5-FU toxicity should be applied. The 5-FU dose should 
be reduced by 20% in subsequent cycles for the following toxicities: febrile 
neutropenia, grade 4 thrombocytopenia, or failure of hematologic recovery to 
neutrophils ≥1500/□L and platelets ≥75000/□L within 2 weeks the scheduled start of 
the next treatment cycle; Grade 3-4 mucositis, diarrhea, or nausea or vomiting despite 
optimal antiemetic prophylaxis. In the mFOLFOX6 protocol, the 5FU bolus should be 
discontinued prior to the aforementioned reduction of continuous 5FU infusion. A 
second 5-FU dose reduction of 20% of the original dose may be made if the above 
toxicities occur again. After reducing the doses, they should not be increased again 
and should be continued for the rest of the treatment. 
• 
Capecitabine: 
 
 

 
 
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Patients with a creatinine clearance of 30-50 mL (minutes should start CAPE 
treatment with 75% of the total dose). Dose modifications for hematological, skin, or 
gastrointestinal toxicity will be based on the worst toxicity observed during the previous 
cycle. Upon recovery, standard dose adjustments for capecitabine toxicity should be 
applied. The capecitabine dose should be reduced by 25% in subsequent cycles for 
the following toxicities: febrile neutropenia, grade 4 thrombocytopenia, or failure of 
hematologic recovery to neutrophils ≥1500/ □L and platelets ≥75000/ □L within 2 
weeks the scheduled start of the next treatment cycle; Grade 3-4 mucositis, hand-foot 
syndrome, diarrhea, or nausea or vomiting despite optimal antiemetic prophylaxis. 
• 
Oxaliplatin; 
If a 5FU dose reduction is performed, the oxaliplatin dose should also be 
reduced by 25%. The neurotoxicity of oxaliplatin should be assessed prior to each 
dose of oxaliplatin. If neurotoxicity is grade 3, the dose of oxaliplatin should be reduced 
by 25%. If toxicity is grade 4, oxaliplatin should be permanently discontinued. For 
Grade 2 or less oxaliplatin infusion reactions to occur, oxaliplatin can be infused for up 
to 6 hours and the patient must receive pre-drugs such as H1 antagonists, H2 
antagonists and corticosteroids. If it happens again or is grade 3 or higher, 
administration of oxaliplatin should be discontinued. Where available, desensitization 
protocols can be applied, 5FU can be continued even if oxaliplatin is discontinued. 
9.2 Radiotherapy toxicity and discontinuation rules 
Toxicity will be evaluated and registered according to acute radiation morbidity 
score criteria of the CTCAE v4.0. 
 
 

 
 
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Table 3: Interruption rules for radiotherapy during chemoradiation. 
Adverse Event 
Definition 
Action 
Diarrhea 
Grade 4 
It should be stopped until the symptoms 
associated with the treatment are reduced. 
Other 
Gastrointestinal 
Toxicities 
Grade 4 
It shall be stopped and restarted according to 
the patient's conditions. 
 
10. SUBJECT DISCONTINUATION 
If the subject experiment any of the reasons below, the investigator must 
discontinue the study drug, the subject must be followed up until the end of the study 
and all procedures described in this Protocol must be performed: 
a) 
Any medical condition that, at the sponsor or the investigator discretion, 
prevents the subject from continuing on treatment, describing the reason, with the 
respective proof; 
b) 
Subjects experiencing a serious adverse event that 
compromise the compliance and safety of the subject; 
The investigator should follow up patients until the adverse event resolves or 
stabilizes and is considered clinically irrelevant at the physician's discretion. In cases 
where the subject presents any reason for discontinuing the clinical trial protocol, the 
sponsor must be informed by the investigator. 
In the event of any eventuality related to participation, the subject can be 
admitted to the hospital, with the full commitment of the medical team that will provide 
assistance to any intercurrences and/or adverse events. 
The criteria for subject discontinuation from clinical trial are: 
 
 

 
 
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a) Consent withdrawal: subjects who revoke consent for any reason. The study drug 
used by that subject will be discontinued and follow-up will also be stopped; 
b) Loss of protocol follow-up: In this case, the participating site must enter information 
regarding telephone contact attempts in the source document and case report form; 
c) Any medical condition that, at the sponsor or the investigator's discretion, prevents 
the subject from comply with the protocol, describing the reason, with the respective 
proof. The study drug will be discontinued and follow-up will also be stopped. 
11. ADVERSE EVENTS 
11.1 Classification of adverse events. 
An adverse event is defined as any medical adverse occurrence in a patient 
or subject to whom a pharmaceutical product was given and which does not 
necessarily have a causal relationship to the treatment (RDC no. 09, dated 
20/Feb/2015). 
The following are considered an adverse event: 
• 
Suspicion of adverse drug reaction (SADR); 
• 
Adverse event due to drug quality deviation; 
• 
Adverse event from unapproved use of drugs; 
• 
Drug-drug interactions; 
• 
Total or partial therapeutic ineffectiveness; 
• 
Intoxications related to drugs; 
• 
Abusive use of drugs; 
• 
Potential and real medication errors; 
• 
Pregnancy; 
 
 

 
 
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• 
If the following occurs, it will be considered an adverse event: 
• 
Any change to laboratory parameters, clinical evaluation, and complementary 
exams. 
The following will not be considered an adverse event: 
Elective procedures planned before the study onset, even when performed 
during the study period, except any complications occurring during the procedure. 
All adverse events observed or spontaneously reported after the signature of 
the Informed Consent Form, regardless of the potential causal relationship with the 
study drug, shall be reported in the “Adverse Event Report Form”, in the case report 
form, as well as the subject’s medical report (source document). Events involving drug 
adverse reactions, diseases occurring during the study should also be notified. 
Classifications and Evaluations made by the investigator regarding the adverse 
event 
The investigator should evaluate each one of the adverse events according to 
the following parameters and definitions: 
Classification of Predictability of adverse event(s) 
To classify the predictability of adverse events reported during the clinical trial, 
we will use the investigator’s brochure as the drug safety reference document. 
• 
Unexpected: event not described as an adverse reaction in the experimental 
drug brochure or in the package leaflet; 
• 
Expected: event described as an adverse reaction in package leaflet. 

 
 
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Classification of the Intensity of adverse event(s) 
• 
Mild: a problem is present in less than 25% of the time, with an intensity that a 
person can tolerate and rarely occurs in the last 30 days; 
• 
Moderate: it means that a problem is present in less than 50% of the time, with 
an intensity that interferes in the daily life of a person and occasionally occurs in the 
last 30 days; 
• 
Severe: it means that a problem is present in more than 50% of the time, with 
an intensity that partially changes the daily life of a person and frequently occurs in the 
last 30 days; 
• 
Complete impairment: it means that a problem is present in more than 95% of 
the time, with an intensity that completely changes the daily life of a person and occurs 
every day in the last 30 days; 
• 
Unspecified: it means that there is no sufficient information to specify the 
intensity; 
• 
Not applicable: it means that it is not appropriate to use a rating (e.g., 
menstrual functions). 
Information on the need to treat adverse events 
Investigators shall report whether a clinical, pharmacological, or surgical treatment was 
required, as well as the need of any other clinical conduct to solve the adverse events 
experienced. 
Classification of the seriousness of adverse event(s) 
All adverse events shall be assessed for seriousness and any event resulting 
in any adverse experience with drugs, biological products or devices, occurring at any 
dose level and resulting in any of the following outcomes will be considered as serious: 
 
 

 
 
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• 
Death; 
• 
Threat to life; 
• 
Persistent or significant incapability/disability; 
• 
Requires hospital admission or prolongs the admission; 
• 
Congenital anomalies or birth defects; 
• 
Any suspicion of infectious agent transmission by means of a 
• 
drug product or; 
• 
Clinically significant event. 
• 
All situations that do not result in above-mentioned clinical endpoints 
are considered as non-serious events. 
Causality assessment of the adverse event(s) with the Investigational product 
(IP) 
For a standardized causality assessment, investigators shall use the WHO-UMC (The 
WHO Uppsala Monitoring Center) system: 
• 
Certain / Defined: 
➢ 
Event or change (abnormal) in laboratory test with plausible temporal 
relationship to the administration of the intervention; 
➢ 
It cannot be explained by disease or other intervention, drug product; 
➢ 
Plausible response to interruption or withdrawal (pharmacologically, 
pathologically); 
➢ 
Pharmacologically or phenomenologically defined event (i.e., an objective and 
specific disorder or a pharmacologically recognized phenomenon); 
➢ 
Satisfactory rechallenge, if necessary; 
• 
Probable 
➢ 
Event or change (abnormal) in laboratory test with reasonable temporal 
relationship to the administration of the intervention; 
 
 

 
 
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➢ 
Unlikely to be attributed to a disease or other intervention, drug product; 
➢ 
Clinically reasonable response to interruption or withdrawal; 
➢ 
Rechallenge not required. 
• 
Possible 
➢ 
Event or change (abnormal) in laboratory test with reasonable temporal 
relationship to the administration of the intervention; 
➢ 
It can also be explained by disease, other interventions or drug products; 
➢ 
Information on the treatment withdrawal or interruption may be absent or 
unclear. 
• 
Unlikely 
➢ 
The relationship with an event or change (abnormal) in laboratory test which 
at the time of intervention administration seems to be unlikely (but not impossible); 
➢ 
Disease or other treatment support feasible explanations. 
• 
Conditional / Unclassified 
➢ 
Event or change (abnormal) in laboratory test; 
➢ 
More data is required for an appropriate assessment, or; 
➢ 
Additional data under investigation. 
• 
Inaccessible / Unclassifiable 
➢ 
The report narrative suggests an adverse reaction; 
➢ 
It cannot be classified as the information is not sufficient or conflicting; 
➢ 
The data cannot be complemented or verified. 
 
 

 
 
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Information on the action taken for the Investigational Product 
• 
None; 
• 
Reduction; 
• 
Held; 
• 
Temporary withdrawal; 
• 
Increase of dose level. 
Information on the subject’s evolution 
The investigator should report the status evolution (clinical outcome), considering the 
following evolution: 
• 
Recovered; 
• 
Not recovered; 
• 
Recovered with after-effects; 
• 
Worsened; 
• 
Death 
In cases of death, the registration of the cause of death data, availability of the death 
certificate or medical autopsy report, if possible, is essential. 
11.2 Follow-up of adverse event reports. 
For all adverse event reports, regardless of their seriousness, in case 
additional information, follow-up is required or if any inconsistency is noted for the 
registry and/or assessment of the adverse event(s), this is under the investigator’s 
responsibility. 
Only adverse events considered to be serious occurring in the country must 
be reported to the IEC/Conep System. Report of a NON-serious adverse event is 
optional, and this is the prerogative of the researcher or sponsor. 
12 
PROCEDURES AND SPECIAL INSTRUCTIONS 
12.1 Changes to Protocol 
Any changes to the study protocol that may be done and influence its 
conduction or the safety of subjects shall be made as an amendment.  
 
 

 
 
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All amendments will be obligatorily submitted for approval by the Independent Ethics 
Committee/Independent Review Board of the participating institutions before being 
implemented, except administrative amendments. 
12.2 Discontinuation of Subjects and Study Interruption 
The study interruption may occur by investigator-sponsor or study 
Independent Ethics Committee/Independent Review Board’s initiative, provided that 
there is a safety-related reason for the subjects at any time during the study conduction 
or other strong reason for such decision. 
In case a subject who has not met the inclusion criteria was inadvertently 
enrolled, this subject shall be discontinued from the study, and the investigator-sponsor 
or its representative should be informed. Another reason that may lead to the subject’s 
discontinuation is the consent withdrawal at any time. The date and reason for 
discontinuation should be noted on the case report form. 
13. CONFIDENTIALITY 
By signing the protocol, the investigator-sponsor agrees to keep all information 
collected for the study in strict secrecy, and to request the same from his/her teams 
and local Independent Ethics Committee/Independent Review Board. All data 
discovered or evidenced by the research results is confidential information which 
belongs to the investigator-sponsor. All information is confidential up to the publication 
of results. 
No study subject shall be identified by their names or personal characteristics, 
and their data should be treated in aggregate and confidential manner, and its 
designation shall be made by a unique identification number. Personal information will 
be omitted throughout data analysis. 
14. CLINICAL ENDPOINTS 
14.1 Primary endpoint 
To reach a complete or nearly complete clinical response achieved at 12 and 
18 weeks from the end of the last day of radiotherapy using clinical (rectal digital), 
endoscopic and radiological (mrTRG classification) criteria, the last two criteria being 
evaluated by a central committee. 
 
 

 
 
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They will be considered as a negative event (negative clinical endpoint) if at 
the assessment of week 12 or 18 the response assessment (defined by the central 
review committee) is incomplete clinical response. 
They will be considered as a positive event (positive clinical endpoint) if at 
assessment of week 12 and 18 the decision (defined by the central review committee) 
is that there was a complete clinical response or near complete clinical response. 
The decision to perform WW or surgery will be at the discretion of the 
designated team from the participating center and the subject himself not being part of 
or interfering with the primary clinical endpoint previously defined by the central 
committee. 
14.2 Secondary endpoints: 
• 
Surgery-free survival in 3 years 
• 
TME-free survival in 3 years 
• 
Metastasis-free survival in 3 years 
• 
Regrowth-free survival in 3 years 
• 
Colostomy-free survival in 3 years 
15. SCHEDULE 
 
Identification of the Step 
Start 
End 
Research Ethics Committee’s Approval 
26/Nov/2021 
22/Feb/2022 
Study Start 
01/Feb/2022 
01/Feb/2026 
Enrollment of Participants 
01/Feb/2022 
01/Feb/2026 
Data analysis, Manuscript preparation 
31/Aug/2026 
31/Dec/2026 
 
16. INTERIM ANALYSIS 
  
The Interim analysis have been established a priori by an independent 
committee of experts in order to provide safety and efficacy monitoring of the study. 
 

 
 
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Safety monitoring – Considering the limited sample size of the target accrual (≤220 
patients), an interim analysis of safety will be performed after accrual of 50% of the 
sample size to estimate grade 3-5 toxicity across both arms of the study. The stopping 
rule for safety will be a 1-sided p-value < 0.01 (Haybittle–Peto boundary) for grade 3-
5 treatment-related toxicity between study arms at the 50% accrual interim reviews. 
Efficacy monitoring - Similar to safety monitoring, the independent committee will 
consider the outcomes for interim efficacy analysis after recruiting 50% of the desired 
sample for the study's primary outcome - decision to perform Watch and Wait due to a 
complete clinical response 18 weeks after the end of radiotherapy. The study 
interruption rule for efficacy will be the observation of a unilateral p-value <0.001 
(Haybittle-Peto limit) for the decision to perform Watch and Wait for complete clinical 
response (complete clinical response rate at 18 weeks) among the study arms in the 
interim analysis of 50% of the sample. 
 
 
 
17. BUDGET 
Costs estimation usually charged at the Institution during diagnostic planning, 
treatment and patients’ follow-up. 
The exams used to evaluate the response to treatment (endoscopy, digital 
examination of the rectum and magnetic resonance imaging) are already well-
established methods, widely used routinely for therapeutic decisions for patients with 
this diagnosis. No intervention, method or examination is foreseen that is not already 
an integral part of the routine treatment and evaluation of patients diagnosed with rectal 
cancer. 
The procedures listed here include procedures that are routinely used for 
patients with rectal cancer as indicated by international guidelines available in the 
literature. 
Table 4. Estimated budget for Research costs. 
Chemoradiotherapy and 
consolidation chemotherapy 
with or without oxaliplatin for 
distal rectal cancer and Watch 
and Wait. (CCHOWW) 
Quantity 
HAOC cost 
(BRL) 
Randomization 
V0 
Week 6 
 V1 
Week 12 
V2 
Week18  
V3 
Magnetic resonance imaging of 
pelvis 
3 
 
1 
 
1 
1 
Flexible sigmoidoscopy with 
biopsy 
3 
BRL 2,416.00 
0 
0 
1 
1 
Capecitabine 1000 mg 
84 
BRL 91.32 
0 
42 
42 
0 
Capecitabine 850 MG 
42 
BRL 72.46 
42 
0 
0 
0 
Chemotherapy per hour QT 
126 
BRL 469.40 
42 
42 
42 
0 
Oxaliplatin 
0 
Included in QT 0 
0 
0 
0 
Leucovorin 
0 
Included in QT 0 
0 
0 
0 
radiotherapy per hour 
127 
BRL 482.00 
1 
42 
42 
42 
 
 
 
 
 
 
 

 
 
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Total HAOC 
BRL 30,092.33 
BRL 
43,794.24 
BRL 
43,794.24 
BRL 
22,660.00 
 
 
 
 
 
 
 
 
Total HAOC value (per patient) 
BRL 140,340.81 
 
 
 
 

 
 
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• CEP 01327 001 • São Paulo • SP [State of São Paulo] 
• Phone: 11 3549 1976  • Fax: 11 3549 0394 
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Date: 23/01/2024 
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