Phase II of Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in Primary High-risk Rectal Cancer
Phase: PHASE2
Conditions: Rectal Cancer
Sponsor: Uppsala University

Version 1.3,  Juni  2018 
 
        
 
 
 
 
 
 
 
 
 
Phase II study of short course radiation therapy followed by 
pre-operative chemotherapy and surgery in primary high-risk 
rectal cancer 
 
LARCT- US 
Locally Advanced Rectal Cancer Trial – Uppsala Style 
 
 
 
 
 
 
 
Principal Investigator 
Investigators 
B. Glimelius  
Åke Berglund, Nina Cavalli-Björkman, Tanweera Khan, 
Ylva Naeser, Marjut Niinivirta, Peter Nygren, Calin Radu 
and Gustav Ullenhag for The Gastrointestinal cancer unit, 
Dept of Oncology, Akademiska sjukhuset, Uppsala, 
Sweden  
 
 
 
2016-06-22 
Protocol version 1.0 submitted to Research Ethical Committee  
2016-09-21 
Protocol version 1.1 
2017-03-30 
Protocol version 1.2 
2018-06-14 
Protocol version 1.3 
 

 
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Table of contents 
TABLE OF CONTENTS ............................................................................................................................................ 3 
PROTOCOL SIGNATURE SHEET ......................................................................................................................... 5 
SYNOPSIS OF THE PROTOCOL ........................................................................................................................... 6 
ABBREVIATIONS ................................................................................................................................................... 10 
BACKGROUND AND INTRODUCTION ............................................................................................................. 11 
1.1 
EPIDEMIOLOGY .............................................................................................................................................. 11 
1.2 
TREATMENT OF RECTAL CANCER ................................................................................................................... 11 
1.2.1 
Surgery ................................................................................................................................................ 11 
1.2.2 
Radiotherapy ....................................................................................................................................... 12 
1.2.3 
Chemotherapy ..................................................................................................................................... 12 
1.3 
RECTAL CANCER STAGING AND RISK EVALUATION ........................................................................................ 12 
1.4 
MOTIVATION FOR THE RAPIDO TRIAL OF PRE-OPERATIVE CHEMOTHERAPY IN RECTAL CANCER ................. 13 
1.4.1 
Systemic relapses ................................................................................................................................ 13 
1.4.2 
Locoregional therapy .......................................................................................................................... 14 
1.5 
DESIGN CONSIDERATIONS OF A TRIAL OF PRE-OPERATIVE CHEMOTHERAPY IN RECTAL CANCER (THE RAPIDO 
TRIAL) ..................................................................................................................................................................... 15 
1.6 
DESIGNS OF THE RAPIDO TRIAL AND THE FOLLOW-UP TRIAL LARCT-US WHILE WAITING FOR THE RESULTS
 
16 
1.7 
PRIMARY OBJECTIVE ..................................................................................................................................... 18 
1.8 
SECONDARY OBJECTIVES .............................................................................................................................. 18 
1.9 
ENDPOINTS .................................................................................................................................................... 18 
1.9.1 
Primary endpoint ................................................................................................................................ 18 
1.9.2 
Secondary endpoints ........................................................................................................................... 18 
2 
TRIAL DESIGN .............................................................................................................................................. 19 
3 
PATIENT SELECTION CRITERIA ............................................................................................................ 20 
3.1 
PRIMARY TUMOUR CHARACTERISTICS ........................................................................................................... 20 
3.2 
GENERAL ....................................................................................................................................................... 20 
3.3 
EXCLUSION CRITERIA .................................................................................................................................... 21 
3.4 
COMMENTS TO THE INCLUSION CRITERIA WITH AN ASSESSMENT OF RISKS .................................................... 21 
4 
THERAPEUTIC REGIMENS, EXPECTED TOXICITY, DOSE MODIFICATIONS ........................... 22 
4.1 
CHEMOTHERAPY AND RADIOTHERAPY .......................................................................................................... 22 
4.1.1 
Radiotherapy ....................................................................................................................................... 22 
4.1.2 
Chemotherapy ..................................................................................................................................... 23 
4.1.3 
Dose modification schedules ............................................................................................................... 23 
4.1.4 
Oxaliplatin .......................................................................................................................................... 25 
4.1.5 
Status of non-haematological toxicity at the start of each treatment cycle. ........................................ 27 
4.1.6 
Status of haematological toxicity at the start of each treatment cycle. ............................................... 27 
4.1.7 
At the start of each treatment cycle. .................................................................................................... 27 
4.1.8 
Permanent discontinuation of individual drugs due to toxicity ........................................................... 27 
4.1.9 
Prophylactic treatments ...................................................................................................................... 27 
4.2 
SURGERY ....................................................................................................................................................... 28 
5 
CLINICAL EVALUATION, LABORATORY TESTS, FOLLOW-UP ..................................................... 29 
5.1 
BEFORE TREATMENT START........................................................................................................................... 29 
5.1.1 
Eligibility evaluation ........................................................................................................................... 29 
5.1.2 
Obstructing tumours ............................................................................................................................ 29 
5.2 
DURING TREATMENT ..................................................................................................................................... 29 
5.2.1 
Experimental arm (5 x 5 Gy, neo-adjuvant chemotherapy, surgery, ................................................... 29 
5.3 
STOPPING RULES DUE TO CHEMOTHERAPY TOXICITY ..................................................................................... 30 
5.4 
RESECTION AND RESPONSE EVALUATION ...................................................................................................... 30 
5.5 
PATHOLOGIC EVALUATION OF THE RECTAL CANCER RESECTION SPECIMEN................................................... 31 
5.5.1 
Quality of resection evaluation ........................................................................................................... 31 

 
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5.5.2 
Tumour regression score .................................................................................................................... 32 
5.6 
AFTER THE END OF TREATMENT: FOLLOW-UP ............................................................................................... 32 
5.6.1 
Requirements for Follow-Up .............................................................................................................. 32 
5.6.2 
Assessment of Recurrent Disease ........................................................................................................ 32 
5.7 
TREATMENT SUMMARY TABLE ..................................................................................................................... 34 
6 
CRITERIA OF EVALUATION .................................................................................................................... 35 
6.1 
DEFINITIONS ................................................................................................................................................. 35 
6.2 
STATISTICAL CONSIDERATIONS ..................................................................................................................... 36 
6.2.1 
Sample size .......................................................................................................................................... 36 
6.3 
INTERIM ANALYSES ...................................................................................................................................... 36 
7 
TRANSLATIONAL RESEARCH ................................................................................................................. 36 
PATIENT REGISTRATION ................................................................................................................................... 37 
8 
FORMS AND PROCEDURES FOR COLLECTING DATA ..................................................................... 37 
8.1 
CASE REPORT FORMS (MODIFIED FROM THE RAPIDO TRIAL) ....................................................................... 37 
8.2 
DATA FLOW ................................................................................................................................................... 37 
REPORTING ADVERSE EVENTS ....................................................................................................................... 38 
8.3 
SECTION 10 WHO EVENT .............................................................................................................................. 38 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS........................................................................................ 38 
8.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSAR) .............................................................. 38 
8.6 
FOLLOW-UP OF ADVERSE EVENTS ................................................................................................................. 39 
9 
QUALITY ASSURANCE ............................................................................................................................... 39 
9.1 
CONTROL OF DATA CONSISTENCY ................................................................................................................. 39 
9.2 
AUDITS .......................................................................................................................................................... 39 
9.3 
REVIEW OF PATHOLOGY ................................................................................................................................ 39 
9.4 
OTHER REVIEW PROCEDURES ........................................................................................................................ 39 
10 
ETHICAL CONSIDERATIONS ................................................................................................................... 39 
10.1 
PATIENT PROTECTION ............................................................................................................................... 39 
10.2 
SUBJECT IDENTIFICATION ......................................................................................................................... 40 
10.3 
INFORMED CONSENT ................................................................................................................................. 40 
11 
PUBLICATION POLICY .............................................................................................................................. 40 
REFERENCES ......................................................................................................................................................... 40 
APPENDIX E - PATIENT INFORMATION AND INFORMED CONSENT  LARCTUS ............................... 43 
 

 
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Protocol Signature Sheet 
We declare that we have read and familiarized ourselves with the following protocol: 
Phase II study of short course radiation therapy  
followed by pre-operative chemotherapy and  
surgery in primary high-risk rectal cancer 
 
LARCT - US 
 
 
 
 
 
Name 
Site 
Signature 
Date 
Study 
Coordinators 
 
 
 
 
 
 
 
 
 
 
 

 
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Synopsis of the protocol 
 
Protocol title 
Phase II study of short course radiation therapy followed by pre-
operative chemotherapy and surgery in patients with high-risk 
primary rectal. 
Protocol Phase 
Final 
Indication 
Primary rectal cancer with high risk of failing locally and/or 
systemically 
Background 
In patients with a newly diagnosed rectal cancer at high risk of failing 
locally and/or systemically standard therapy long-course preoperative 
radiotherapy with concomitant chemotherapy followed by surgery 
after 6-8 weeks has been standard therapy after a previous Nordic 
study in locally advanced rectal cancer. Despite lack of strong 
scientific evidence, postoperative adjuvant chemotherapy during 6 
months has been added in many centres.  
In a randomized study, the RAPIDO trial, this chemoradiotherapy 
(CRT) has been compared with an experimental treatment starting 
with short-course radiotherapy (RT) followed by 6 courses of neo-
adjuvant chemotherapy with capecitabine and oxaliplatin (CAPOX). 
The trial closed patient entry early June 2016 after having 
randomized the planned number of 920 patients. Almost half of the 
patients were included in Sweden. The immediate experience with 
the experimental treatment is that it is well tolerated by most patients, 
provided that the patient does not have remaining radiation toxicity at 
the start of the chemotherapy. No results will be available until 2018 
when some secondary variables can be analysed. The primary 
outcome will not be available until late 2019. 
During the inclusion period of the RAPIDO trial, a Polish group 
randomized similar patients, however not all staged with MRI, to 
CRT or to an experimental therapy starting also with short-course RT 
followed by three cycles of FOLFOX, being equivalent to two cycles 
of CAPOX. The results were published in May 2016 [1]. They 
showed that the experimental treatment was better tolerated than 
CRT, preferred by more patients and that overall survival was 
improved. The latter is hard to explain since disease-free survival was 
not influenced. However, the experimental treatment can at least be 
considered equivalent to the previous standard therapy and it has 
better compliance.  
In the light of the favourable immediate experience with short-course 
RT followed by neo-adjuvant therapy in the RAPIDO trial together 
with the apparently favourable experience with a similar treatment in 
the randomized trial by the Polish group, the GI-oncologists in 
Uppsala have decided that the coming reference treatment for these 
patients should be short-course RT followed by chemotherapy and 
then surgery. The decision was to recommend four cycles of CAPOX 
and not six as in the RAPIDO trial or two as in the Polish trial. Since 
the evidence for positive effects from adjuvant postoperative 
chemotherapy in rectal cancer after preoperative therapy is limited, it 

 
Page 7 of 43 
was decided not to give a full period of 6 months of adjuvant therapy 
prior to surgery in patients fit for this therapy, but rather 3 months 
(corresponding to 4 cycles of CAPOX) since the present standard of 
6 months of adjuvant therapy will be shortened to 3 months for some 
patient groups after the results of the large trials comparing 6 and 3 
months of therapy (IDEA, final results released in May 2017). 
Endpoints 
Primary endpoint:  
•         Pathological complete response (pCR) rate 
Secondary endpoints:  
•        Clinical complete response (cCR) rate 
• NAR-score 
•        3-year disease-free survival 
•         Overall survival 
•        Short and long-term toxicity 
Study design 
Patients will be treated with the short course 5 x 5 Gy radiation 
scheme followed by four cycles of combination chemotherapy 
(capecitabine and oxaliplatin) and TME surgery. In patients at risk 
for chemotherapy toxicity, the number of courses may be limited to 
two.  
Total number of 
centres 
Akademiska sjukhuset, Uppsala 
Other centres in Sweden, Norway and Denmark, most participating in 
the RAPIDO trial have decided to adopt this regimen as reference 
treatment until the results of the RAPIDO trial is known, thus 
participating in LARCT-US 
Selection criteria 
Patients with a primary rectal cancer without detectable distant 
metastasis who after locoregional therapy only, meaning preoperative 
radio(chemo)therapy plus surgery have at least a 40% risk of not 
having a CRM negative resection or a recurrence, local or distant, 
within three years.  
Main criteria for 
inclusion 
Primary tumour characteristics (identical to those in the 
preceding RAPIDO trial): 
• Histological proof of newly diagnosed primary adenocarcinoma 
of the rectum. 
• Locally advanced tumour fulfilling at least one of the following 
criteria on pelvic MRI indicating high risk of failing locally and/or 
systemically (T4b, i.e. overgrowth to an adjacent organ or structure 
like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-
wall (according to TNM version 7), cT4a, i.e. peritoneal 
involvement, extramural vascular invasion (EMVI+). N2, i.e. four or 
more lymph nodes in the mesorectum showing morphological signs 
on MRI indicating metastatic disease. Four or more nodes, whether 
enlarged or not, with a rounded, homogeneous appearance is thus not 
sufficient. Positive MRF (previously named CRM), i.e. tumour or 
lymph node < 1 mm from the mesorectal fascia [60]. Enlarged lateral 
nodes, > 1 cm (lat LN+). 
 

 
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General: 
• Staging done within 6 weeks before start of radiotherapy. 
• No contraindications to chemotherapy with CAPOX or FOLFOX, 
including adequate blood counts: 
 
- white blood count 4.0 x 109/L 
 
- platelet count 100 x 109/L 
 
- clinically acceptable haemoglobin levels 
 
- creatinine levels indicating renal clearance of  50 ml/min 
 
- bilirubin 35 µmol/l. 
• ECOG performance score  1. 
• Patient is considered to be mentally and physically fit for 
chemotherapy as judged by the oncologist. 
• Age  18 years 
• Written informed consent. 
• Adequate potential for follow-up. 
Exclusion criteria 
• See detailed description in the protocol 
Main parameters of 
efficacy 
Primary: pCR – rate. Patients who receive a clinical complete 
response and where surgery is postponed will also be considered 
Secondary: Clinical response as assessed using MRI, digital 
palpation and endoscopy, disease-free survival after 3 years, overall 
survival and toxicity, CRM negative resection rate, NAR score 
Main parameters of 
safety 
Adverse events, graded according to the NCI CTCAE (version 4.0). 
• Frequency of patients able to undergo full treatment schedule.  
Screening 
 Baseline screening includes: 
• CT (or MRI) of the abdomen and liver 
• MRI of the pelvis 
• CT of the thorax 
• Routine blood tests 
Treatment 
Week 1: 5 x 5 Gy 
Week 3-14: 4 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 
day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3 weeks) 
Week 17-20: Surgery (TME) 
Statistical 
considerations  
No statistical evaluations have been performed, but the pCR rates 
should be at least comparable to the ones seen in multiple trials using 
CRT, and in the trial using 5x5 Gy with 3 cycles of FOLFOX 
(corresponding to 2 cycles of CAPOX) and in the same order of 
magnitude as will be seen in the experimental arm in the RAPIDO 
trial. The NAR score should aim at to be below 14. 
Planned sample size 
The number of patients to be included has not been fixed, but it is 
estimated to be at least 60 during the period until RAPIDO data will 
be available. 
Analysis plan 
The primary endpoint will be analysed when the last patient has 
completed treatment including the surgery. For patients who are not 
operated because of a cCR, minimal follow-up should be 12 months. 

 
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Duration of the study 
About two-year inclusion, and at least two-year follow up after 
inclusion of the last patient.  

 
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Abbreviations 
ANC   
 
 
absolute neoutrophil count 
APR   
 
 
abdominoperineal resection 
BED   
 
 
biological effective dose 
CAPOX  
 
 
capecitabine and oxaliplatin 
CEA   
 
 
carcinoembryonic antigen 
CRM   
 
 
circumferential resection margin 
CRF   
 
 
case record form or case report form 
CT  
 
 
 
computer tomography 
CTCAE  
 
 
Common Terminology Criteria for Adverse Events  
DPD   
 
 
dihydropyrimidine dehydrogenase 
DFS   
 
 
disease free survival 
DSMB  
 
 
Data Safety Monitoring Board 
ECOG  
 
 
Eastern Cooperative Oncology Group 
EMVI   
 
 
extramural vascular invasion 
EORTC  
 
 
European Organisation for Research and Treatment of Cancer 
5HT3   
 
 
5-hydroxytryptamine (serotonin) receptor 3A 
LAR   
 
 
low anterior resection 
IMRT   
 
 
intensity-modulated radiotherapy 
ICRU   
 
 
international commission on radiation unit and measurements 
MDT  
 
 
multidisciplinary team 
MRF  
 
 
mesorectal fascia 
MRI   
 
 
magnetic resonance imaging 
NCI   
 
 
national cancer institute 
RT  
 
 
 
radiotherapy 
OS  
 
 
 
overall survival 
pCR   
 
 
pathological complete response 
PET   
 
 
positron emission tomography 
PME   
 
 
partial mesorectal excision 
QoL   
 
 
quality of life 
SAE 
 
 
 
serious adverse event 
SUSAR 
 
 
suspected unexpected serious adverse event 
TNM   
 
 
tumour node metastasis classification 
TME   
 
 
total mesorectal excision 

 
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Background and introduction 
 
1.1 
Epidemiology 
Colorectal cancer is globally, and in the Western world, with about 1 million new cases annually, 
the third most common cancer. Its incidence is relatively stable in the western world,but 
increases in many developing countries. It is estimated that about 600 000 individuals every year 
die from colorectal cancer. In many western countries, it is the second cancer killer. In 2012, 600 
new colorectal cancer patients were registered in Sweden [2]. About every third colorectal 
cancer starts in the rectum, or the most distal 15 cm of the large bowel. The rest starts in the 
colon, most frequently in the sigmoid part or in caecum. Rectal cancers are more common in 
males.  
 
1.2 
Treatment of rectal cancer 
1.2.1 
Surgery 
Surgery was for long the only curative treatment and is still the most important treatment. If a 
macro- and microscopically radical resection (R0 resection) cannot be achieved, the chances of 
cure are very low. A few small tumours in the rectum can be treated with external and local 
radiotherapy [3] and there are indications that some, likewise small rectal cancers that are very 
chemoradiosensitive can be successfully handled without (major) surgery [4]. 
Although some early, mostly polypoid tumours without unfavourable characteristics can be 
operated with a local, i.e. transanal procedure, most patients with a rectal cancer are operated 
with an abdominal procedure with a resection of the affected bowel segment and adjacent fatty 
tissues with its vessels and lymph nodes. Depending upon location, standardized procedures are 
done, at least if the aim is cure.  
Recognition of the importance of the circumferential resection margin led to the understanding 
that the entire mesorectum must be completely removed in one package to obtain low local 
failure rates [5]. The presently only accepted surgical method is to do a sharp dissection and a 
total mesorectal excision (TME) in all rectal cancers except in those in the upper third where at 
least a 5 cm distal margin within the mesorectum should be aimed at. The procedure in which the 
mesorectum and bowel are transected 5 cm distally of tumour is commonly termed partial 
mesorectal excision (PME). Most centres applying standardised TME/PME techniques can today 
report local failure rates of 5 to 10% in the group of patients where the intention is to do a radical 
procedure [6].  
If the tumour involves the mesorectal fascia (MRF i.e. if a standard TME is done, there is a high 
risk that the circumferential resection margin will be positive, CRM+) or extends to adjacent 
structures or organs (T4b), a more extended procedure is required in order to reach an CRM 
negative resection. In certain patients, this may mean a full or partial pelvic exenteration or 
resection of parts of sacrum.  

 
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1.2.2 
Radiotherapy 
Radiotherapy has been extensively used in rectal cancer during the past decades. The purpose of 
adding radiotherapy to surgery has been mainly two-fold, firstly to reduce the risk of a local 
failure, even if an R0 surgery is considered likely and accomplished, or, secondly, to increase the 
chances of an R0-resection in a locally advanced tumour considered ‘non-resectable’. In the first 
situation, a short-course schedule, like 5 x 5 Gy, with immediate surgery, is one option, since no 
down-sizing or down-staging is required. Data from randomized trials strongly support this 
approach in resectable rectal cancer [7-9]. In the second situation, long-course, conventionally 
fractionated (1.8 – 2 Gy/fraction) to a dose of 45 – 50.4 Gy is used with a delay prior to surgery 
to allow for down-sizing/staging. Concomitant chemotherapy to the long-course radiotherapy 
(RT) improves local control [10-12] and is thus standard treatment to patients who are suitable 
for this combined therapy. As an alternative to chemoradiotherapy (CRT), the short-course 
schedule with a delay prior to surgery has been used in unfit patients, with results that appear 
promising [13, 14]. This approach was used in the completed randomized trial in resectable 
patients (Stockholm III study) [15, 16]. The results show that downsizing and downstaging is 
seen after 5x5 Gy with delayed surgery that is at least as large as that seen after long-course RT 
to 50 Gy without chemotherapy. There are no differences in local recurrence rates, disease-free 
and overall survival between the groups. The surgical morbidity after 5x5 Gy with immediate 
surgery is higher than after delayed surgery; however, radiation induced adverse effects requiring 
hospitalization is seen in 5-7% of the patients in the delay groups. 
1.2.3 
Chemotherapy 
Systemic relapses constitute a major problem in colorectal cancer. The most widely used method 
to decrease systemic relapse rates is to give postoperative adjuvant systemic therapy, presently 
chemotherapy. This approach has been successful in many tumours, such as breast and colon 
cancer with meaningful reductions in relapse rates and post-operative adjuvant chemotherapy in 
colon cancer stage III and high-risk stage II is standard treatment. Presently six months of 
treatment is used, but several large groups have run about five large trials comparing three and 
six months of oxaliplatin-containing therapy. There are no results from these comparisons but 
several of them have completed patient inclusion a few years ago. In rectal cancer, as opposed to 
colon cancer, the scientific support for sufficient activity from adjuvant chemotherapy is less 
strong, and its use is controversial. At many centres post-operative adjuvant chemotherapy is 
standard in rectal cancer but recent randomized trials have not been able to detect any significant 
gains if RT or CRT were given prior to surgery [17-19]. 
1.3 
Rectal cancer staging and risk evaluation 
Appropriate ‘up-to-date’ staging of rectal cancer includes Magnetic Resonance Imaging (MRI) 
of the pelvis together with imaging of the lungs, liver and abdomen to exclude distant 
metastases. Pelvic MRI has evolved as the method of choice since it evaluates the periphery of 
the tumour and its relations to the mesorectal fascia and surrounding structures better than other 
techniques. Positron emission tomography (PET) is also sometimes used to detect tumour 
manifestations not otherwise detectable [20]. Using MRI, rectal tumours can be grouped into 
categories having different risks of failing locally and, more recently, also systemically. A 
European project, The Magnetic Resonance Imaging and Rectal Cancer European Equivalence 
study (MERCURY) prospectively evaluated the risk of failing locally, and has published criteria 
dividing rectal tumours into three groups (low, intermediate and high, or ‘good’, ‘bad’ and 
‘ugly’) [21, 22]. There is presently no international consensus about the criteria, but there is 
sufficient evidence to allow for identification of patients with a sufficiently high risk to fail either 

 
Page 13 of 43 
locally and/or systemically to be included in a trial exploring the value of treating patients with 
neo-adjuvant chemotherapy. 
 
1.4 
Motivation 
for 
the 
RAPIDO 
trial 
of 
pre-operative 
chemotherapy in rectal cancer 
Better staging, improved decision-making at multidisciplinary team (MDT) meetings, more 
refined surgery (TME), appropriate use of preoperative radiotherapy, being superior to 
postoperative CRT together with quality control (pathology and registries) have resulted in 
substantial lowering of local failure rates (from above 30% to below 5-10% in many 
populations). It can then be stated that ‘the local problem in rectal cancer is in principal solved’. 
Although this may be true for rectal cancer patients in general, certain subgroups of patients still 
suffer a substantial risk of not having R0 surgery or a local failure. In addition, survival for rectal 
cancer patients has improved, but not nearly to the same extent as local failure rates have. Thus, 
it is important to study treatment approaches aimed at reducing the risk of systemic relapse 
without compromising local control. It is not reasonable to believe that further improvements in 
the loco-regional treatment of the primary will reduce the systemic relapses. The chapters below 
(1.4-1.5) constituted the motivation for the now recently closed RAPIDO trial and the design is 
defined in chapter 1.6. 
1.4.1 
Systemic relapses  
About 40-60% of patients with locally advanced rectal cancer (cT3c/d-4 and/or N1-2) develop 
distant metastases. Systemic chemotherapy aims at treating occult or micro-metastatic sub-
clinical disease that later can appear as distant metastases.  Current standard treatment for 
patients at high risk of failing locally and/or systemically includes pre-operative chemoradiation. 
Administration of chemotherapy concomitantly during radiotherapy improves local control in 
randomized trials [10-12]. In the Nordic trial cancer-specific survival was also improved [12]. 
However, when giving chemotherapy concomitantly toxicity increases, and dosage of 
chemotherapy must be reduced which may influence the systemic efficacy. In many centres post-
operative adjuvant chemotherapy is prescribed to these patients but since rectal cancer surgery is 
associated with relatively high complication rates (e.g. anastomotic leakage in 19% [23]) many 
patients cannot receive chemotherapy postoperatively. In a German randomized rectal cancer 
trial comparing pre-operative chemoradiation to post-operative chemoradiation only 50 % of 
patients in the post-operative arm received full-dose chemotherapy compared to 89 % in the pre-
operative arm [24]. 
An alternative approach is to administer the systemic therapy before surgery, which is often 
termed “neo-adjuvant” therapy. Support of greater efficacy from neo-adjuvant (or combined neo-
adjuvant and adjuvant, so called peri-operative treatment) comes from some other tumour types, 
but not universally. The strongest support likely comes from gastric cancer, where peri-operative 
platinum-based therapy resulted in better overall survival than surgery alone (by about 13 – 
14%-units), MAGIC trial [25] and FFCD trial [26]. In colorectal cancer metastatic to the liver, a 
gain in event-free survival was seen in an EORTC trial [27] with peri-operative chemotherapy. 
The difference was seen during the first 10 weeks, indicating that the preoperative part of the 
chemotherapy was more important than the postoperative. Neo-adjuvant treatment with 
chemotherapy has also been explored in e.g. head- and neck cancer and oesophageal cancer (in 
the MAGIC and FFCD gastric cancer trials, patients with oesophageal adenocarcinoma were also 
included) and muscle invasive bladder cancer [28], with unequivocal results. In early breast 

 
Page 14 of 43 
cancer, it does not appear to be important to initiate the systemic therapy early, although up-front 
systemic chemotherapy is the treatment of choice in locally advanced breast cancer.  
In the Dutch “M1 trial” short course radiation therapy, neoadjuvant chemotherapy with 
bevacizumab and radical resection of primary tumour and metastases in primary stage IV rectal 
cancer was evaluated [29]. The study included 50 patients (approximately 75 % with T3/T4/N+ 
tumours) who were treated with 5 x 5 Gy radiotherapy followed by 6 cycles of bevacizumab (7.5 
mg/kg every 3 weeks), oxaliplatin (130 mg/m2 every 3 weeks) and capecitabine (1000 mg daily 
day 1-14 mg/m2). Eight weeks after last dose of bevacizumab surgery was performed. The 
completion rate for all (six) cycles of chemotherapy was 85% and more than 90 % completed at 
least 4 cycles. No significant tumour progression of the primary rectal cancer was observed 
during chemotherapy.  None of the patients could not be operated on their local rectal tumour 
due local tumour progression. Only 1 patient had significant morbidity of the primary tumour 
due to the pre-operative treatment, this was caused by a perforation and pelvic abscess due to a 
massive tumour response with tumour necrosis. In 91% of patients a R0 resection of the primary 
tumour was performed. Pathological evaluation of rectal specimens showed a complete response 
rate of 27%. This is higher than after standard chemoradiotherapy. No severe toxicity was 
observed upon radiotherapy and chemotherapy related toxicity was mostly mild. 
Thus, it appears reasonable to assume that pre-operative chemotherapy is more likely to be 
administered in full doses (giving full systemic effect) compared to concomitant or post-
operative chemotherapy.  
1.4.2 
Locoregional therapy 
In many centres the current standard of treatment for rectal tumours at high-risk of failing locally 
or non-resectable tumours is pre-operative long-course chemoradiation (1.8-2 Gy x 25-28 with 
capecitabine) whereas low-risk patients with resectable tumours receive short-course 
radiotherapy (5 Gy x 5). The biological effective dose (BED) of a fractionated radiation scheme 
is calculated as LQ time = n.d(1+d//) – (/)(T-Tk) in which n is the number of fractions, d is 
the dose (Gy) per fraction, / is the common linear-quadratic quotient (set to 10 Gy), / is the 
repair rate (set to 0.6 Gy/day), T is the total treatment time (days), and Tk is the initial delay time 
(days, set to 7 days).  Using this formula, the BED of 5 x 5 Gy equals to 37.5 Gy and the BED of 
28 x 1.8 Gy equals to 40.9 Gy.  
In patients with more advanced tumours (e.g. T4, MRF-positive, positive lateral nodes) the pre-
operative therapy aims at down-staging or down-sizing the tumour whereby the chances of 
performing a R0-resection are increased. Long-course radiotherapy, in particular in combination 
with concomitant chemotherapy increases resectability and improves local control [29]. When 
long-course chemoradiation is delivered, surgery is postponed for 4-8 weeks allowing for acute 
radiation-induced tissue reactions to settle prior to surgery and this “waiting period” also allows 
for down-sizing to occur [30]. When short-course radiotherapy is used, surgery is generally 
performed the following week without a “waiting period” and it has been questioned whether 
any down-staging occurs following this regimen. A Polish trial demonstrated that significantly 
more down staging occurred when a conventional radiotherapy scheme (50.4 Gy, surgery after 4-
6 weeks) combined with chemotherapy (5-FU/leucovorin) was compared with short-term 
preoperative radiotherapy (5 x 5 Gy, surgery within 7 days), but with no difference in local 
recurrence rate and survival [31]. Similar results were reported from an Australasian trial [32]. 
The Stockholm III trial randomized patients with resectable rectal cancer to either long-course 
radiotherapy (50 Gy), short-course radiotherapy with immediate surgery or short-course 
radiotherapy with delayed surgery (4-8 weeks “waiting period”) and data have demonstrated that 
short-course radiotherapy with delayed surgery is feasible, result is low toxicity and causes 
down-staging [16, 33]. Retrospective observational data have shown that short-course 

 
Page 15 of 43 
radiotherapy with delayed surgery can produce significant down-staging and also pCR) in some 
patients [13, 14, 34]. 
In the M1 trial where systemic chemotherapy was administered after short-course before surgery 
no significant local tumour progression during chemotherapy was seen [29]. As stated above in 
11 of 41 (27%) resected rectal specimens a pCR was observed. 
Thus, data to support that short-course pre-operative radiotherapy with delayed surgery is 
feasible and that down-staging or down-sizing may occur following this regimen are present in 
the literature. Furthermore, the interval between radiotherapy and surgery can be prolonged and 
if chemotherapy is delivered in this interval, significant effects can be seen on the primary rectal 
tumour.  
 
1.5 
Design 
considerations 
of 
a 
trial 
of 
pre-operative 
chemotherapy in rectal cancer (the RAPIDO trial) 
In patients with a newly diagnosed rectal cancer at high risk of failing locally and/or systemically 
standard therapy is long-course preoperative radiotherapy with concomitant chemotherapy 
followed by surgery after 4-8 weeks. Despite lack of indisputable scientific evidence, 
postoperative adjuvant chemotherapy is added in many centres.  
To achieve higher compliance and better effect of chemotherapy, the aim is to deliver the 
systemic treatment pre-operatively. Most standard adjuvant chemotherapy schedules in 
colorectal cancer have a duration of 24 weeks. Modifications of current standard therapy could 
theoretically include increase of dose or number of chemotherapy agents for the concomitant 
therapy but that would increase toxicity and possibly decrease compliance. To postpone all 
locoregional therapy in order to start with systemic chemotherapy would not gain acceptance 
because of the risk of local progression.  
A peri-operative chemotherapy regimen was successfully explored for liver metastases of 
colorectal cancer in the EORTC-EPOC trial and with a similar schedule a trial with an 
experimental arm consisting of 12 weeks of chemotherapy pre-operatively followed by short-
course radiotherapy and immediate surgery and 12 weeks of post-operative chemotherapy could 
be considered [27]. This design would, however, have some drawbacks including no 
locoregional therapy initially and the risk of not being able to deliver half of the chemotherapy to 
a substantial proportion of the patients. Moreover, when surgery is performed immediately after 
radiotherapy, the desired down-staging on these locally advanced tumours may not occur, 
leading to a potential risk of decreased local control rates. 
Another alternative is to explore possibilities connected with using the short-course radiotherapy 
with delayed surgery as the locoregional therapy. One of the advantages of the short-course 
schedule is the low toxicity (in particular acute toxicity) which implies that a vast majority of 
patients would be able to start full-dose systemic chemotherapy a week or two after radiotherapy. 
Data from the retrospective trials [13, 14]and the M1 trial [29] support the notion that systemic 
chemotherapy also acts on the primary tumour, thus leading to improved locoregional therapy as 
compared to short-course and a “waiting period”. However, in order to reduce the interval 
between radiotherapy and surgery and still being able to deliver all systemic chemotherapy prior 
to surgery, adjustments of standard chemotherapy schedules for colorectal cancer may be 
necessary. The schedule explored in the M1 trial consisting of 18 weeks with 
oxaliplatin/capecitabine is 6 weeks (2 cycles) shorter than commonly used in post-operative 
adjuvant schedules and offers an attractive alternative. Bevacizumab was included in the “M1 

 
Page 16 of 43 
trial” but there is no data suggesting that bevacizumab or cetuximab improves the antitumour 
effects against subclinical disease.  
 
1.6 
Designs of the RAPIDO trial and the follow-up trial LARCT-US 
while waiting for the results 
RAPIDO was a randomized multicentre Phase III trial in patients with non-metastatic primary 
rectal cancer with a high risk of failing locally and/or systemically. Standardised MRI criteria 
will be used to identify eligible patients. Patients were randomized between a standard therapy 
arm (A) and an experimental arm (B). 
A: Long-course radiotherapy (1.8-2 Gy x 25-28) with concomitant capecitabine. After a “waiting 
period” of 8-10 weeks during which response is evaluated, surgery according to TME/PME 
principles will be performed. In this arm it is allowed according to the local protocol of the 
participating institute to admit after recovery, optimally within 6-8 weeks, post-operative 
adjuvant chemotherapy consisting of 8 cycles oxaliplatin/capecitabine. 
B: Short-course radiotherapy (5 Gy x 5). Within 11-18 days after the last day of radiotherapy 
pre-operative systemic chemotherapy with oxaliplatin/capecitabine will commence and is 
delivered in 6 cycles. After six cycles response is evaluated. Within 2-4 weeks after the final 
chemotherapy cycle surgery according to TME/PME principles will be performed. No 
postoperative therapy will be given. 
LARCT-US  
The RAPIDO trial closed patient entry early June 2016 after having randomized the planned 
number of 920 patients. 106 patients were included at Akademiska sjukhuset, Uppsala, being the 
largest centre. The immediate experience with the experimental treatment is that it is well 
tolerated by most patients, provided that the patient does not have remaining radiation toxicity at 
the start of the chemotherapy. No results are available until 2017 when only results of some 
secondary variables can be analysed. The primary outcome will not be available until  late 2019 
at the earliest. 
During the inclusion period of the RAPIDO trial, a Polish group randomized similar patients, 
however not all staged with MRI, to CRT or to an experimental therapy starting also with short-
course RT followed by three cycles of FOLFOX, being equivalent to two cycles of CAPOX. The 
results were presented in Ann Oncol in May 2016 [1]. They showed that the experimental 
treatment was better tolerated than CRT, preferred by more patients and that overall survival was 
improved. The latter is hard to explain since disease-free survival was not influenced. However, 
the experimental treatment can at least be considered equivalent to the previous standard therapy 
and with better compliance.  
In the light of the favourable immediate experience with short-course RT followed by neo-
adjuvant therapy in the RAPIDO trial together with the apparently favourable experience with a 
similar treatment in a randomized trial by the Polish group, the GI-oncologists in Uppsala 
decided that the coming reference treatment for these patients should be short-course RT 
followed by chemotherapy and then surgery. The decision was to recommend four cycles of 
CAPOX and not six as in the RAPIDO trial or two as in the Polish trial. Since the evidence for 
positive effects from adjuvant postoperative chemotherapy in rectal cancer after preoperative 
therapy is limited, it was decided not to give a full 6 months period of adjuvant chemotherapy 
prior to surgery in patients fit for this therapy, but rather 3 months since it can be expected that 
the present standard postoperatively of 6 months of adjuvant therapy will be shortened to 3 

 
Page 17 of 43 
months after the results of the large trials comparing 6 and 3 months of therapy (IDEA, final 
results were released in May 2017 and have been published in full in 2018 (Grothey et al, NEJM 
2018; Iveson et al Lancet Oncol 2018; Sobrero et al JCO 2018). The results briefly showed that 3 
months of chemotherapy is not inferior, at least not for large groups of patients, to 6 months of 
therapy. In patients that are not expected to tolerate the planned four treatments, e.g. because of 
very high age or co-morbidities, two cycles can be given.  
This treatment will be given within a prospective phase II trial to be able to evaluate the results 
properly and compare them with those reported by the Polish group and the coming results in the 
RAPIDO trial. A formalized protocol will likely also result in that the treatments are given with 
higher quality. The inclusion criteria, and routines in the trial will be identical to the RAPIDO 
trial, facilitating future comparisons. The inclusion criteria are also similar to those in the Polish 
study, although inter-trial comparisons are always difficult to interpret.  
A large series of US patients with rectal cancer treated with CRT recently reported that patients 
could be divided into three prognostic groups according the pretreatment stage and pathological 
stage {George, 2015 #13175}. The score (neo-adjuvant rectal, NAR, score) considers the 
pathological N-stage and the difference between clinical and pathological T-stage according to 
the following formulation:  
 
The NAR score has recently been prospectively evaluated or validated in other patient materials 
(Fokas et al Ann Oncol 2018; Rosello et al Clin Colorectal Cancer 2018), and is used by a large 
US co-operative group (NRG) to prospectively identify the best neo-adjuvant treatment, 
replacing CRT. A NAR score of 14 or less is then considered promising in a phase II study, 
motivating further testing. 
The LARCT-US protocol has been used in Uppsala since July 2016 and has since attracted other 
clinics in Sweden, Norway and Denmark to adopt the same idea while waiting for the RAPIDO 
results. Ethical approval for participating in the trial has been obtained from more and more 
centres since then, even if the committee in Uppsala considered this as routine therapy not 
formally requiring approval before being used.  

 
Page 18 of 43 
Objectives of the trial 
1.7 
Primary objective  
• To investigate the complete pathological remission rate. 
1.8 
Secondary Objectives 
• To describe the toxicity profile of the combined modality treatment in schedule. 
• To determine the completion rate of the neo-adjuvant treatment. 
• To determine the fraction of patients with a radical resection (negative CRM) 
• To determine the clinical response rate as assessed at the MRI-investigation, palpation 
and endoscopy after the preoperative therapy 
• To determine the postoperative complications 
• To describe the local recurrence rate after 3 years follow-up. 
• To describe disease-free and overall survival after 3 and 5 years of follow-up. 
 
1.9 
Endpoints 
1.9.1 
Primary endpoint 
Pathological complete remission (pCR).  
1.9.2 
Secondary endpoints 
• Treatment associated toxicity, including surgical morbidity 
• Completion rate of neo-adjuvant treatment 
• Negative CRM (margin > 1 mm) 
• Clinical complete response (cCR) evaluated using MRI palpation and endoscopy. In patients 
where surgery is not primarily done, cCRs with a duration exceeding 12 months will be 
considered together with the pCR rates.  
• Postoperative complications 
• Local recurrence at 3 years 
• Disease-free and overall survival 
 
For an exact definition of the parameters used as end-points, and the detailed method of 
assessment: see section 6. 
 

 
Page 19 of 43 
2 
Trial design 
This trial is a prospective phase II trial, initially run at one centre (Uppsala) but later expanded to 
other centres. 
Patients will be treated with short course 5 x 5 Gy radiation scheme followed by four (two in risk 
patients for toxicity) cycles of combination chemotherapy (capecitabine and oxaliplatin) and 
surgery. The rectal tumour will be removed by TME/PME surgery or more extensive surgery if 
required because of tumour extent.  
 
Treatment Plan:  
Study Flow Chart 
 
 
Locally advanced  
rectal cancer 
 
Inclusion 
5x5 Gy RT 
Week 1 
 
4 cycles of CAPOX 
Week 3-14 
Response evaluation  
by CT and MRI 
Week 16-17 
Resectable  
Surgery 
Week 17-20 
Irresectable  
Palliative treatment  
 
Baseline CT and MRI 

 
Page 20 of 43 
3 
Patient selection criteria 
 
3.1 
Primary tumour characteristics 
• Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of 
the tumour less than 16 cm from the anal verge using a rigid rectoscope or flexible 
endoscope. 
• Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI 
indicating high risk of failing locally and/or systemically: 
o Clinical stage (c) T4a, i.e. overgrowth to an adjacent organ or structure like the 
prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to 
TNM version 5). 
o cT4b, i.e. peritoneal involvement. 
o Extramural vascular invasion (EMVI+). 
o N2, i.e. four or more lymph nodes in the mesorectum showing morphological 
signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged 
or not, with a rounded, homogeneous appearance is thus not sufficient. 
o Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal 
fascia. 
o Metastatic lateral nodes, > 1 cm (lat LN+), see appendix G (see the RAPIDO 
protocol). 
 
3.2 
General 
• Staging done within 6 weeks before start of radiotherapy. No contraindications to 
chemotherapy with CAPOX including adequate blood counts, (within 5 weeks prior to 
randomisation): 
 
- white blood count 4.0 x 109/L 
 
- platelet count 100 x 109/L 
 
- clinically acceptable haemoglobin levels 
 
- creatinine levels indicating renal clearance of  50 ml/min 
 
- bilirubin 35 µmol/l. 
• ECOG performance score  1, see appendix B (see the RAPIDO protocol). 
• Patient is considered to be mentally and physically fit for chemotherapy with CAPOX as 
judged by the oncologist. 
• Age  18 years 
• Written informed consent. 
• Adequate potential for follow-up. 

 
Page 21 of 43 
3.3 
Exclusion criteria  
• 
Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots 
indicating that surgery will never be possible even if substantial tumour down-sizing is seen. 
 
• Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis 
coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease 
or active ulcerative Colitis. 
• Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin 
or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free 
for at least 5 years. 
• Known DPD deficiency. 
• Any contraindications to MRI (e.g. patients with pacemakers). 
• Medical or psychiatric conditions that compromise the patient’s ability to give informed 
consent. 
• Concurrent uncontrolled medical conditions. 
• Any investigational treatment for rectal cancer within the past month. 
• Pregnancy or breast feeding. 
• Patients with known malabsorption syndromes or a lack of physical integrity of the upper 
gastrointestinal tract. 
• Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic 
coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled 
with medication) or myocardial infarction within the past 12 months. 
• Patients with symptoms of peripheral neuropathy. 
 
3.4 
Comments to the inclusion criteria with an assessment of 
risks 
The presence of one or more of the risk factors indicates that the estimated risk of failing (no 
CRM negative resection, local pelvic or systemic recurrence) within 3 years is 60% or above if 
surgery is the primary treatment and 40% or above if radiotherapy with 5FU chemotherapy 
followed by surgery (and adjuvant chemotherapy) is the primary treatment. It is assumed that at 
least a TME/PME is performed. In patients with overgrowth to adjacent organs or structures, 
these are removed en bloc. 
The criteria mentioned all indicate that the risk of systemic relapse is high, whereas not all 
indicate that the risk of failing locally is high.  

 
Page 22 of 43 
4 
Therapeutic regimens, expected toxicity, 
dose modifications 
 
4.1 
Chemotherapy and radiotherapy  
4.1.1 
Radiotherapy 
Preoperative radiotherapy will be delivered on a linear accelerator in prone or supine position, 
preferably with full bladder. The use of a belly board is allowed.  Isocentric 3 or 4 beams, as well 
as an IMRT technique is allowed, as long as all beams are treated on a daily basis.  
The dose distribution and calculation should be performed on CT scans or MRI scans and 
specified according to the ICRU 50 guidelines. 
 
4.1.1.1 
Dose specification  
 
All patients will receive 5 daily fractions of 5 Gy up to a total dose of 25 Gy. Overall treatment 
time should be maximum eight days.  
A boost dose to the tumour bed is optional. 
 
4.1.1.2 
Target volume 
Pelvic field (see Appendix F for further details found in the RAPIDO protocol) 
Tumour bed with a margin, plus regional lymph nodes according to tumour location and growth. 
The mesorectal and pre-sacral lymph nodes are always included whereas the lateral obturator 
nodes and internal iliac nodes are only included if the tumour grows below the peritoneal 
reflection.  The external iliac nodes should be included if the primary tumour invades the 
bladder, prostate, cervix or vagina to such an extent that the external nodes are at risk for 
metastases. Napping or minimal overgrowth dorsally is not sufficient.   
If it is decided to give an additional boost, the boost will include the assessable (via MRI, CT, 
clinical examination) tumour with a 1 cm margin within the same anatomical compartment as the 
tumour is located in. 
 
4.1.1.3 
Toxicity and stopping rules 
Toxicity will be assessed and recorded according to the CCTAE v4.0 acute radiation morbidity 
scoring criteria.  
 
There is a risk of acute neuropathic pain. If this occurs, the upper border of the beams can be 
lowered by a few cm or, alternatively attempts to block the sacral nerve roots should be done if 
possible considering the tumour extent. This usually results in that the pain disappears. If not, 
treatment should be interrupted. A short period of corticosteroid treatment may help. 
  

 
Page 23 of 43 
4.1.2 
Chemotherapy 
Neo-adjuvant chemotherapy consists of a combination of capecitabine and oxaliplatin.  
Oxaliplatin 
The standard dose of oxaliplatin in the CAPOX regimen is 130 mg/m2 (5 mg/ml concentrate for 
solution for infusion) in 500 ml glucose 5% i.v. infusion in 30-120 minutes and should never be 
dissolved in NaCl. If FOLFOX is used instead, the oxaliplatin dose is 85 mg/m2. 
When prescribing oxaliplatin, the contra-indications, special warnings and interactions, as 
described in the latest version of the Summary Product Characteristics (SMP) (1B text), should 
be observed. 
Capecitabine 
For practical reasons dosing of capecitabine should be rounded to the nearest dose that can be 
administered using the 150 and 500 mg tablets.  When prescribing capecitabine, the contra-
indications, special warnings and interactions, as described in the latest version of the SmPC (1B 
text), should be observed. 
Other medication 
Anti-emetic prophylaxis with a 5HT3 antagonist and a glucocorticosteroid is required for all 
patients prior to each oxaliplatin dose. 
Other standard supportive therapies should be administered as clinically indicated. 
 
4.1.2.1 
Chemotherapy doses and timing 
Neoadjuvant chemotherapy 
Preferably, chemotherapy will start within 11-18 days after the last day of radiotherapy. 
However, in case of treatment related diarrhoea or other toxicity, further delay until the toxicity 
is resolved is allowed till 4 weeks after the last day of radiotherapy. If there are signs of tumour 
progression during the neo-adjuvant chemotherapy, this treatment should be stopped, and the 
patient should be evaluated as soon as possible for surgery.  
 
drug 
dose 
frequency 
Every 3 week 
cycle, in total 4 
cycles 
Capecitabine 
1000 mg/m2 
Twice daily, day 1-14 
Oxaliplatin 
130 mg/m2 
Every 3 weeks 
 Table 2 Dose of (neo) adjuvant chemotherapy 
As an alternative to CAPOX, particularly if capecitabine is not well tolerated, mFOLFOX-6 can 
be used.  
4.1.3 
Dose modification schedules  
4.1.3.1 
Capecitabine 
The most frequently occurring non-haematologic toxicities are: hand-foot syndrome, 
asymptomatic hyperbilirubinaemia, diarrhoea, nausea/vomiting (not requiring anti-emetic 
prophylaxis), abdominal pain, stomatitis, and anorexia.  
In case of grade 2-3 hand-foot syndrome, capecitabine dosing should be interrupted until 
recovery until  grade 1. The omitted doses should not be administered after resuming of 
treatment, i.e. the total length of each capecitabine treatment period should not exceed 14 days 
(during induction or reintroduction of MTD chemotherapy). 

 
Page 24 of 43 
If painful swelling or erythema of hands or feet occur, emollients are beneficial. Pyridoxin, 
vitamin B6 50 – 150 mg/day has been reported to be of possible benefit to the patients. Pyridoxin 
is not licensed for that indication.  
 
Diarrhoea 
Prophylactic treatment: 
No prophylaxis must be given, especially no loperamide should be administered 
prophylactically. 
In case of diarrhoea grade 2-4, capecitabine intake should be interrupted immediately. 
Capecitabine can only be restarted when diarrhoea is resolved to grade ≤ 1.  
In case of interruption of capecitabine therapy, the omitted doses should not be administered 
after resuming of treatment, i.e. the total length of each capecitabine treatment period should not 
exceed 14 days. 
Patients experiencing severe diarrhoea should be followed cautiously. In case of risk of 
dehydration, fluids and electrolytes should be administered. Standard treatment for diarrhoea 
should be prescribed (i.e. loperamide).  
If diarrhoea persists for more than 48 hours despite the recommended loperamide treatment, the 
patient should be hospitalised for parenteral support. Loperamide may be replaced by other anti-
diarrhoeal treatment (e.g. octreotide etc.). 
Patients who experience concomitant vomiting or fever or have a performance status > 2 should 
be hospitalised immediately for i.v. rehydration. 
Capecitabine treatment interruption during the cycle 
Capecitabine intake must be interrupted in case of ≥ grade 2 non-haematologic toxicity and can 
be resumed after improvement to ≤ grade 1. During induction treatment the omitted doses should 
not be administered after resuming of treatment, i.e. the total length of each capecitabine 
treatment period should not exceed 14 days. In case recovery to ≤ grade 1 does not occur within 
2 weeks, the treatment should be discontinued. 
Capecitabine dose adaptations for non-haematological toxicity 
No dose reduction for the 1st occurrence of grade 2 toxicity, but treatment should be interrupted 
until recovery of symptoms to grade 0-1. The dose should be reduced 25% relative to the 
previous cycle at the 2nd occurrence of grade 2 or the occurrence of any grade 3 toxicity. The 
dose should be reduced 50% relative to the previous cycle at the 3rd occurrence of any grade 2 
toxicity or a 2nd occurrence of any grade 3 toxicity or the occurrence of any grade 4 toxicity. 
Treatment should be discontinued if despite these dose reductions, a given toxicity occurs for a 
4th time at grade 2, a 3rd time at grade 3, or a 2nd time at grade 4 (see table 3 below). 

 
Page 25 of 43 
 
 
Grade 2 
Grade 3 
Grade 4 
1st occurrence Interrupt treatment 
 Until symptom 
recovery to grade 0-1 
 Continue with 100% 
of the capecitabine 
dose 
Interrupt treatment 
 Until symptom recovery 
to grade 0-1 
 Continue with 75% of 
the capecitabine dose 
 
Interrupt treatment  
 Until symptom recovery to 
grade 0-1 
 Continue with 50% of the  
capecitabine dose 
 
2nd 
occurrence 
Interrupt treatment 
 Until symptom 
recovery to grade 0-1  
 Continue with 75% of 
the  capecitabine dose 
Interrupt treatment 
 Until symptom recovery 
to grade 0-1 
 Continue with 50% of 
the capecitabine dose 
 
Discontinue treatment 
 
3rd occurrence Interrupt treatment 
 Until symptom 
recovery to grade 0-1 
 Continue with 50% of 
the capecitabine dose 
Discontinue treatment 
 
 
4th occurrence Discontinue treatment 
 
 
 
 
Table 3. Dose adaptions of capecitabine for non-haematological toxicity. 
 
In the case of cardiac symptoms (angina, arrhythmia) considered possibly related to 
capecitabine, CAPOX can be replaced with Nordic FLOX (5-FU 500 mg/m2 iv and  
calciumfolinate 100 mg iv days 1 and 2 with oxaliplatin 85 mg/m2  iv day 1 q 2 weeks) for the 
corresponding time of neoadjuvant treatment.  
4.1.4 
Oxaliplatin 
The most frequently occurring non-haematologic toxicities are: sensory neuropathy, 
nausea/vomiting (requiring anti-emetic prophylaxis), diarrhoea, mucositis/stomatitis.  
Sensory neuropathy 
A 25% dose reduction of oxaliplatin in case of persistent (≥ 14 days) paresthesia or temporary 
(7-14 days) painful paresthesia or functional impairment. In case of persistent (≥ 14 days) painful 
paresthesia or functional impairment, oxaliplatin should be omitted until recovery and may be 
restarted at 50% of the dose. If despite of a 50% dose reduction, neurotoxicity does recur, and 
oxaliplatin will be discontinued permanently and patients will continue treatment with 
capecitabine (or 5-FU, see above). In case oxaliplatin infusion is not possible according to this 
schedule on day 1 of the next cycle, this cycle should not be delayed, and oxaliplatin should be 
withheld until the following cycle. Acute neurosensory effects (acute laryngeopharyngeal 
dysesthesia with subjective feelings of dyspnea and dysphagia without signs of bronchospasms 
or pulmonary abnormalities) have been observed. See also table 4 below. 

 
Page 26 of 43 
 
Sensory neuropathy 
Oxaliplatin dose 
Non-painful paresthesia ≥ 14 days or  
temporary (7-14 days) painful paresthesia/functional impairment 
25% reduction 
Persistent (pain≥ 14 days) painful paresthesia/functional impairment 
Omit until recovery, then 
restart at 50% 
Recurrent neurotoxicity after 50% dose reduction 
Permanently discontinued 
Table 4. Dose adaptions for oxaliplatin for sensory neuropathy (cycles 1 – 6(8)) 
 
Extravasation of oxaliplatin 
No severe extravasation reactions have been observed so far with oxaliplatin. 
As a general recommendation in the event of extravasation, the following measures are advised 
(like for any other cytotoxic drug): 
1. 
Stop the infusion immediately. 
2. 
Do not remove the needle or cannula. 
3. 
Aspirate with the same needle as much infiltrated drug as possible from the subcutaneous 
site. 
4. 
Apply ice to area for 15 to 20 minutes every 4 to 6 hours for the first 72 hours. 
5. 
Watch the area closely during the following days in order to determine whether any 
further treatment is necessary. 
 
 
Allergic/ideosyncratic reactions to oxaliplatin 
These reactions have been described occurring shortly after oxaliplatin infusion, and a massive 
cytokine release has been suggested as its cause. In case such a reaction occurs, prophylaxis with 
steroids ± anti-histamines is indicated. 
 
Dose adaptions for oxaliplatin and capecitabine for non-haematological toxicity: see Table 5 
below. 
Toxicity during previous 
cycle 
Grade 
Next dose 
Oxaliplatin 
Next dose 
Capecitabine 
Diarrhoea 
3/4 
75% 
75%/50% 
Mucositis 
3/4 
Full dose 
75%/50% 
Skin 
3/4 
Full dose 
75%/50% 
Hand-foot-syndrome 
2-3 
Full dose 
See Table 3. 
Neurotoxicity 
See Table 4 
See Table 4 
Full dose 
Other non haematologic 
toxicities  
3/4 
75% 
75%/50% 
Table 5. Dose adjustment relative to the previous cycle for next cycle. 
 

 
Page 27 of 43 
4.1.5 
Status of non-haematological toxicity at the start of each treatment cycle. 
Non-haematological toxicity should be ≤ grade 1 before start of the next treatment cycle. If these 
conditions are not met dosing of all drugs should be delayed for a maximum of two weeks until 
recovery to ≤ grade 1. In case recovery to ≤ grade 1 does not occur within 2 weeks, the treatment 
will be discontinued. The only exception will be the occurrence of sensory neuropathy induced 
by oxaliplatin: in case oxaliplatin infusion is not possible after a 2 week delay, the next cycle 
should not be further delayed, but oxaliplatin should be withheld until the following cycle. 
 
4.1.6 
Status of haematological toxicity at the start of each treatment cycle. 
Haematological toxicity may be induced by oxaliplatin, and less frequently by capecitabine.  
 
Table 6. Dose adaptations for oxaliplatin and capecitabine for haematological toxicity relative 
to the previous cycle for the next cycle. 
 
If these toxicities recur after dose reduction for previous toxicity, the next cycle should be given 
with a 25% dose reduction of capecitabine. If these toxicities occur again, a 50% dose reduction 
of oxaliplatin should be given. Treatment should be discontinued if these toxicities recur despite 
these dose reductions.  
 
4.1.7 
At the start of each treatment cycle. 
WBC and platelet counts should have been recovered to ≥ 3.0 and ≥ 75 x 109/L, respectively, 
before the start of the next treatment cycle. If these conditions are not met dosing should be 
delayed for a maximum of 2 weeks. If haematological toxicity has not recovered to the above-
mentioned values after 2 weeks delay patients will discontinue treatment with chemotherapy.  
 
4.1.8 
Permanent discontinuation of individual drugs due to toxicity 
If patients experience severe toxicity despite dose reductions which necessitate the 
discontinuation of individual or all drugs, these patients will remain on study and should be 
followed for progression of disease according to the specified timelines.  
 
4.1.9 
Prophylactic treatments 
Anti-emetic prophylaxis 
The prophylactic use of a 5HT3 antagonist i.v. is indicated prior to administration of oxaliplatin. 
Corticosteroids may be added as prophylaxis. All patients should be provided with a prescription 
for anti-emetics (metoclopramide or 5-HT3 antagonists) and should receive instructions on how 
to use this medication in case nausea/vomiting occurs at home. 
Neutrophils 
(109/l) 
WBC  
(109/l) 
Platelets 
(109/l) 
Next dose 
oxaliplatin 
Next dose 
capecitabine 
 0.5 (grade 4) or 
febrile neutropenia 
< 1.0 (grade 4) 
< 25 (grade 4) 
-25% 
No adjustment 

 
Page 28 of 43 
Trombo-embolic prophylaxis 
Trombo-embolic prophylaxis can be used according to local protocols during pre-operative 
treatment, peri-operatively and during adjuvant treatment.  
 
4.2 
Surgery  
Patients are treated with tromboembolic prophylaxis, antibiotic prophylaxis and bowel 
preparation according to local protocols. An open or laparoscopic approach may be used.  
After entering the abdomen, the liver, the peritoneum and retroperitoneum are screened for 
metastatic disease. The operation starts with mobilization of the sigmoid from the lateral or 
medial approach, dependent upon experience of the surgeon, and whether or not the procedure is 
done open or laparoscopic. Care has to be taken to identify the hypogastric nerves to avoid 
damage. The vascular supply is ligated. Ligation of the inferior mesenteric artery at its origin 
from aorta (“high tie”) is not mandatory and ligation the superior rectal artery is considered 
oncologically adequate. The inferior mesenteric vein is divided at the level of convenience. After 
the vessels are divided the sigmoid colon is transected. The dissection continues in the avascular 
plane between the mesentery and the parietal structures leaving the ureter covered by its fascia. 
The pelvic nerves and the inferior pelvic autonomic nerve plexus are identified and preserved if 
it is oncologically possible. The anterior dissection should always be carried out anteriorly to the 
Denonvilliers’fascia. The dissection is carried out keeping the mesorectal fascia intact, ending up 
with a total mesorectal excision (TME). The resection of the primary tumour is carried out using 
sharp dissection to encompass the circumference of the mesorectum. In high rectal tumours (>12 
cm from the anal verge) a partial mesorectal excision (PME) may be used granted that the distal 
margin in both the bowel and the mesorectum is at least 5 cm. In mid or low rectal tumours (< 12 
cm) a TME down to the pelvic floor has to be performed. When an anterior resection or a 
Hartmann’s procedure is performed, rectum should be irrigated prior to division of the bowel. If 
a colo-anal anastomosis is planned for a very low rectal cancer, at least a 1 cm distal margin 
from the tumour is required. In case of an abdominal perineal resection (APR) in low tumours a 
perineal resection with the extra-levator technique aiming at a cylindrical specimen without 
“waisting” is mandatory. In patients with poor bowel function, a Hartmann´s procedure or an 
inter-sphincteric APR may be used if oncologically safe. 
Potentially invaded adjacent structures are resected en bloc with the rectum. This may include 
small bowel, ureter(s), bladder, vaginal wall and/or uterus and also the sacrum below the level of 
S3. Thus, patients may require a partial or full pelvic exenteration. Following APR, closure of 
the perineal wound is up to discretion to each surgeon, but musculocutaneous flaps are advisable. 
Omental flaps and drains can be used according to surgeon preference. Following an anterior 
resection, a covering stoma and drains can be used according to surgeon preference. 

 
Page 29 of 43 
 
5 
Clinical evaluation, laboratory tests, 
follow-up 
 
5.1 
Before treatment start 
5.1.1 
Eligibility evaluation 
 
The following studies are required upon entry into the study, maximum 6 weeks prior to start of 
radiotherapy: 
• Physical examination, including blood pressure, ECOG performance score 
• Rigid sigmoidoscopy (rectoscopy) or colonoscopy with biopsy of the tumour and a “clean 
colon” investigation with CT-colonography, barium enema or colonoscopy 
• Contrast enhanced multi-detector CT scan of thorax, abdomen and pelvis 
• Laboratory tests: haemoglobin, white blood cell count, platelets, bilirubin, ALP, ASAT, 
ALAT, creatinine, and CEA. 
• MRI scan of the pelvis (see Appendix G in the RAPIDO protocol). 
5.1.2 
Obstructing tumours  
Patients who present with obstructing tumours may be candidates for a diverting colostomy 
which can be performed laparoscopically.  
5.2 
During treatment 
5.2.1 
Experimental arm (5 x 5 Gy, neo-adjuvant chemotherapy, surgery,  
5.2.1.1 
Interval between short course radiation and chemotherapy 
In case of no or moderate toxicity chemotherapy starts the following week, ideally 11 – 18 days 
after the last radiation fraction. In case of more than moderate toxicity chemotherapy will be 
postponed with one week, or longer if necessary (see also Chapter 4.1.1.3)  
5.2.1.2 
Evaluation during neo-adjuvant chemotherapy 
Prior to all cycles (1 to 4): 
• ECOG performance status 
• Haematology  
• Physical examination 
• Biochemistry (Na, K, bilirubin, ALP, ALAT, ASAT, creatinine) 

 
Page 30 of 43 
 
5.2.1.3 
Re-staging  
After the end of chemotherapy (1 – 2 weeks after the last dose) resectability of the primary 
tumour is evaluated by MRI of the pelvis. Appearance of metastatic disease is evaluated with 
contrast-enhanced multi-detector CT scan of thorax, abdomen and pelvis, at the end of 
chemotherapy.  
5.2.1.4 
Interval between chemotherapy and surgery 
After completing the neo-adjuvant chemotherapy, time must be allowed for the patient to 
recover. Surgery (rectal resection) should be planned within 2 to 4 weeks after the last dose of 
capecitabine in the last cycle of chemotherapy. 
5.3 
Stopping rules due to chemotherapy toxicity 
This may be the case if severe adverse events are persistent.  
A patient should be withdrawn from treatment in any case due to toxicity, if one of the following 
toxicities persists despite withholding the capecitabine and oxaliplatin for a maximum delay of 
two weeks: 
• Absolute neutrophils count (ANC)  < 1.0  and platelets <100 x 109/L, respectively 
• If the chemotherapy-induced gastrointestinal toxicity does not normalize 
• If any other toxicity ≥ grade 3 persists 
Toxicity will be assessed and documented according the CTCAE version 4.0. Most common 
grade 3-4 toxicity are demonstrated in Tables 3, 4, 5, 6, 7 in Chapter 4. 
 
5.4 
Resection and response evaluation 
A multidisciplinary team with a panel of radiologist, rectal surgeons, medical-oncologist and 
radiation-oncologist will evaluate the imaging studies to assess resectability and tumour 
response. Tumours will be considered resectable unless on imaging: 
• T4 tumour with invasion of the sacrum above the level of S3. 
• Encasement of lumbosacral nerve root(s) 
• Para-aortic pathological nodes (=M1) 
• Inguinal lymph nodes (=M1) 
• Carcinosis peritonei (=M1) 
Special notes on the assessment of target lesions regarding lymph nodes. Lymph nodes identified 
as target lesions should always have the actual short axis measurement recorded (measured in the 
same anatomical plane as the baseline examination), even if the nodes regress to below 10mm on 
study. This means that when lymph nodes are included as target lesions, the ‘sum’ of lesions 
may not be zero even if complete response criteria are met, since a normal lymph node is defined 
as having a short axis of <10mm. Case report forms or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, in order 

 
Page 31 of 43 
to qualify for CR, each node must achieve a short axis <10mm. For PR, SD and PD, the actual 
short axis should be given. 
 
5.5 
Pathologic 
evaluation 
of 
the 
rectal 
cancer resection 
specimen  
Pathological evaluation of the resection specimen will be conducted according to national 
guidelines and will include standardized workup (see appendix C in the RAPIDO protocol) as 
well as standardized reporting. Key features in the reporting of rectal carcinoma include 
investigation of depth of tumour invasion and the presence of lymph node involvement. Using 
these parameters, TNM classification can be assessed. The 7th edition of TNM will be used in 
this study. In addition, an evaluation of the involvement of circumferential resection margins 
(CRM) [35], quality of surgery by photo [36] and tumour regression must be done. A 
circumferential margin of 1 mm or less is considered positive. The exact measurements of the 
CRM should be given, and, in cases of lymph nodes or tumour deposits being closer to the CRM 
than the mass of the primary tumour, two separate CRMs should be measured (one of the closest 
margin and the other one from the primary tumour mass). It should be noted that CRM can only 
be evaluated postoperatively; preoperatively the evaluation should relate to anatomical 
structures, like the mesorectal fascia [37]. 
5.5.1 
Quality of resection evaluation 
The quality of resection is evaluated at two different levels for APRs (mesorectum as well as 
anal canal) and at one level for anterior resections or Hartmann’s (mesorectum).  
The mesorectal score is based on the surgical plane which is achieved: 
• Mesorectal plane (Complete): intact mesorectum with only minor irregularities of smooth 
mesorectal surface. No defect is deeper than 5 mm, and there is no coning toward the distal 
margin of the specimen. There is a smooth circumferential resection margin on slicing. 
• Intramesorectal plane (Nearly complete): moderate bulk to the mesorectum, but irregularities 
of the mesorectal surface. Moderate coning of the specimen is allowed. At no site is the 
muscularis propria visible, with the exception of the insertion of the levator muscles. 
• Muscularis propria plane (Incomplete): little bulk to mesorectum with defects down onto 
muscularis propria and/or very irregular circumferential resection margin. 
In analogy, the score of the anal canal is:  
• Outside levator plane: This plane has a cylindrical specimen with the levators removed en 
bloc 
• Sphincteric plane: This plane has CRM on the surface of the sphincteric muscular tube, but 
this is intact. 
• Intramuscular/submucosal plane: This plane has perforation or missing areas of muscularis 
propria indicating entry into the muscular tube at this level 
 

 
Page 32 of 43 
5.5.2 
Tumour regression score 
Tumour regression is scored using a three-tiered system: no regression, regression and complete 
response. Complete pathological response is only used after standardized workup of the 
specimen which includes blocking of the whole tumour area and cutting three levels of each 
block (at 250 um). 
 
5.6 
After the end of treatment: Follow-up 
If pre-operatively no complete colonoscopy could be performed a total colonoscopy has to be 
performed within the first year after treatment. At  baseline, 12, 36 and 60 months after date of 
surgery will be done by taking history, physical examination, ECOG performance score, 
symptoms according to CTC (see case record forms) and CEA. Follow-up visits with CEA and 
pulmonary x-ray and ultrasound of the liver or CT of thorax and abdomen should be done after 
12, and 36 months (see also Table 8). On indication other diagnostic or imaging techniques 
(MRI, FDG-PET, colonoscopy) can be used to confirm or detect recurrent or metastatic disease. 
When recurrent or metastatic disease is detected this time is marked as the time to progression 
starting from start of radiotherapy. Hereby the disease-free survival can be calculated. After five 
years, routine follow-up will be ended in case of no evidence of disease after performing a final 
colonoscopy. More intense follow-up is allowed if this is routinely done. 
If a centre participation in the quality-of-life (QoL) evaluation after 3 years in the RAPIDO 
study, it is desirable to have this done also in LARCT-US.  
5.6.1 
Requirements for Follow-Up 
 
 
Months since date of surgery 
 
12 
36 
60 
 
History, incl. morbidity assessment 
 
X 
X 
X 
Physical Examination 
 
X 
X 
X 
CEA 
 
X 
X 
X 
X-thorax & US-liver or CT thorax-abdomen 
 
X 
X 
 
Colonoscopy 
 
 
 
X 
Quality-of-life (optional) 
 
 
X 
 
Table 8: follow-up scheme. More intense follow-up is allowed if this is routinely done. 
5.6.2 
Assessment of Recurrent Disease 
Evidence of recurrent disease is accepted when one of the following criteria is present: 
• Positive histology or cytology of adenocarcinoma, compatible with the primary tumour in 
any location. 

 
Page 33 of 43 
• Liver metastases on Ultrasound and/or (PET)CT. 
• Lung metastases on X-ray and/or (PET)CT or MRI scan. 
• Bone metastases on X-ray and/or bone-scintigraphy and/or MRI 
• Brain metastases on MRI 
• Distant lymph node metastases 
• Changes in soft tissue outlines on (PET)CT or MRI– pelvis in combination with an increased 
CEA to differentiate from fibrosis. Parameters for Recurrent Disease 
The following parameters will be recorded and studied:  
• Loco-regional recurrence site and date (local within the pelvis). 
• Distant recurrence site and date (outside the pelvis). 
• Cause of death: local failure, local failure and metastases, metastases only, complications due to 
treatment, intercurrent disease and unknown cause. 
 

 
Page 34 of 43 
5.7 
Treatment Summary table 
 
 
Baseline 
WEEK 
Required Investigations 
 
1 
2 
3-4 
6-7 
9-10 12-13   
16-17 
17-20 
Physical examination 
x 
 
 
x 
 
 
 
  
 
x 
ECOG performance score 
x 
 
 
x 
x 
x 
x 
  
 
x 
Tumour related symptoms 
x 
 
 
x 
x 
x 
x 
  
 
x 
Blood Pressure 
x 
 
 
x 
 
 
 
  
 
x 
Haematology1 
x 
 
 
x 
x 
x 
x 
  
 
x 
Biochemistry2 
x 
 
 
x 
 
 
 
  
 
x 
CEA3 
x 
 
 
 
 
 
 
  
 
 
CT thorax-abdomen-pelvis 
x 
 
 
 
 
 
 
  
x 
 
MRI pelvis 
x 
 
 
 
 
 
 
  
x 
 
Colonoscopy/rectoscopy4 
x 
 
 
 
 
 
 
  
 
 
Toxicity evaluation 
 
 
x 
x 
x 
x 
x 
  
 
x 
Radiotherapy 
 
x 
 
 
 
 
 
  
 
 
Oxaliplatin 
 
 
 
x 
x 
x 
x 
  
 
 
Capecitabine 
 
 
 
x 
x 
x 
x 
  
 
 
Surgery 
 
 
 
 
 
 
 
   
x 
 
 
1) Hb, WBC count, , platelet count 
At baseline: < 72 hour prior to start of chemotherapy 
2) Na, K, creatinin, ALP, ALAT, ASAT, , bilirubin 
At baseline: < 72 hour prior to start of chemotherapy 
3) Within 5 weeks prior to start of radiotherapy  
4) Biopsy taken 
 
Treatment/drug 
dose 
frequency 
Radiotherapy 
5x5Gy 
week 1 day 1-5  
Capecitabine 
1000 
mg/m2 
b.i.d. day 1-14 every 3 week cycle 
starting at week 3 
Oxaliplatin 
130 
mg/m2 
day 1 every 3 week cycle 
starting at week 3 

 
Page 35 of 43 
6 
Criteria of evaluation 
6.1 
Definitions 
Disease-free survival 
Disease-free survival will be computed as the time between start of radiotherapy and either local 
or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of non-
rectal cancer related death patients will be censored at date of death. In case of a second primary 
tumour patients will be censored at the date of diagnosis of the second primary tumour. Patients 
lost to follow-up will be censored the last date of patient visit.   
Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment. Toxicity (acute 
and late) will be assessed and documented according the CTCAE version 4.0. Adverse events 
and serious adverse events will be reported as described in section 8.4. 
Fraction of radical resection (CRM > 1 mm) 
Negative CRM will be evaluated according the pathology protocol described by Quirke [36].  
Complete pathological response (pCR). 
pCR evaluation is done by the method described in the pathology Appendix C. 
Neoadjuvant rectal score (NAR) 
As described in the Background, a novel score will be an additional way to evaluate the results 
of the study and compare with the results of previous and ongoing trials testing different neo-
adjuvant treatments.  
Local recurrence 
Local recurrence is described as relapse of tumour in the pelvic region.  
Distant relapse  
Distant relapse is described as relapse of tumour outside the pelvic region. This will be assessed 
by clinical investigation and imaging studies. Special attention has to be made on the liver and 
lung since these are the predominant side of metastases. 
Local control 
Local control will be computed as the time between randomization and local relapse. If the 
primary tumour cannot be removed macroscopically radically, the time to local failure is zero 
months. Patients who died or are lost to follow-up without evidence of local relapse are censored 
at the date of death or the last date of patient visit. 

 
Page 36 of 43 
Overall survival 
Overall survival will be computed as the time between randomization and all causes of death. 
Patients lost to follow-up will be censored the last date of patient visit.  In case of a second 
primary tumour patients will be censored at the date of diagnosis of the second primary tumour. 
Follow-up is described in Chapter 6.  
6.2 
Statistical considerations 
6.2.1 
Sample size 
No specific considerations have been taken since this is intended to be a trial that is run between 
the end of the preceding randomized RAPIDO trial prior to the results of the trial are available or 
another trial, like the planned CREATE, has been initiated. Since this time is likely to be in the 
order of two years, it can be expected that about 60 patients will be included. This number is 
sufficient to allow a proper evaluation of the primary outcome and a good evaluation of the 
toxicity from the treatment in relation to that seen in other trials. It is possible to make a more 
proper estimation of sample size if it turns out that it is motivated to continue inclusion further 
prior to a more conclusive trial will be initiated. 
 All efficacy analyses will be based on intention-to-treat. Per-protocol analyses will be 
performed as secondary analyses. 
Safety analyses will be based on treatment received and will include only eligible patients. 
Survival curves for disease-free survival and overall survival will be constructed using the 
method of Kaplan-Meier. Cumulative incidence of local recurrence will be computed accounting 
for death as competing risk. Differences in survival between subgroups will be tested with the 
log-rank test. Hazard ratios and 95% confidence intervals (CI) will be computed using Cox 
regression. 
All tests will be two-sided.  
A table will present the completion rate of the neo-adjuvant treatment, pCR frequency and 
percentages, fraction of patients with a radical resection with 90 and 95% CI. 
Frequency and percentages for toxicity will be presented according to the CTCAEv4.0 (see 
appendix D in the RAPIDO protocol). All proportions will be presented with 95% CI. 
6.3 
Interim Analyses 
No interim analysis is planned  
7 
Translational research 
Proteomics, genomics, and circulating tumour cell analyses of plasma and tumour tissue along 
the treatment schedule may provide insight in biomarkers associated with response and 
prognosis. A tissue block (or two-three cores for tissue microarray, TMA) will be collected from 
the preoperative biopsy (if sufficient material is available) and from the operative specimen (See 
appendix C). Optional collection of fresh tissue for freezing and blood samples include: 

 
Page 37 of 43 
• 
Tumour biopsy (at time of colonoscopy), and directly after surgical resection of the 
rectum, stored at -80˚C.  
• 
No specific blood samples will be taken for the study. It is expected that most patients 
will be included in the U-CAN project. Blood samples are then taken prior to the start of therapy 
at diagnosis, after the neo-adjuvant treatment prior to surgery, 6-8 weeks after surgery and 1 and 
3 years after during routine follow-up visits. 
Patient registration  
8 
Forms and procedures for collecting data 
The case record forms (CRF’s) for this study are available on paper and electronically. They are 
the same as used in the RAPIDO trial with appropriate modifications. They are divided in 
different numbered sections. All CRF’s are identified by the patient´s study number and month 
and year of birth.  All CRF’s have to be signed and dated by the person filling in the form.  
All CRF’s allow registration of optional collection of tissue or plasma for translational research. 
A logistical form will be kept up to date with all planned clinic appointments and admissions, 
scheduled studies and treatments.  
8.1 
Case report forms (modified from the RAPIDO trial) 
➢ F01 Inclusion Form 
➢ F02 History and Staging Form  
➢ F03 Baseline Radiology Form 
➢ F04 Radiotherapy Form  
➢ F05a Pre-operative CAPOX Form  
➢ F05b Pre-operative FOLFOX Form 
➢ F06 Restaging Radiology Form  
➢ F07 Surgery/Post-surgery Form 
➢ F08 Pathology Form 
➢ F11 Follow-up Form  
➢ F12 Recurrence Form 
➢ F13 End of Pre-operative Treatment Form  
➢ F20 Death Form  
➢ F30 Adverse Events/SAE Form 
➢ F50 Comment Form 
 
8.2 
Data flow 
Paper CRFs will be filled in by treating physicians or data managers at all participating centers 
and departments.  

 
Page 38 of 43 
Reporting adverse events  
8.3 
Section 10 WHO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects 
and the reviewing accredited METC if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except 
insofar as suspension would jeopardise the subjects’ health. The investigator will take care that 
all subjects are kept informed. 
 
8.4 
Adverse events and serious adverse events 
NOTE In this study, the following events are not reported as an AE or SAE: 
- planned surgery (e.g. stoma removal) 
- planned hospitalisation (e.g. for administering chemotherapy) or recurrences. 
- For recurrences, the CRF “new primary / recurrences” has to be filled in; 
- death due to progression of disease; 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to [the investigational product / the experimental treatment. 
Only adverse events reported spontaneously by the subject or observed by the investigator or his 
staff of grade 3 or 4 will be recorded. 
A serious adverse event is any untoward medical occurrence or effect that at any dose:  
- results in death; 
- is life threatening (at the time of the event); 
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; 
- is a new event of the trial likely to affect the safety of the subjects, such as an unexpected 
outcome of an adverse reaction, lack of efficacy of an IMP used for the treatment of a life- 
threatening disease, major safety finding from a newly completed animal study, etc. 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first knowledge of 
the adverse reaction. This is for a preliminary report with another 8 days for completion of the 
report.  
 
All SAEs, irrespective of relationship to the study treatment must be reported to the Datacentre. 
The SAE report should include the investigator’s assessment of causality. If follow-up 
information changes the investigator’s assessment of causality, this should be noted on the SAEs 
occurring within 30 days after discontinuation of the study treatment should be reported. 
 
8.5 
Suspected unexpected serious adverse reactions (SUSAR) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not 
consistent with the applicable product information (e.g. Investigator’s Brochure for an 
unapproved IMP or Summary of Product Characteristics (SPC) for an authorised medicinal 

 
Page 39 of 43 
product).  
 
8.6 
 
Follow-up of adverse events 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures 
as indicated, and/or referral to the general physician or a medical specialist. 
9 
Quality assurance  
9.1 
Control of data consistency 
Data for this study will be recorded via using Case Report Forms (CRF). On-site quality control  
A monitoring committee will be appointed which will perform monitoring every 6 months after 
start of this trial.  
When necessary regular visits by research nurses, data managers of the regional cancer center or 
monitoring committee members will be organized. 
9.2 
Audits 
The investigator, by accepting to participate to this protocol, agrees to co-operate fully with any 
quality assurance visit undertaken by third parties, including representatives from the “Sponsor”, 
national and/or foreign regulatory authorities or company supplying the product under 
investigation, as well as to allow direct access to documentation pertaining to the clinical trial 
(including CRFs, source documents, hospital patient charts and other study files) to these 
authorized individuals. 
9.3 
Review of pathology 
In order to optimize pathology quality, review of pathology will be performed after inclusion of 
the last patient. A committee of experienced rectal cancer pathologists will be appointed. This 
board will review biopsies and resected rectal cancer specimens according to the pathology 
protocol described in section 6 and Appendix C (see the RAPIDO protocol). 
9.4 
Other review procedures 
In order to optimize pre-operative staging, radiology review will be performed after the inclusion 
of the last patient. A committee of experienced rectal cancer radiologists will be appointed to 
review all pre-operative CT and MRI scans. 
10 
Ethical considerations 
10.1 
Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with most 
recent version of the Declaration of Helsinki and with the laws and regulations of the country. 
The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline for Good Clinical Practice.  
The protocol will be approved by the Local Ethics Committee. 

 
Page 40 of 43 
10.2 
Subject identification 
The investigator must assure that patients’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents submitted to the data 
centre, patients should only be identified by the identification code and month and year of birth. 
The investigator and each investigator in each participating hospital should keep a patient 
enrolment log showing codes, names and addresses.  
10.3 
Informed consent 
All patients will be informed of the aims of the study, the possible adverse events, the procedures 
and possible hazards to which he/she will be exposed. They will be informed as to the strict 
confidentiality of their patient data, but that their medical records may be reviewed for trial 
purposes by authorized individuals other than their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse 
further participation in the protocol whenever he/she wants. This will not prejudice the patient’s 
subsequent care. Documented informed consent must be obtained for all patients included in the 
study before they are registered in the study. This must be done in accordance with the national 
and local regulatory requirements. 
For European Union member states, the informed consent procedure must conform to the ICH 
guidelines on Good Clinical Practice. This implies that “the written informed consent form 
should be signed and personally dated by the patient”. 
11 
Publication policy 
The trial will be published after completion of the inclusion and completion of follow-up of 
patients with respect to results regarding the primary and secondary endpoints. The main results 
regarding the primary and secondary endpoints have to be published first, compared to 
publication of results of side-studies. The principal investigators will be first author and/or last 
authors of main papers based on this study. In case of papers of side results authors have to be 
appointed by the writing committee based on the topic studied and investigators involved.   
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Appendix E - Patient Information and Informed 
Consent  LARCTUS 
 
 
INFORMED CONSENT FORM