Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.
Phase: PHASE3
Conditions: Rectal Cancer
Sponsor: University Medical Center Groningen

Version 3.2, 13 June 2019 
Randomized Multicentre Phase III study of short course radiation 
therapy followed by prolonged pre-operative chemotherapy and 
surgery in primary high risk rectal cancer compared to standard 
chemoradiotherapy and surgery and optional adjuvant 
chemotherapy. 
RAPIDO  
Rectal cancer And Pre-operative Induction therapy followed by Dedicated 
Operation 
NL36315.042.11 
EudraCT number 2010-023957-12 
CKS number 2011-4997 
NCT01558921 
NTR 3230/NL3082 
Principal Investigators 
B. van Etten, surgery, The Netherlands
B. Glimelius, radiation- & medical-oncology, Sweden
G.A.P. Hospers, medical-oncology, The Netherlands
C.A.M. Marijnen, radiation-oncology, The Netherlands
P.J. Nilsson,surgery, Sweden
C.J.H. van de Velde, surgery, The Netherlands
Writing Committee 
R. Beets-Tan
L. Blomqvist
J.C. Beukema
B. van Etten
B. Glimelius
G.A.P. Hospers
E. Kapiteijn
C.A.M. Marijnen
I.D. Nagtegaal
P.J. Nilsson
L. Påhlman †
C.J.H. van de Velde
T. Wiggers
D.J.A. de Groot

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23-09-2010 
Protocol version 1.0 submitted to CKS-KWF 
13-01-2011 
Protocol version 1.0 submitted to EC UMCG 
12-04-2011 
Protocol version 1.0 submitted to CKS-KWF 
23-06-2011 
Swedish Version 
26-09-2011 
EC comments included 
14-10-2011 
Central Ethical Approval EC UMCG 
07-11-2011 
CKS-KWF Approval 
01-12-2011 
Protocol Version 2.0 Amendment 
27-02-2012 
Central Ethical Approval EC UMCG version 2.0 amendment 
01-03-2012 
Initiation Date Netherlands 
26-03-2013 
Protocol Version 2.1.1 Amendment 
08-05-2013 
Central Ethical Approval EC UMCG version 2.1.1. amendment 
30-04-2014 
Protocol Version 2.2 Amendment (approved as 3.0) 
20-06-2014 
Central Ethical Approval EC UMCG Substantial amendment 3.0  
08-01-2016 
Protocol Version 3.1 Amendment 
07-03-2016 
Central Ethical Approval EC UMCG amendment version 3.1 
13-06-2019 
Protocol Version 3.2 Amendment (Statistics) 
04-09-2019 
Central Ethical Approval EC UMCG amendment version 3.2 
Steering committee: 
 
R. Beets-Tan, radiology, NKI-AvL-Amsterdam 
J. C. Beukema, radiotherapy, UMC Groningen 
L. Blomqvist, radiology, Karolinska UH, Stockholm 
A. Cats, gastro-enterology, NKI-AVL-Amsterdam 
B. van Etten, surgery, UMCG 
B. Glimelius, radiation-medical oncology, KUH and Uppsala UH 
D.J.A. de Groot, medical oncology, UMCG 
K. Havenga, surgery UMCG 
T. Holm, surgery KUH  
G.A.P. Hospers, medical oncology, UMCG 
E. Kapiteijn, medical oncology, LUMC 
C.A.M. Marijnen, radiotherapy, LUMC/NKI-AvL -Amsterdam 
I.D. Nagtegaal, pathology, Radboudumc Nijmegen 
P.J. Nilsson, surgery KUH 
H. Putter, statistics LUMC 
C.J.H. van de Velde, surgery, LUMC 
T. Wiggers, surgery, UMCG 
Independent physician H.J.M. Groen, pneumonologist UMCG 
h.j.m.groen@umcg.nl, Phone:  +31 50-3618045 
Sponsor 
UMCG, Groningen, The Netherlands 

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Study Coordinators 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery Netherlands 
B. van Etten 
Department of Surgery 
University Medical Center Groningen, The Netherlands 
Phone: +31-50-3612317, Fax: +31-50-3614873 
E-mail: b.van.etten@umcg.nl 
 
 
Medical Oncology, Netherlands 
G.A.P. Hospers  
Department of Medical Oncology  
University Medical Center Groningen, The Netherlands 
Phone: +31-50-3612775, Fax: +31-50-3614862 
E-mail: g.a.p.hospers@umcg.nl 
 
Radiotherapy, The Netherlands 
C.A.M. Marijnen 
Department of Radiotherapy 
Leiden University Medical Center/Netherlands Cancer Institute 
Phone: +31-20 5262153 
E-mail: c.marijnen@nki.nl 
 
Pathology, The Netherlands 
I. Nagtegaal 
Dept of Pathology 824 
Radboud UMC, Nijmegen, The Netherlands 
Phone: +31 24 3610229, Fax: +31 24 3668750 
E-mail: Iris.Nagtegaal@RadboudUMC.nl 
 
Radiotherapy & Medical Oncology, Sweden 
B. Glimelius 
Dept of immunology, genetics and pathology  
Akademiska sjukhuset, Uppsala,  Sweden 
Phone: +46 18 611 55 13; 611 29 60 
Fax: +46 18 611 10 27 
E-mail: Bengt.Glimelius@igp.uu.se 
 
Surgery, Sweden 
P.J. Nilsson 
Department of Surgery,  
Karolinska University Hospital , Stockholm, Sweden 
Phone: +46 8 51772817 
Fax: +46 8 331587 
E-mail: Per.J.Nilsson@sll.se 

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International relations coordinator 
C.J.H. van de Velde 
Department of Surgery 
Leiden University Medical Center, The Netherlands 
Phone: +31 71 526 2309, Fax: +31 71 526 6750 
E-mail: C.J.H.van_de_Velde@lumc.nl 
 
SAE / SUSAR assessment  
D.J.A.de Groot 
Department of Medical Oncology  
University Medical Center Groningen, The Netherlands 
Phone: +31-50-3611567, Fax: +31-50-3614862 
E-mail: D.J.A.de.Groot@umcg.nl 
 
E. Kapiteijn 
Department of Medical Oncology 
Leiden University Medical Center, The Netherlands 
Phone: +31 71 526 3206, Fax: +31-71-5266760 
E-mail: H.W.Kapiteijn@lumc.nl 
 
Statistician  
H. Putter, LUMC 
Department of Medical Statistics 
Leiden University Medical Center, The Netherlands 
E-mail: H.Putter@lumc.nl 
 
Datacenter Contacts  
LUMC Datacenter 
A.G.H. Roodvoets or E. Meershoek - Klein Kranenbarg  
Leiden University Medical Center 
Datacenter, Department of Surgery, K6-R 
P.O. Box 9600, 2300 RC  LEIDEN, the Netherlands 
Phone: +31-71-526 3500, Fax: +31-71-526 6744 
E-mail: datacenter@lumc.nl 
URL:    www.dccg.nl/trial/rapido  
 
Data Safety 
Monitoring Board 
H. van Tinteren, methodology/statistics, NKI/AvL the Netherlands 
J.W.R. Nortier, medical oncology, LUMC, the Netherlands 
R. van Hillegersberg, surgery, UMCU, the Netherlands 
K. Haustermans, radiotherapy, UZ Leuven, Belgium 
 
National investigators 
see Appendix J 

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Table of contents 
TABLE OF CONTENTS ............................................................................................................................................... 5 
REASONS FOR AMENDMENTS ............................................................................................................................... 8 
PROTOCOL SIGNATURE SHEET ............................................................................................................................ 9 
SYNOPSIS OF THE PROTOCOL ............................................................................................................................ 10 
ABBREVIATIONS ....................................................................................................................................................... 14 
1. 
BACKGROUND AND INTRODUCTION ...................................................................................................... 15 
1.1 
EPIDEMIOLOGY ................................................................................................................................................. 15 
1.2 
TREATMENT OF RECTAL CANCER ..................................................................................................................... 15 
1.2.1 
Surgery ................................................................................................................................................... 15 
1.2.2 
Radiotherapy .......................................................................................................................................... 16 
1.2.3 
Chemotherapy ........................................................................................................................................ 16 
1.3 
RECTAL CANCER STAGING AND RISK EVALUATION .......................................................................................... 16 
1.4 
MOTIVATION FOR A TRIAL OF PRE-OPERATIVE CHEMOTHERAPY IN RECTAL CANCER ..................................... 17 
1.4.1 
Systemic relapses ................................................................................................................................... 17 
1.4.2 
Locoregional therapy ............................................................................................................................. 18 
1.5 
DESIGN CONSIDERATIONS OF A TRIAL OF PRE-OPERATIVE CHEMOTHERAPY IN RECTAL CANCER .................... 19 
1.6 
PROPOSED  TRIAL DESIGN ................................................................................................................................. 20 
2. 
OBJECTIVES OF THE TRIAL ....................................................................................................................... 21 
2.1 
PRIMARY OBJECTIVE ......................................................................................................................................... 21 
2.2 
SECONDARY OBJECTIVES ................................................................................................................................. 21 
2.3 
END-POINTS ...................................................................................................................................................... 21 
2.3.1 
Primary endpoint.................................................................................................................................... 21 
2.3.2 
Secondary endpoints .............................................................................................................................. 21 
3. 
TRIAL DESIGN ................................................................................................................................................. 22 
4. 
PATIENT SELECTION CRITERIA ............................................................................................................... 24 
4.1 
PRIMARY TUMOUR CHARACTERISTICS ............................................................................................................. 24 
4.2 
GENERAL .......................................................................................................................................................... 24 
4.3 
EXCLUSION CRITERIA ....................................................................................................................................... 25 
4.4 
COMMENTS TO THE INCLUSION CRITERIA WITH AN ASSESSMENT OF RISKS ..................................................... 25 
5. 
THERAPEUTIC REGIMENS, EXPECTED TOXICITY, DOSE MODIFICATIONS ............................ 26 
5.1 
CHEMOTHERAPY AND RADIOTHERAPY (IN ARM A AND B) .............................................................................. 26 
5.1.1 
Radiotherapy .......................................................................................................................................... 26 
5.1.2 
Chemotherapy ........................................................................................................................................ 27 
5.1.3 
Dose modification schedules .................................................................................................................. 29 
5.1.4 
Oxaliplatin .............................................................................................................................................. 32 
5.1.5 
Status of non-haematological toxicity at the start of each treatment cycle. ......................................... 33 
5.1.6 
Status of haematological toxicity at the start of each treatment cycle. ................................................ 33 
5.1.7 
At the start of each treatment cycle. ...................................................................................................... 33 
5.1.8 
Permanent discontinuation of individual drugs due to toxicity ............................................................ 34 
5.1.9 
Prophylactic treatments ......................................................................................................................... 34 
5.1.10 
Other concomitant medication .......................................................................................................... 34 
5.2 
SURGERY (IN ARM A AND B)............................................................................................................................ 34 
6. 
CLINICAL EVALUATION, LABORATORY TESTS, FOLLOW-UP ...................................................... 36 
6.1 
BEFORE TREATMENT START ............................................................................................................................. 36 
6.1.1 
Eligibility evaluation .............................................................................................................................. 36 
6.1.2 
Obstructing tumours............................................................................................................................... 36 
6.2 
DURING TREATMENT ........................................................................................................................................ 36 
6.2.1 
Standard arm (chemoradiotherapy – surgery (group A) ...................................................................... 36 
6.2.2 
Experimental arm (5 x 5 Gy, neo-adjuvant chemotherapy, surgery (group B), ................................... 37 
6.3 
STOPPING RULES DUE TO CHEMOTHERAPY TOXICITY ....................................................................................... 38 
6.4 
RESECTION AND RESPONSE EVALUATION ......................................................................................................... 38 
6.5 
PATHOLOGIC EVALUATION OF THE RECTAL CANCER RESECTION SPECIMEN .................................................... 39 
6.5.1 
Quality of resection evaluation .............................................................................................................. 39 

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6.5.2 
Tumour regression score ....................................................................................................................... 39 
6.6 
AFTER THE END OF TREATMENT: FOLLOW-UP .................................................................................................. 40 
6.6.1 
Requirements for Follow-Up ................................................................................................................. 40 
6.6.2 
Assessment of Recurrent Disease .......................................................................................................... 40 
6.7 
TREATMENT SUMMARY TABLE......................................................................................................................... 42 
6.7.1 
Standard arm (group A) ......................................................................................................................... 42 
6.7.2. 
Experimental arm (group B) .................................................................................................................. 43 
7. 
CRITERIA OF EVALUATION ....................................................................................................................... 46 
7.1 
DEFINITIONS ..................................................................................................................................................... 46 
7.1.1 
Toxicity ................................................................................................................................................... 46 
7.1.2 
Fraction of radical resection (CRM > 1 mm) ....................................................................................... 46 
7.1.3 
Complete pathological response (pCR). ................................................................................................ 46 
7.1.4 
Local recurrence .................................................................................................................................... 46 
7.1.5 
Distant relapse ....................................................................................................................................... 46 
7.1.6 
Local control .......................................................................................................................................... 46 
7.1.7 
Overall survival ...................................................................................................................................... 46 
7.1.8 
Quality of Life (QoL) .............................................................................................................................. 47 
7.2 
STATISTICAL CONSIDERATIONS ........................................................................................................................ 47 
7.2.1 
Sample size ............................................................................................................................................. 47 
7.2.2 
Randomization and stratification ........................................................................................................... 47 
7.2.3 
Statistical analyses ................................................................................................................................. 47 
7.3 
INTERIM ANALYSES .......................................................................................................................................... 48 
7.4 
DATA SAFETY MONITORING COMMITTEE (DSMB) .......................................................................................... 48 
8. 
QUALITY OF LIFE ASSESSMENT ............................................................................................................... 49 
8.1 
RATIONALE ....................................................................................................................................................... 49 
8.2 
QL QUESTIONNAIRES ........................................................................................................................................ 49 
8.3 
STUDY DESIGN .................................................................................................................................................. 49 
8.4 
STATISTICAL CONSIDERATIONS ........................................................................................................................ 50 
9. 
TRANSLATIONAL RESEARCH .................................................................................................................... 51 
10. 
INVESTIGATOR AUTHORIZATION PROCEDURE ................................................................................ 52 
11. 
PATIENT REGISTRATION / RANDOMIZATION PROCEDURE .......................................................... 53 
11.1 
RANDOMIZATION ......................................................................................................................................... 53 
11.1.1 
Randomization by facsimile, email or phone .................................................................................... 53 
11.1.2 
Online randomization ........................................................................................................................ 53 
12. 
FORMS AND PROCEDURES FOR COLLECTING DATA ....................................................................... 54 
12.1 
CASE REPORT FORMS ................................................................................................................................... 54 
12.2 
DATA FLOW .................................................................................................................................................. 55 
13. 
REPORTING ADVERSE EVENTS ................................................................................................................. 56 
13.1 
SECTION 10 WHO EVENT ............................................................................................................................ 56 
13.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................................................................... 56 
13.3 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSAR) .......................................................... 57 
13.4 
ANNUAL SAFETY REPORT ............................................................................................................................ 57 
13.5 
FOLLOW-UP OF ADVERSE EVENTS ................................................................................................................ 58 
13.6 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................................ 58 
14. 
QUALITY ASSURANCE .................................................................................................................................. 59 
14.1 
CONTROL OF DATA CONSISTENCY ............................................................................................................... 59 
14.2 
ON-SITE QUALITY CONTROL ........................................................................................................................ 59 
14.3 
AUDITS ......................................................................................................................................................... 59 
14.4 
CENTRAL REVIEW OF PATHOLOGY ............................................................................................................... 59 
14.5 
CENTRAL REVIEW OF RADIOLOGY ............................................................................................................... 59 
15. 
ETHICAL CONSIDERATIONS ...................................................................................................................... 60 
15.1 
PATIENT PROTECTION .................................................................................................................................. 60 
15.2 
SUBJECT IDENTIFICATION ............................................................................................................................ 60 
15.3 
INFORMED CONSENT .................................................................................................................................... 60 
16. 
TRIAL SPONSORSHIP AND FINANCING .................................................................................................. 61 

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17. 
TRIAL INSURANCE ......................................................................................................................................... 61 
18. 
PUBLICATION POLICY ................................................................................................................................. 61 
19. 
REFERENCES .................................................................................................................................................... 62 
APPENDIX A - TNM- CLASSIFICATION OF RECTAL CANCER .................................................................. 66 
APPENDIX B - ECOG PERFORMANCE STATUS ............................................................................................... 68 
APPENDIX C – PATHOLOGY PROTOCOL ......................................................................................................... 69 
APPENDIX D – CTCAE V4 ....................................................................................................................................... 73 
APPENDIX E - ENGLISH PATIENT INFORMATION AND INFORMED CONSENT  RAPIDO TRIAL 
(WITH CAPOX) ........................................................................................................................................................... 74 
APPENDIX F - RADIATION THERAPY ................................................................................................................ 82 
APPENDIX G - MAGNETIC RESONANCE IMAGING ....................................................................................... 84 
APPENDIX H - EORTC  QUALITY OF LIFE QUESTIONNAIRE, COLORECTAL MODULE AND 
CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY ....................................................................... 87 
APPENDIX J - NATIONAL COORDINATORS ..................................................................................................... 88 
APPENDIX K – LOCAL PRINCIPAL INVESTIGATORS .................................................................................. 89 
APPENDIX L  - COLLECTION OF BLOOD SAMPLES ..................................................................................... 91 
APPENDIX M - LARS SCORE .................................................................................................................................. 96 
APPENDIX N - ENGLISH PATIENT INFORMATION AND INFORMED CONSENT  RAPIDO TRIAL 
(WITH FOLFOX4 TREATMENT) ........................................................................................................................... 97 
 

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Reasons for amendments 
 
Changes from protocol version 3.0 to 3.1 
In protocol version 3.0, 3-year disease free survival (DFS) was the primary endpoint. But DFS is 
not a suitable outcome measure in a neo-adjuvant setting where all patients experience disease at 
time of randomisation. Some of the patients will never become free of disease.  
For this reason the protocol was amended. A new primary endpoint was formulated in protocol 
version 3.0: Time to Disease related Treatment Failure (tDrTF). Failures were defined as: 
 Locoregional recurrence  
 Distant metastases  
 Second primary, colorectal cancer 
 Death from same colorectal cancer  
 Treatment-related death  
 No resection/R2 resection  
 No surgery at all (PD, not fit)  
 M1 at restaging/during surgery  
 Local regrowth after Wait&Watch and no resection/R2 resection  
 Distant metastases only in FUP after Wait&Watch 
 
Changes from protocol version 3.1 to 3.2 
After a median follow-up of more than 3 years, the number of events is much lower than 
anticipated and the required number (n=452) would never be reached. Reasons for the lower 
number of events are: change of the endpoint in amendment 3.1 (e.g. death due to other reasons 
is no event, new primary other tumor is no event), maximum duration of follow-up of 5 year 
(statistical programs assume endless follow-up) and perhaps better overall outcome of patients. 
Therefore, the hypothesis is changed from 50% → 40% Disease related Treatment Failures into 
30 → 22.5% DrTF events. These numbers correspond to 280 required events. 
 
Further changes: 
 
Administrative changes (e.g. contact details) 
 
Clarification of  time between neo-adjuvant treatment and surgery 
 
Additional data-collection for recurrence and survival at 7.5 and 10 years 

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Synopsis of the protocol 
Protocol title 
Randomized multicentre phase III study of short course radiation 
therapy followed by prolonged pre-operative chemotherapy and 
surgery in patients with high risk primary rectal cancer compared to 
standard preoperative chemoradiotherapy and surgery and optional 
adjuvant chemotherapy. 
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 is long-course 
preoperative radiotherapy with concomitant chemotherapy followed 
by surgery preferably after 8 weeks (±2 weeks). Despite lack of 
strong 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 this would 
increase toxicity and possibly decrease compliance. Long course 
radiotherapy takes 5-6 weeks to deliver but to omit this and start with 
systemic chemotherapy would not gain acceptance because of the 
risk of local progression. An alternative to modifications of the 
present long-course schedule is to explore the possibilities of using a 
short-course radiotherapy regimen in the locoregional therapy and 
combine this with pre-operative chemotherapy. 
A peri-operative chemotherapy regimen was successfully explored 
for liver metastases of colorectal cancer in the EORTC-EPOC trial. A 
trial with a similar schedule 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 [1]. 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. 
Yet another alternative is to explore possibilities connected with 
using the short-course radiotherapy with delayed surgery as the 
locoregional therapy. Again there would be potential problems 
connected with starting with systemic therapy whereas putting the 
week of radiotherapy first is an option that offers part of the 
locoregional therapy first. 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 retrospective trials [2, 3] and the “M1 trial” [4] support the 

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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” without chemotherapy. However, in 
order to minimise 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 
shorter than commonly used in post-operative adjuvant schedules and 
offers an attractive alternative. Bevacizumab was included in the 
“M1 trial” but there is no data suggesting that bevacizumab [5] or 
cetuximab [6] improves the antitumour effects against subclinical 
disease.  
Endpoints 
Primary endpoint:  
 Disease related treatment failure (DrTF ) 
Secondary endpoint:  
 
Overall survival 
 
CRM negative (margin > 1 mm) rate 
 
Pathological complete response (pCR) rate 
 
Short and long-term toxicity 
 Surgical complications 
 Quality of life 
Study design 
Patients will be randomized between an experimental group (arm B) 
in which short course 5 x 5 Gy radiation scheme is followed by six 
cycles of combination chemotherapy (capecitabine and oxaliplatin; or 
alternatively nine cycles of folinic acid, fluorouracil and oxaliplatin 
(FOLFOX4)) and surgery and a control group (arm A) with long 
course chemoradiotherapy followed by surgery. In arm A adjuvant  
chemotherapy is allowed according to the local protocol of the 
institution. In both groups the rectal tumour will be removed by TME 
surgery or more extensive surgery if required because of tumour 
extent. 
Total number of 
centres 
All hospitals in Sweden and The Netherlands treating rectal cancer 
patients can be involved. Centers in Norway, Slovenia, Denmark, 
Spain and US are also participating.  
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: 
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 (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), cT4b, i.e. peritoneal 

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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 ≤ 1 
mm from the mesorectal fascia [60]. Enlarged lateral nodes, > 1 cm 
(lat LN+). 
 
General: 
Staging done within 5 weeks before randomization. 
No contraindications to chemotherapy, 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, see appendix B. 
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: Disease related treatment failure (DrTF) 
Secondary: Overall survival, CRM negative resection rate and pCR 
rate 
Main parameters of 
safety 
 Adverse events, graded according to the NCI CTCAE (version 
4.0). 
 CRM negative resection rate  
Screening 
 Baseline screening includes: 
 CT (or MRI) of the abdomen and liver 
 MRI of the pelvis 
 CT of the thorax 
 Routine blood tests 
Stratification 
parameters 
 
 
 
 Institution 
 Performance score 0 versus 1 
 Clinical T-stage cT2 or cT3 versus cT4 
 Clinical lymph node status cN- versus cN+ 

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Treatment 
Standard Arm A: 
week 1-6 : Chemoradiotherapy (CRT): 28 x 1.8 Gy or 25x2 Gy at 
working days combined with capecitabine b.i.d. 825 mg/m2  (twice 
daily) day 1-33-38.  
8 weeks (±2 weeks) after CRT: Surgery (TME).  
Adjuvant chemotherapy (8 cycles of CAPOX (Capecitabine 
b.i.d.1000 mg/m2 (twice daily) day 1-14 every 3 weeks, Oxaliplatin 
130 mg/m2 day 1 every 3 weeks or alternatively twelve cycles of 
folinic acid, fluorouracil and oxaliplatin (FOLFOX4) allowed 
according to the local protocol of the particular institute. 
 
Experimental Arm B:  
Week 1: 5 x 5 Gy 
Week 3-20: 6 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 
(twice daily) day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 
every 3 weeks or alternatively nine cycles of folinic acid, fluorouracil 
and oxaliplatin (FOLFOX4).  
Week 22-24: Surgery (TME) 
Statistical 
considerations  
This randomized phase III study compares an experimental treatment 
against the present standard treatment. Of relevance is also the 
immediate anti-tumour secondary endpoints, CRM negative and pCR 
rates.  
It is expected that 3-year DrTF in the control group (arm A) is 30%. 
The hypothesis is that the experimental treatment will decrease this 
figure to 22.5%. 
Planned sample size 
842 evaluable patients, with estimated drop-out of 5 % : 920 patients 
to be included, at least 421 evaluable patients in each arm. 
Analysis plan 
The primary endpoint will be analyzed two years after the last patient 
was included. At this timepoint median follow up is three years. 
Duration of the study 
Four year inclusion, two year follow up after inclusion of the last 
patient. Estimated duration of the study is six year. 
 

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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  
CTV  
 
 
clinical target volume  
DFS   
 
 
disease free survival 
DPD   
 
 
dihydropyrimidine dehydrogenase 
DSMB  
 
 
Data Safety Monitoring Board 
ECOG  
 
 
Eastern Cooperative Oncology Group 
EMVI   
 
 
extramural vascular invasion 
EORTC  
 
 
European Organisation for Research and Treatment of Cancer 
FOLFOX 
 
 
folinic acid, fluorouracil and oxaliplatin 
5FU 
 
 
 
5fluorouracil 
GTV  
 
 
gross target volume  
5HT3   
 
 
5-hydroxytryptamine (serotonin) receptor 3A 
LAR   
 
 
low anterior resection 
LV  
 
 
 
leucovorin or folinic acid 
IMRT   
 
 
intensity-modulated radiotherapy 
ICRU   
 
 
international commission on radiation unit and measurements 
MDT  
 
 
multidisciplinairy 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 
DrTF   
 
 
disease related treatment failure 
TTF 
 
 
 
time to treatment failure 
TNM   
 
 
tumour node metastasis classification 
TME   
 
 
total mesorectal excision 
W&W  
 
 
Wait & Watch policy or Watchful Waiting policy 

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1. 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 2006, 
more than 11000 new colorectal cancer patients were registered in the Netherlands, and 5500 in 
Sweden [7, 8]. 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 [9] and there are indications that some, likewise small rectal cancers that are very 
chemoradiosensitive can be successfully handled without (major) surgery [10]. 
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 [11] led to the 
understanding that the entire mesorectum must be completely removed in one package to obtain 
low local failure rates [12]. 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 10 of 15% in the group of patients 
where the intention is to do a radical procedure [13].  
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 (T4a), 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 [14-16]. 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 
improves local control [17-19] and is thus standard treatment to patients who are suitable for this 
combined therapy. As an alternative to radiochemotherapy, the short-course schedule with a 
delay prior to surgery has been used in unfit patients, with results that appear promising [3, 20]. 
This approach is used in a now ongoing randomized trial in resectable patients (Stockholm III 
study) [21].  
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 [62] [[63].This approach has been successful in many tumours, such as breast and 
colon cancer with meaningful reductions in relapse rates [22, 23] and post-operative adjuvant 
chemotherapy in colon cancer stage III and high-risk stage II is standard treatment. 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  [18, 24-26], although some recent trials 
show that gains are present in a low-risk group (chiefly stage II) of patients [27, 28]. At many 
centres post-operative adjuvant chemotherapy is standard in rectal cancer [25]. However, the 
results of the PROCTOR/SCRIPT trials did not show a benefit of adjuvant chemotherapy [61]. 
 
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 [29-31]. Positron emission tomography (PET) is also sometimes used to detect 
tumour manifestations not otherwise detectable [32, 33]. 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 recently published criteria dividing rectal tumours into three groups (low, intermediate 
and high, or ‘good’, ‘bad’ and ‘ugly’) [34, 35]. 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 locally and/or systemically to be included in a trial exploring 
the value of treating patients with neo-adjuvant chemotherapy. 
 

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1.4 
Motivation for a trial of pre-operative chemotherapy in rectal 
cancer 
Better staging, improved decision-making at multidisciplinary team (MDT) meetings, more 
refined surgery (TME/PME), appropriate use of preoperative radiotherapy, being superior to 
postoperative chemoradiation together with quality control (pathology and registries) have 
resulted in substantial lowering of local failure rates (from above 30% to below 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. 
1.4.1 
Systemic relapses  
About 25-65% of patients with locally advanced rectal cancer (cT3c/d-4 and/or N1-2) develop 
distant metastases [36-38]. Systemic chemotherapy aim 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 [17-19]. In the Nordic trial cancer-specific survival was also improved [14]. 
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% [39]) 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 [40]. 
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 [41] and FFCD trial [42]. In colorectal cancer metastatic to the liver, a 
gain in event-free survival was seen in an EORTC trial [1] 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 [43], with unequivocal results. In early breast 
cancer, it does not appear to be important to initiate the systemic therapy early [22], 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 [4]. 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 twice 
daily day 1-14 mg/m2). Eight weeks after last dose of bevacizumab surgery was performed. The 

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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 
hypofractionated 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 [44].  
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 [45-47]. 
When long-course chemoradiation is delivered, surgery is post-poned 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. 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 recent 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 [45]. Similar results were reported (ASCO 2010) from an 
Australasian trial [48]. An ongoing trial (Stockholm III) is randomizing 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 recently data from an interim analysis including 300 patients demonstrated that 
short-course radiotherapy with delayed surgery is feasible [21]. Retrospective observational data 
have shown that short-course radiotherapy with delayed surgery can produce significant down-
staging and also pathological complete response (pCR) in some patients .[2, 3, 49] 
In the M1 trial where systemic chemotherapy was administered after short-course before surgery 
no significant local tumour progression during chemotherapy was seen [4]. 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 

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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 
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 [1]. 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 [2, 3] and the M1 trial [4] 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 
trial” but there is no data suggesting that bevacizumab [5] or cetuximab [6] improves the 
antitumour effects against subclinical disease.  
 

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1.6 
Proposed  trial design 
This study protocol proposes 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 will be 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 weeks (±2 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 (or alternatively 24 weeks 
of FOLFOX4). 
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. Alternatively 18 weeks cycles of FOLFOX4  is an option. Response is 
evaluated after the systemic chemotherapy. Within 2-4 weeks after the final chemotherapy cycle 
surgery according to TME/PME principles will be performed. No postoperative therapy will be 
given. 

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2. Objectives of the trial 
 
2.1 
Primary objective  
 To decrease disease related treatment failure (DrTF)  
 
2.2 
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 pathological complete response rate (pCR). 
 To determine the postoperative complications 
 To describe the local recurrence rate. 
 To evaluate quality of life. 
 To evaluate functional outcome. 
 To increase overall survival. 
 
2.3 
End-points 
2.3.1 
Primary endpoint 
Disease related treatment failure (DrTF) is the primary endpoint.  
2.3.2 
Secondary endpoints 
 Treatment associated toxicity, including surgical morbidity 
 Completion rate of neo-adjuvant treatment 
 Negative CRM (margin > 1 mm) 
 pCR 
 Postoperative complications 
 Local recurrence 
 Overall survival 
 Functional outcome 
 Quality of life 
 
For an exact definition of the parameters used as end-points, and the detailed method of 
assessment: see section 7. 

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3. Trial design 
 
This trial is a multicentre, randomized, open-label, phase III trial organized by the Dutch 
Colorectal Cancer Group and the Nordic Gastrointestinal Tumour Therapy Group. 
Patients will be randomized between a standard group (arm A) with long course 
chemoradiotherapy followed by surgery and optional postoperative chemotherapy (eight cycles 
of capecitabine and oxaliplatin; or alternatively twelve cycles of FOLFOX4) and an 
experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six 
cycles of combination chemotherapy (capecitabine and oxaliplatin, or alternatively nine cycles of 
FOLFOX4 and surgery. In both groups the rectal tumour will be removed by TME/PME surgery 
or more extensive surgery if required because of tumour extent.  
Randomization is performed to avoid bias by investigators and minimize bias in the assessment 
of the disease and follow-up of the patient. The following stratification factors will be used with 
the randomization:  
Institution, performance score, clinical T-stage, clinical lymph node status 
Disease related treatment failure (DrTF ) is the primary endpoint. This definition of DrTF is based 
on the consensus agreement for Time to Treatment Failure (TTF) as described for the adjuvant 
setting [67]. DrTF is an adaptation for the neo-adjuvante setting.  
Disease related treatment failure (DrTF ) 
Endpoints 
  
Event 
TTF 
DrTF 
time from randomisation until*: 
Locoregional recurrence 
E 
E 
date locoregional recurrence 
Distant metastases 
E 
E 
date distant metastases 
Second primary, same (colorectal) cancer 
E 
E 
date second primary 
Second primary, other cancer 
E 
I 
  
Death from same (colorectal) cancer 
E 
E 
date of death 
Death from other cancer 
E 
C 
date of death 
Non‐cancer‐related death 
C 
C 
date of death 
Treatment‐related death 
E 
E 
date of death 
Lost to follow‐up 
C 
C 
date last fup 
No resection/R2 resection 
E 
date of progression / surgery 
No surgery at all (PD) 
E 
date of progression 
M1 at restaging/during surgery 
E 
date of progression / surgery 
Local regrowth after WW and R0/R1 resection  
I 
Local regrowth after WW and no resection/R2 resection  
E 
date of diagnosis local regrowth  
Distant metastases only in FUP after WW 
E 
date distant metastases 
TTF = time to treatment failure 
  
DrTF = disease related treatment failure 
  
E = event; C = censor; I = ignore 
  
* whichever date comes first 
  
 

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Study Flow Chart 
 
 
 
 

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4. Patient Selection Criteria 
 
4.1 
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, see appendix G.  
o Positive MRF, i.e. tumour one mm or less from the mesorectal fascia. 
o Metastatic lateral nodes, > 1 cm (lat LN+)., see appendix G 
 
4.2 
General 
 Staging done within 5 weeks before randomization. 
 No contraindications to chemotherapy, including adequate blood counts, (within 5 weeks 
prior to randomsation): 
 
- 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. 
 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. 

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4.3 
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. 
 Previous radiotherapy in the pelvic region (e.g. prostate) or previous rectal surgery (e.g. 
TEM) or 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 or history of peripheral neuropathy. 
 
4.4 
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 [34].  

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5. Therapeutic regimens, expected toxicity,  
dose modifications 
 
5.1 
Chemotherapy and radiotherapy (in Arm A and B) 
5.1.1 
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 fields, 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 or MRI and specified 
according to the ICRU 50 guidelines. 
 
5.1.1.1 
Dose specification  
Arm A = standard treatment: 
All patients will receive 28 daily fractions of 1.8 Gy up to a total dose of 50.4 Gy or 25 fractions 
of 2.0 Gy up to a total dose of 50.0 Gy to the pelvic field including the tumour bed with a margin 
and the regional lymph nodes. A field reduction after 45 (1.8 Gy schedule) or 46 (2.0 Gy 
schedule) is recommended. The last fractions will then be given to the tumour bed with a margin. 
Institutions must indicate which schedule they will use and whether field reduction will routinely 
take place in their patients. 
Capecitabine will be given during radiotherapy day 1-38 or day 1-33 in a dose of 825 mg/m2 bid 
(twice daily) (see section 5.1.2). 
 
Arm B = experimental treatment  
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. 
 
5.1.1.2 
Target volume 
Pelvic field (see Appendix F for further details) 
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. 
 

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5.1.1.3 
Toxicity and stopping rules 
Toxicity will be assessed and recorded according to the  CTCAE v4.0 acute radiation morbidity 
scoring criteria. Toxicity for the different treatment arms may be different. Stopping rules are 
therefore defined per treatment arm. 
 
Arm A: 
Adverse event 
Definition 
Action 
Other 
RADIOTHERAPY 
Diarrhoea 
Grade 4 
should be interrupted until the 
treatment-related symptoms have 
been reduced and parental support is 
no longer necessary 
 
Other gastro-
intestinal toxicity 
Grade 4 
should be interrupted and restarted 
according to the patients' condition 
 
Table 1. Dose modification schedule for radiotherapy during chemoradiation. 
 
Arm B: 
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. 
  
 
5.1.2 
Chemotherapy 
 
5.1.2.1  CAP(OX) 
 
The concomitant chemotherapy in arm A consists of capecitabine only.  
(Neo)adjuvant chemotherapy consists of a combination of capecitabine and oxaliplatin 
Oxaliplatin 
The standard dose of oxaliplatin is 130 mg/m2 (5 mg/ml concentrate for solution for infusion) in 
500 ml glucose 5% i.v. infusion in 2 hours and should never be dissolved in NaCl.  
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 (Xeloda®) 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. 
 

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5.1.2.2 FOLFOX4 
Alternatively  FOLFOX4  can be given. [62] [68] 
Then, oxaliplatin (85 mg/m2) is administered as a 2-hour infusion on day 1; leucovorin (200 
mg/m2) administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-
FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered  for a period of 22 hours on day 
1 and day 2 every 2 weeks. When prescribing 5-FU, the contra-indications, special warnings and 
interactions, as described in the latest version of the SmPC (1B text), should be observed. When 
prescribing leucovorin, 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. 
 
5.1.2.1 
Chemotherapy doses and timing 
Arm A: 
Concomitant chemotherapy: 
Capecitabine will be given during radiotherapy day 1-33 or 38, also in weekends, in a dose of 
825 mg/m2 bid (twice daily).  
Optional Adjuvant chemotherapy  
Adjuvant chemotherapy with capecitabine and oxaliplatin is allowed to start after the recovery of 
surgery (scheme and dose see Table 2.). Optimal time for start of the adjuvant chemotherapy is 
6-8 weeks after surgery with a maximum of 12 weeks. In total eight cycles will be administrated. 
An alternative option is twelve cycles of FOLFOX4 .  
 
Arm B: 
Neoadjuvant chemotherapy 
Preferably, chemotherapy in the experimental arm 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 until 4 weeks after the last day of radiotherapy. If this is 
not feasible for your patient then please discuss this with the principle investigator of your 
country. 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 6 
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 alternative nine cycles of FOLFOX4 is allowed. 
Oxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1; leucovorin (200 mg/m2) 
administered as a 2-hour infusion on day 1 and day 2; followed by a loading dose of 5-FU (400 

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mg/m2) IV bolus, then 5-FU (600 mg/m2) administered  for a period of 22 hours on day 1 and 
day 2 every 2 weeks. 
 
 
5.1.3 
Dose modification schedules  
These are the same for the concomitant and adjuvant chemotherapy in the standard arm (group 
A) and for the neoadjuvant chemotherapy in the experimental arm (group B). 
Doses that have been reduced for toxicity must never be re-escalated. 
 
5.1.3.1 
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). 
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 

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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). 
 
 
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. 
 
 
5.1.3.2 
5-FU/LV 
The most frequently occurring non-haematologic toxicities are: diarrhoea, nausea/vomiting (not 
requiring anti-emetic prophylaxis), abdominal pain, stomatitis, and anorexia.  
 
Diarrhoea 
Prophylactic treatment: 
No prophylaxis must be given, especially no loperamide should be administered 
prophylactically. 

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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. 
 
 
5-FU/LV 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 4 below). 
 
 
 
Grade 2 
Grade 3 
Grade 4 
1st occurrence Interrupt treatment 
 Until symptom 
recovery to grade 0-1 
 Continue with 100% 
of the 5FU/LV dose 
Interrupt treatment 
 Until symptom recovery 
to grade 0-1 
 Continue with 75% of 
the 5FU/LV dose 
 
Interrupt treatment  
 Until symptom recovery to 
grade 0-1 
 Continue with 50% of the 
5FU/LV dose 
 
2nd 
occurrence 
Interrupt treatment 
 Until symptom 
recovery to grade 0-1  
 Continue with 75% of 
the  5FU/LV dose 
Interrupt treatment 
 Until symptom recovery 
to grade 0-1 
 Continue with 50% of 
the 5FU/LV dose 
 
Discontinue treatment 
 
3rd occurrence Interrupt treatment 
 Until symptom 
recovery to grade 0-1 
 Continue with 50% of 
the 5FU/LV dose 
Discontinue treatment 
 
 
4th occurrence Discontinue treatment 
 
 
 
Table 4. Dose adaptions of 5FU/LV for non-haematological toxicity. 

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5.1.4 
Oxaliplatin 
The most frequently occurring non-hematologic 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 a 50% dose reduction, neurotoxicity does recur,  
oxaliplatin will be discontinued permanently and patients will continue treatment with 
capecitabine. 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 5 below. 
 
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 5. Dose adaptions for oxaliplatin for sensory neuropathy (cycles 1 – 12) 
 
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 [49, 50]. In case such a reaction occurs, 
prophylaxis with steroids ± anti-histamines is indicated. 
 
 

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Dose adaptions for oxaliplatin and capecitabine /5-FU&LV for non-haematological toxicity: see 
Table 6 below. 
Toxicity during previous 
cycle 
Grade 
Next dose 
Oxaliplatin 
Next dose 
Capecitabine/5-FU&LV 
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 6. Dose adjustment relative to the previous cycle for next cycle. 
 
5.1.5 
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. 
 
5.1.6 
Status of haematological toxicity at the start of each treatment cycle. 
Haematological toxicity may be induced by oxaliplatin, and less frequently by capecitabine or 5-
FU.  
Table 7. Dose adaptations for oxaliplatin and capecitabine/5FU&LV 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/5-FU&LV. 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.  
 
5.1.7 
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.  
 
Neutrophils 
(109/l) 
WBC  
(109/l) 
Platelets 
(109/l) 
Next dose 
oxaliplatin 
Next dose 
Capecitabine/5-FU 
 0.5 (grade 4) or 
febrile neutropenia 
< 1.0 (grade 4) 
< 25 (grade 4) 
-25% 
No adjustment 

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5.1.8 
Permanent discontinuation of individual drugs due to toxicity 
If patients experience severe toxicity despite dose reductions which necessitates the 
discontinuation of individual drugs, these patients will remain on study and should be followed 
for progression of disease according to the specified timelines. If neo-adjuvant treatment is 
preliminary discontinued proceed with staging to determine if surgery can be done 
 
5.1.9 
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. 
Trombo-embolic profylaxis 
Trombo-embolic prophylaxis can be used according to local protocols during pre-operative 
treatment, peri-operatively and during adjuvant treatment.  
 
5.1.10 
Other concomitant medication 
All concomitant medication must be documented in the patients’ file at time of randomization, 
and at the end of study treatment or death.  
 
5.2 
Surgery (in Arm A and B) 
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 

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“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. 
 

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6. Clinical evaluation, laboratory tests, follow-
up 
 
6.1 
Before treatment start 
6.1.1 
Eligibility evaluation 
 
The following studies are required upon entry into the study, maximum 5 weeks prior to 
randomisation: 
 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 of thorax, abdomen and pelvis 
 Laboratory tests: haemoglobin, white blood cell count, platelets, bilirubin, ALP, ALAT, 
creatinine, and CEA. 
 MRI of the pelvis (protocol see Appendix G) 
6.1.2 
Obstructing tumours  
Patients who present with obstructing tumours may be candidates for a diverting colostomy 
which can be performed laparoscopically. Randomization will only be performed after treatment 
of clinically significant obstruction. 
 
6.2 
During treatment 
6.2.1 
Standard arm (chemoradiotherapy – surgery (group A) 
6.2.1.1 
Evaluation during chemoradiation 
Toxicity, haematology and ECOG performance status is evaluated weekly. 
6.2.1.2 
Stopping rules due to chemoradiation toxicity. 
See chapter 5.1.3. 
6.2.1.3 
Restaging 
In the standard treatment group (arm A) after finishing the chemoradiotherapy, 2 – 3 weeks prior 
to planned surgery re-staging is performed by CT of thorax, abdomen and pelvis and MRI of the 
pelvis. 
6.2.1.4 
Interval between long-course chemoradiation and surgery 
Surgery should be performed between 6-10 weeks after the last radiation fraction. 

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6.2.1.5 
Stopping rules due to chemotherapy toxicity. 
See chapter 5.3 
6.2.1.6 
Interval between surgery and adjuvant chemotherapy 
The adjuvant chemotherapy is optional according to the local protocol of the participating 
institute. It should start as soon as the patient has recovered from surgery, in practise between 6 – 
8 weeks after surgery, at maximum 12 weeks after surgery. 
6.2.1.7 
Evaluation during adjuvant chemotherapy 
Prior to all cycles (1 to 12) 
 ECOG performance status 
 Haematology 
 Physical examination 
 Biochemistry (Na, K, bilirubin, ALP, ASAT, creatinine) 
 
6.2.2 
Experimental arm (5 x 5 Gy, neo-adjuvant chemotherapy, surgery (group B),  
6.2.2.1 
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 5.1.1.3)  
6.2.2.2 
Evaluation during neo-adjuvant chemotherapy 
Prior to all cycles (1 to 6): 
 ECOG performance status 
 Haematology  
 Physical examination 
 Biochemistry (Na, K, bilirubin, ALP, ASAT, creatinine) 
 
6.2.2.3 
Re-staging  
After the end of chemotherapy (1 – 2 weeks after the last cycle) resectability of the primary 
tumour is evaluated by MRI of the pelvis. Appearance of metastatic disease is evaluated with 
contrast-enhanced multi-detector CT of thorax, abdomen and pelvis, at the end of chemotherapy.  
An MRI of the pelvis is recommended to be performed in the middle of the neo-adjuvant 
chemotherapy (week 12-14) particularly in case there are clinical signs or uncertainties about 
tumour progression.  
6.2.2.4 
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 end (day 21) 
of the last cycle of CAPOX or 2 to 4 weeks after the end (day 14) of the last cycle of FOLFOX4. 

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6.3 
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 or 5-FU/LV 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 2 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 5. 
 
6.4 
Resection and response evaluation 
A multidisciplinary team with a panel of radiologist, rectal surgeons, medical-oncologist and 
radiation-oncologist will evaluate the imaging studies in both groups (A+B) 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) 
In order to have Quality Control before analysis of the primary and secondary endpoints MRI’s 
have to be collected and evaluated after inclusion of all patients.  Response of target lesions will 
be scored by a selected board of radiologists. These assessments will be done according the 
criteria in Appendix G): 
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 
to qualify for CR, each node must achieve a short axis <10mm. For PR, SD and PD, the actual 
short axis should be given. 
 

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6.5 
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) 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 5th edition of TNM will be used in this study, again according 
to Dutch and European guidelines for rectal cancer [53, 54]. In addition, an evaluation of the 
involvement of circumferential resection margins (CRM) [55], quality of surgery by photo [56-
58] and tumour regression must be done. A circumferential margin of 1 mm or less for tumour or 
lymph node 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).  
6.5.1 
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 
 
6.5.2 
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). 

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6.6 
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 6, 12, 24 and 36 and 60 months after date 
surgery, physical examination, ECOG performance score, symptoms according to CTC (see case 
record forms) and CEA will be done. 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). Quality of Life assessment should be done at 3 years  after surgery. If more intense 
follow-up is routinely done, outcomes of these assessments are to be reported. On indication 
other diagnostic or imaging techniques (MRI, FDG-PET, colonoscopy, endoluminal ultrasound) 
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 time of 
randomization. Hereby disease related treatment failure (DrTF ). can be calculated (see also 
chapter 7). 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 routinely done. 
6.6.1 
Requirements for Follow-Up 
 
Months since date of surgery 
 
6 
12 
24 
36 
48 
60 
90 
120 
 
History, incl. morbidity assessment 
X 
X 
X 
X 
(X) 
X 
 
 
Physical Examination 
X 
X 
X 
X 
(X) 
X 
 
 
QoL Assessments and LARS score  
 
 
 
X 
 
 
 
 
CEA 
X 
X 
X 
X 
(X) 
X 
 
 
X-thorax & US-liver or CT thorax-abdomen 
 
X 
 
X 
 
 
 
 
Colonoscopy 
 
 
 
 
 
X 
 
 
Survival and Recurrence 
X 
X 
X 
X 
(X) 
X 
X* 
X* 
*Data-collection only, no additional trial visit.   
Table 8: follow-up scheme. More intense follow-up is allowed if this is routinely done. 
6.6.2 
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. 
 Liver metastases on Ultrasound and/or (PET)CT. 
 Lung metastases on X-ray and/or (PET)CT or MRI. 
 Bone metastases on X-ray and/or bone-scintigraphy and/or MRI 
 Brain metastases on MRI 
 Distant lymph node metastases 
Pelvic pathology on PET/CT, PET/MRI or MRI of the pelvis combined with increased CEA 
levels together consistent with local recurrence 
Parameters for Recurrent Disease: 
The following parameters will be recorded and studied:  
 Loco-regional recurrence site and date (local within the pelvis). 

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 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. 

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6.7 
Treatment Summary table  
6.7.1 
Standard arm (group A) 

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6.7.2. Experimental arm (group B) 

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7. Criteria of evaluation 
 
7.1 
Definitions 
Disease related treatment failure (DrTF ) will be computed as the time between randomization 
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. See also the table depicted in Chapter 3. Patients lost to follow-up will be censored the 
last date of patient visit.  Follow-up is described in Chapter 6.  
7.1.1 
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 6. See also 
Appendix D. 
7.1.2 
Fraction of radical resection (CRM > 1 mm) 
Negative CRM will be evaluated according the pathology protocol described by Quirke et al. 
(see also chapter 6 and appendix C) 
7.1.3 
Complete pathological response (pCR). 
pCR evaluation is done by the method described in section 6. 
7.1.4 
Local recurrence 
Local recurrence is described as relapse of tumour in the pelvic region. This will be assessed by 
clinical investigation and imaging studies as described in chapter 6. 
7.1.5 
Distant relapse  
Distant relapse is described as relapse of tumour outside the pelvic region. This will be assessed 
by clinical investigation and imaging studies as described in chapter 6. Special attention has to 
made on the liver and lung since these are the predominant side of metastases. 
7.1.6 
Local control 
Local control will be computed as the time between randomization and local relapse. If the 
primary tumour can not 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. 
7.1.7 
Overall survival 
Overall survival will be computed as the time between randomization and colorectal cancer or 
treatment related 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. See table depicted in Chapter 3.Follow-up is described in Chapter 6.  

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7.1.8 
Quality of Life (QoL) 
Quality of life including functional outcome will be studied as described in Chapter 8. 
 
7.2 
Statistical considerations 
7.2.1 
Sample size 
The hypothesis is that the new treatment (arm B) decreases Disease related Treatment Failure 
(DrTF) after 3 years of follow-up from 30 to 22.5%. This difference of 7.5% in DrTF after 3 
years corresponds to a hazard ratio of 0.715. 
A two-sided logrank test with a total of 280 DrTF events achieves 80% power at  = 0.05 
significance level to detect a hazard ratio of 0.715 when the proportion of patients with a DrTF 
event in the control group is 30%. The original power calculation was based on four years of 
uniform accrual and two years of additional follow-up after the last patient has been included 
(six years total), a total of 842 evaluable patients will be required to achieve 452 DrTF events. 
With a drop-out of 5% the total number of patients to be included was anticipated to be 885, or 
up to 920 if needed to have 421 evaluable patients per arm. However, due to much lower event 
rates than anticipated, and due to the fact that follow-up collection for the majority of patients 
was limited to five years after surgery, event projections showed that this number would never 
be reached. This led to the decision to amend the protocol and lower the event rates in the 
calculation of number of events required. At the time of writing of this amendment, with a 
median follow-up of 3.5 years, 267 DrTF events were observed, and 280 DrTF events seems 
feasible.  
7.2.2 
Randomization and stratification 
Randomization will be performed stratifying by institution, performance score 0 or 1, clinical T 
stage (cT2-T3 or cT4), clinical N stage (cN- or cN+). 
7.2.3 
Statistical analyses 
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. 
Curves for disease related treatment failure and overall survival will be constructed using the 
method of Kaplan and  Meier. Cumulative incidence of local recurrence will be computed 
accounting for death as competing risk. Differences in survival 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). 
All proportions will be presented with 95% CI. 

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7.3 
Interim Analyses 
One efficacy interim analysis has been performed in October 2017 after 244 DFS events and 215 
DrTF events, The interim analyses was performed with a nominal alpha level of 0.008, based on 
O’Brien-Fleming boundary, anticipating a second interim analysis. The second interim analysis 
will be omitted, and only the final analysis will be performed at a nominal alpha level of 0.0424. 
The interim analysis was conducted by a team external to the sponsor project team and the 
results were reviewed by the external independent data monitoring committee (DSMB). The 
interim analysis included the primary efficacy endpoint as well as key safety parameters, 
including radiotherapy and chemotherapy induced toxicity, negative CRM, mortality during 
treatment, recurrent disease after radical resection. The DSMB concluded that there was no 
urgency at that time to release the data on the primary efficacy endpoint. The data need to 
mature.  
 
7.4 
Data safety monitoring committee (DSMB) 
A data safety monitoring board (DSMB) has been appointed by the study coordinators and is 
composed of experts in the field of medical oncology, surgery, radiotherapy, biostatistics, 
epidemiology and medical ethics. The DSMB has been established at the onset of the trial and 
acts independent of the trial organizers and participating investigators. A DSMB charter is 
available. 

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8. Quality of life assessment 
 
8.1 
Rationale 
Rectal cancer negatively impacts patients’ quality of life. In curative treatment, major surgery 
has to be performed. Consequently, post-operatively, physical and mental well-being are 
affected, in particular bowel function, sexual function and body image. Moreover, pre-operative 
chemotherapy has an impact due to toxic side-effects. Since patients in the experimental arm in 
the current study will receive chemotherapy preoperatively, insight is needed into the impact on 
quality of life as compared to patients in the standard arm that receive chemoradiotherapy only. 
In the experimental arm no adjuvant chemotherapy is given so quality of life may be different 
compared to the standard arm in which adjuvant chemotherapy is optionally given after recovery 
from surgery. 
Several quality of life issues are considered relevant: late effects, psychological domains, 
colorectal cancer related items. 
 
8.2 
QL questionnaires 
The following questionnaires developed by the European Organization for Research and 
Treatment of Cancer (EORTC) will be used (see also Appendix H):  
QLQ-C30: to assess cancer specific but generic aspects of quality of life  
QLQ-CR29: the colorectal module to assess the quality of life and the functional outcome. To 
optimally evaluate the sexual functioning, for male patients questions 56 and 57 from QLQ CR-
29 have been replaced by questions 50 to 55 from QLQ PR-25, whereas for female patients 
questions 58 and 59 from QLQ CR-29 have been replaced by questions 49 to 54 from QLQ EN-
24. 
QLQ-CIPN20: the module to assess the chemotherapy induced peripheral neuropathy [64] 
LARS score: a validated questionnaire consisting of 5 questions and evaluating the low anterior 
resection syndrome [65] [66] 
 
8.3 
Study design 
Timing of assessments;  
 3 years after surgery 
Questionnaires have to be given to the patient by the treating physician or staff member. The 
local center will call patients if questionnaires are not returned within two weeks. They will send 
the questionnaires to the Datacenter in Leiden.  

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8.4 
Statistical considerations 
All patients included still alive and disease free will be asked to complete the quality of life 
questionnaires 3,5 years after randomisation. 
Descriptive analyses will be performed to describe the study population. Chi-square tests and 
unpaired t-tests will be computed to compare relevant sociodemographic and illness related 
variables of those who agree to participate with those who decline participation.. Effect sizes will 
be computed to examine clinical relevance of change and of between group differences.  
Additionally, a difference of 5-10 points on an EORTC QoL functional subscale is considered to 
be a small clinically meaningful difference, a difference of 10-20 points is considered to be a 
moderate clinically meaningful difference and a difference of >20 points is considered to be a 
large clinically meaningful difference [59]. 
Univariate and multivariate analyses will be performed to examine relationships between QoL 
and the sociodemographic and illness related variables.  

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9. 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: 
 
Tumour biopsy (at time of colonoscopy), and directly after surgical resection of the 
rectum, stored at -80˚C. At the time of inclusion, the buffy coat will be collected and frozen 
separetely. 
 
Two blood samples at two time points, collected by venapunction in 10 ml EDTA tubes. 
One 10 ml EDTA tube with fresh whole blood should be aliquoted in four to five 2.0 ml 
Eppendorf tubes. If this is not feasible, whole blood can be stored in two 5 ml EDTA tubes. The 
second 10 ml EDTA tube should be centrifuged at 1500 x g for 10 minutes at 4˚ C within 10 
minutes after collection. Blood plasma will be aliquoted in 2 Eppendorf tubes. All Eppendorf 
tubes should be marked with a waterproof pen (study number, center number, patients code, date 
of birth (day/month/year), sample date and sample description (t=0 before radiotherapy; t=1 
before operation)) and stored at -20 or -80˚ C directly (see appendix K).   
Control arm (group A):  
 2 Blood samples may be collected at the following moments during treatment:  
 at time of inclusion, before the start of chemoradiation therapy  
 before surgical resection  
 
Experimental arm (group B):  
 2 Blood samples may be collected at the following moments during treatment:  
 at time of inclusion, before the start of radiation therapy  
 before surgical resection  
 
 It is up to each participating center to decide if they will participate in the translational 
research side study, but this is highly recommended after the patient has given informed consent.  
 

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10. Investigator authorization procedure 
 
This study is designed to be carried out in multiple centres in the Netherlands and Sweden. The 
study concept was conceived at the University Medical Center Groningen (UMCG) and the 
Leiden University Medical Centre from the Netherlands, the Uppsala University, Uppsala and 
the Karolinska Institutet in Stockholm from Sweden. Other centers, also from other countries, 
may enter the study based on consensus between investigators. Approval from the UMCG 
central medical ethical committee will serve as basis for medical ethical approval in other 
institutions, according to Dutch law and national laws is other countries.  
 

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11. Patient registration / randomization 
procedure 
 
11.1 
Randomization 
Patient randomization will only be allowed from authorized investigators, their authorized staff members 
or data manager. A patient can be randomized only after verification of eligibility. Randomization can be 
performed by the LUMC Datacenter Surgery, the Central Datacenter or online through the ProMISe 
randomization programme. 
 
11.1.1 
Randomization by facsimile, email or phone 
Randomization can be done by facsimile +31-71-526 6744, email datacenter@lumc.nl or telephone +31 
71 526 3500; Monday-Friday; 9:00-17:00. 
During the randomization procedure eligibility criteria will be checked. E-mails with the answered 
questions, the allocated treatment and the patient number will be automatically sent to the local team and 
the person responsible for CRF completion. 
After randomization, a sequential identification number will be applied. This number has to be recorded 
on the randomization form, along with the randomization date. The randomization form must be signed 
by the investigator (in case of faxed and mailed randomization, the confirmation of the data manager also 
has to be signed by the investigator) and filed with the CRFs. 
 
11.1.2 
Online randomization 
Randomization can also be performed online 24 hours per day through the ProMISe randomization 
programme. Go to:  
www.clinicalresearch.nl/PROMISE/S/HEIT/S_O_LUMC_C_HEELK_RAPIDO_/LOGON/INDEX.
HEI  
Investigators or comprehensive cancer centers can apply to the Central Datacenter for a username and 
password. E-mails with the answered questions, the allocated treatment and the patient number will be 
automatically sent to the local team and the person responsible for CRF completion.  
 
Datacenter details: 
LUMC Datacenter   
Ms Annet Roodvoets or Ms Elma Meershoek - Klein Kranenbarg  
Leiden University Medical Center 
Datacenter, Department of Surgery, K6-R 
P.O. Box 9600 
2300 RC  LEIDEN, the Netherlands 
phone +31-71-526 3500 
fax: 
+31-71-526 6744 
e-mail: datacenter@lumc.nl 

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12. Forms and procedures for collecting data 
 
The case record forms (CRF’s) for this study are available on paper and electronically. They are 
divided in different numbered sections. All CRF’s are identified by the patients 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.  
12.1 
Case report forms 
 F01 Randomization Form 
 F02 History and Staging  Form  
 F03 Baseline Radiology Form 
 F04 Radiotherapy Form for both groups  
 F05a Pre-operative Chemotherapy Form standard group (Arm A) 
 F05b Pre-operative CAPOX Form experimental group (Arm B) 
 F05c Post-operative CAPOX Form standard group (Arm A) 
 F05d Pre-operative FOLFOX  Form experimental group (Arm B) 
 F05e Post-operative FOLFOX Form standard group (Arm A) 
 F06 Restaging Radiology Form  
 F07 Surgery Form 
 F08 Post-surgery Form 
 F09 Pathology Form 
 F11 Follow-up Form  
 F12a Locoregional Recurrence Form 
 F12b Distant Recurrence Form 
 F12c New Primary Tumour Form  
 F13 End of Pre-operative Treatment Form  
 F14 Off Study Form 
 F20 Death Form  
 F30 Adverse Events Form 
 F40 Serious Adverse Event Form 
 F50 Comment Form 
 
The central data center will collect all CRFs and questionnaires and when applicable complete 
the form as much as possible. 

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12.2 
Data flow 
Paper CRFs may be filled in by treating physicians or data managers at all participating centers 
and departments. Data of completed and submitted paper CRFs will also be entered in the same 
database. The system will automatically generate queries, which will be sent to the person 
responsible for CRF completion. It is not possible to relate the data entered in the database to a 
specific patient. A copy of the paper CRFs will be kept in the patient file and a copy will be sent 
to the Datacenter. Missing or due forms will be identified using the database system. In this case, 
the responsible physician, investigator, nurse or data manager will be contacted by the study 
coordinators or data managers from the central datacenter. 
 

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13. Reporting adverse events 
  
13.1 
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. 
 
13.2 
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) 
- 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. All 
adverse events reported spontaneously by the subject or observed by the investigator or his staff 
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. 
The Datacenter will report SAEs through the web portal ToetsingOnline to the accredited METC 
that approved the protocol, within 15 days after the sponsor has first knowledge of the serious 
adverse reactions. 
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 Datacenter 
by fax: +31-71-5266744 or email: datacenter@lumc.nl as soon as possible but no later than 
one working day. The datacenter will inform the international trial coordinators Prof Dr G.A.P. 
Hospers, Dr D.J.A. de Groot, Dr. W.H. Kapiteijn, Dr B. van Etten and the national trial 
coordinators. The datacenter will also inform the Medical Ethics Committee(s) and the 
Competent Authority as described in the previous section.  

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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 
follow-up SAE form. SAEs occurring within 30 days after discontinuation of the study treatment 
should be reported. 
 
13.3 
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 
product).  
The Datacenter will report expedited the following SUSARs for Dutch participants through the 
web portal ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects involved in 
the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once 
every half year to the METC. This line-listing provides an overview of all SUSARs from the 
study medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as 
notification to the competent authority. 
The Datacenter will report expedited all SUSARs to the national principal investigators in other 
Member States. The national principal investigators will report expedited all SUSARs to the 
competent authorities, according to the requirements of the Member States.  
The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of 
the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a 
preliminary report with another 8 days for completion of the report.  
 
13.4 
Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
Medicine Evaluation Board and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ system, per 
study; 
- a report concerning the safety of the subjects, consisting of a complete safety analysis and an 
evaluation of the balance between the efficacy and the harmfulness of the medicine under 
investigation. 
 

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13.5 
 
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. 
 
13.6 
Data Safety Monitoring Board (DSMB) 
A DSMB is established to perform ongoing safety surveillance and to evaluate interim analyses 
on the safety data. This committee is independent of the conducted trial. The DSMB is composed 
by a president, secretary and three independent members, of whom at least one is a statician. The 
members of the DSMB are independent and have no conflicts of interest with the conducted trial, 
principal investigator or sponsor of the study. 
Interim analyses are performed according to chapter 7. Accumulating data is reviewed, including 
updated figures on recruitment, data quality, primary outcome and safety data. The interim-
analysis will be performed by an independent statistician. The statistician will report to the 
independent DSMB. The DSMB will discuss the results of the interim-analysis and advice the 
steering committee. Discontinuation of the trial is advised by the DSMB according to the pre-
defined stopping guidelines stated in paragraph 7.3.  

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14. Quality assurance 
 
14.1 
Control of data consistency 
Data for this study will be recorded using Case Report Forms CRF. It will be transcribed by the 
site from the source documents onto the CRF. In no case is the CRF to be considered as source 
data for this trial. Accurate and reliable data collection will be assured by verification and cross–
check of the CRFs against the investigator’s records by the study monitor (source document 
verification). 
Central data management will be performed by LUMC Datacenter 
The data managers will verify the data and discrepancy reports will be generated accordingly for 
resolution by the investigator / local data manager. 
 
14.2 
On-site quality control  
A monitoring committee will be appointed which will perform onsite monitoring two  months 
after the first patient in the experimental arm underwent surgery and when the first three patients 
who ended the study are two months post surgery. To ensure quality of data, study integrity, and 
compliance with the protocol and the various applicable regulations and guidelines, the 
“Sponsor” may conduct site visits to institutions participating to protocols.   
When necessary regular visits by research nurses, data managers of the regional cancer center or 
monitoring committee members will be organized. 
 
14.3 
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. 
 
14.4 
Central review of pathology 
In order to optimize pathology quality, central 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  
 
14.5 
Central review of radiology 
In order to optimize pre-operative staging and restaging, central 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. 

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15. Ethical considerations 
 
15.1 
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 
(ref: 
http://www.ifpma.org/pdfifpma/e6.pdf). 
The protocol will be approved by the Local, Regional or National Ethics Committees. 
 
15.2 
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 
center, 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 .  
 
15.3 
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, and the mechanism of treatment 
allocation. 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. An example of a patient informed consent statement is given as an 
appendix to this protocol. 
It is the responsibility of the individual investigator to translate the enclosed informed consent 
document. The translated version should be dated and version controlled.  
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 or randomized 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”. 
 

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16. Trial sponsorship and financing 
The trial is supported by the DCCG (Dutch Colorectal Cancer Group, www.dccg.nl) and by the 
NGTTG (Nordic Gastrointestinal Tumour Trial Group). Data management is financed by the 
Dutch and Swedish cancer societies.  
 
 
17. Trial insurance 
In accordance with the Dutch W.M.O. insurance coverage for all participating patients from all 
centers, has to be arranged. A participating hospital has to arrange the insurance coverage for all 
patients participating at this center. 
 
 
18. 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. Members of the writing committee and central datacenter and investigators from centers 
who have entered the top 8 of included patients qualify for co-authorship. The others qualify for 
acknowledgements. 
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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19. References 
 
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38. Mawdsley, S., et al., Can histopathologic assessment of circumferential margin after 
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50. Santini, D., et al., Idiosyncratic reaction after oxaliplatin infusion. Ann Oncol, 2001. 12(1): p. 
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51. Stahl, M., W. Koster, and H. Wilke, Reaction after oxaliplatin--prevention with 
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operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG 
CO16 randomised clinical trial. Lancet, 2009. 373(9666): p. 821-8. 

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57. Nagtegaal, I.D., et al., Low rectal cancer: a call for a change of approach in 
abdominoperineal resection. J Clin Oncol, 2005. 23(36): p. 9257-64. 
58. Nagtegaal, I.D., et al., Macroscopic evaluation of rectal cancer resection specimen: clinical 
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(modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III 
colorectal cancer BMC Cancer. 2015 May 10;15:384.  

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Appendix A - TNM- Classification of Rectal 
Cancer 
 
TNM 5th edition. Sobin and Wittekind, 1997 is used in the Netherlands and will be used in this 
study 
TNM 7th edition 2011, is used in Sweden 
 
TNM 5th edition: 
Primary tumour (T) 
T0:  
No evidence of primary tumour 
Tis:  
Carcinoma in situ: intraepithelial or invasion of the lamina propria* 
T1:  
Tumour invades submucosa 
T2:  
Tumour invades muscularis propria 
T3:  
Tumour invades through the muscularis propria into the subserosa, or into  
 
 
nonperitonealized pericolic or perirectal tissues 
T4:  
Tumour directly invades other organs or structures, and/or perforates visceral 
 
 
peritoneum**,*** 
 
* Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) 
orlamina propria (intramucosal) with no extension through the muscularis mucosae into the 
submucosa. 
** Direct invasion in T4 includes invasion of other segments of the colorectum by way of the 
serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.  
*** 
Tumour that is adherent to other organs or structures, macroscopically, is classified T4. 
However, if no tumour is present in the adhesion, microscopically, the classification should be 
pT3.  
Regional Lymph Nodes (N) 
 
N0:  
No regional lymph node metastasis 
 
N1:  
Metastasis in 1 to 3 regional lymph nodes 
 
N2:  
Metastasis in 4 or more regional lymph node 
 
A tumour nodule greater than 3 mm in diameter in the pericolorectal adipose tissue of a primary 
carcinoma without histologic evidence of a residual node in the nodule is classified in the pN 
category as a regional lymph node metastasis. 
 
Distant metastasis (M) 
 
M0:  
No distant metastasis 
 
M1:  
Distant metastasis 
 

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STAGE GROUPING 
 
AJCC/UICC  
 
 
 
 
Stage 0 
Tis 
N0 
M0 
 
 
 
Stage I  
T1 
N0 
M0 
 
 
 
 
 
T2 
N0 
M0 
 
 
Stage II 
T3 
N0 
M0 
 
 
 
 
 
T4 
N0 
M0 
 
 
Stage III 
any T N1 
M0 
 
 
 
 
 
anyT N2 
M0 
 
 
Stage IV 
anyT anyN M1 
 
 
 

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Appendix B - ECOG Performance Status 
 
 
Grade 
ECOG 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
 
5 
Dead 
 
 
Reference: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982 
 
 

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Appendix C – Pathology protocol 
 
Guidelines for the Dissection Method: (based on Nagtegaal ID, Quirke P. What is the role for 
the circumferential margin in the modern treatment of rectal cancer. J Clin Oncol 2008, 26(2): 
303-312). 
 
The unopened resected specimen is received fresh, carefully inspected for lacerations both of the 
peritoneal and the non-peritoneal covered surface. The plane of resection should be determined 
in order to grade the quality of the resection specimen and the specimen should be photographed 
before inking and opening the specimen. Subsequently, the specimen should be opened 
anteriorly except in the area of the tumour where the full circumference of the bowel should be 
left intact. This allows the adequate examination of the bowel wall for circumferential margin 
involvement as well as peritoneal involvement. The specimen should be pinned under gentle 
tension to a cork board and fixed by immersion in formalin for at least 48 hours. If possible, 
tissue should be inserted in the unopened bowel to improve fixation of the tumour. After 
fixation, the peritoneal reflection is identified and the relative position of the tumour noted i.e. 
below, partially covered by peritoneum or totally covered by peritoneum. Areas covered by 
peritoneum are inspected for serosal penetration and if apparent are sampled separately. Tumours 
completely covered by peritoneum are handled in the routine manner for colonic specimens, 
whereas those with a retroperitoneal component are subjected to close scrutiny for 
circumferential margin involvement by tumour. Before slicing the specimen, the CRM should be 
inked. The site of the tumour is sliced as thinly as possible (approximately 0.3 - 0.5 cm) 
including up to 2 cm above and below, and laid out on a flat surface for macroscopic inspection. 
Slides are photographed, with special emphasis on deepest levels of tumour invasion and the 
circumferential margin (CRM). Again the plane of resection should be evaluated and compared 
with the earlier score. 
The extent of tumour involvement of the perirectal tissue is assessed with particular attention 
being paid to the circumferential resection margin. The maximum extent of tumour spread from 
the outer limit of the muscularis propria is measured using a ruler. This should be to the edge of 
tumour's greatest distance of penetration from the muscular wall, be it direct, discontinuous, 
vascular or lymph node involvement. Area(s) of involvement can usually be seen with the naked 
eye and any suspicious area or areas should be sampled for histology. One block should be 
sufficient, but up to six might need to be taken in cases with extensive spread before it is possible 
to be certain that all the margins are free of tumour. On average four blocks will suffice for the 
majority of tumours. 
Whilst incising the mesentery and the mesorectum, lymph nodes and tumour deposits should be 
identified and sampled. Metastases and lymph nodes adjacent to the circumferential margin 
should be sampled "en-bloc" with the resection margin. 
Lymph nodes further than 1 cm from the circumferential resection margin or present in the 
mesentery of the sigmoid colon may be sampled in a routine fashion. The distal resection margin 
should be sampled (and can be used as a background “normal mucosa” in most cases).Accurate 
measurement of the minimum distance between tumour or involved lymph node and 
circumferential resection margin should be performed by microscopy on the haematoxylin and 
eosin stained slide using a scale on the microscope stage. Shrinkage of tissue occurs during 
processing but this does not materially affect the accuracy of this measurement. Assessment by 
microscopy is preferred as a florid peri-tumoural inflammatory reaction or fibrosis will lead to an 
overestimate of macroscopic tumour spread. 
 
 
 
 

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Schematic representation of the circumferential margin. A. Circumferential growing tumour with 
lymph node metastasis, in one part of the figure the tumour approaches the inked resection 
margin. The positive lymph node is nearer to the inked margin, and should be mentioned 
separately. B. Tumour growing into the inked resection margin. Note that only the mesorectal 
surface is inked, not the visceral peritoneum. The tumour is apparently located in the 
rectosigmoid area. 
When a positive lymph node is closer to the circumferential margin than the tumour itself, the 
margin between the positive node and the CRM should be registered in addition to the margin 
between the tumour and the CRM (see above figure). 
If the circumferential margin is between 1 and 2 mm, deeper levels should be cut to exclude 
margin involvement. 
 
Evaluation of quality of the resection and tumour response: 
The quality of resection is evaluated at two different levels for APRs (mesorectum as well as 
anal canal) and at one level for LAR (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. 

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 
Intramuscular/submucosal plane: This plane has perforation or missing areas of 
muscularis propria indicating entry into the muscular tube at this level 
 
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 µm). 
 
TME procedure 
Paraffin embedded tissue block of the tumour will be collected  from both the preoperative 
biopsy and the resection specimen by the datacenter in Leiden at certain time points during the 
trial. When sufficient material is available, two or three cores will be taken to make a Tissue 
Micro Array (TMA). The TMAs will be made by the pathology department in Nijmegen, the 
Netherlands. 
Briefly, a section of tissue will be stained using haematoxylin & eosin (H&E) to identify areas of 
tumour. Three tumour areas will be selected and 0.6 or 2 mm2 cores of tumour tissue will be 
removed in total from each block. These cores of tumour tissue will be transferred to recipient 
blocks (multiple cores per block) to form tissue TMAs. From each tissue array up to 100 4 m 
sections will be taken for analysis of biomarkers.  
In addition, up to 20 serial 4 m tissue sections will be taken for evaluation of additional factors 
and DNA extraction. 
 
Contact details pathology review: 
Prof. Dr.  I.D. Nagtegaal, study coordinator, pathology RAPIDO 
+31 24-3610229 
UMC St Radboud 
Afdeling pathologie 824 
Postbus 9101 
6500 HB Nijmegen, The Netherlands 

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References: 
Nagtegaal, I.D. and P. Quirke, What is the role for the circumferential margin in the modern treatment of rectal 
cancer? J Clin Oncol, 2008. 26(2): p. 303-12. 
Quirke, P., et al., Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: 
a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. 
Lancet, 2009. 373(9666): p. 821-8. 
Nagtegaal, I.D., et al., Low rectal cancer: a call for a change of approach in abdominoperineal resection. J Clin 
Oncol, 2005. 23(36): p. 9257-64. 
Nagtegaal, I.D., et al., Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the 
pathologist in quality control. J Clin Oncol, 2002. 20(7): p. 1729-34. 
Take multiple sections (100-300) from the tissue array block containing 100-500 tumours per 
section 
Use for IHC, etc 
Remove tumour tissue from the 
donor block by 2-3 core (0.6 mm) 
biopsies
Transfer 2-3 cores to 2-3 new 
recipient blocks 

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Appendix D – CTCAE V4 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES 
National Institutes of Health 
National Cancer Institute 
See website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 

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Appendix E - English Patient Information and 
Informed Consent  RAPIDO TRIAL (with CAPOX) 
 
 
A study investigating the difference in effect of short term radiotherapy and 
chemotherapy followed by surgery compared to standard treatment of high risk rectal 
cancer. 
 
Original title in English: Randomised Multicentre Phase III study of short course 
radiation therapy followed by prolonged pre-operative chemotherapy and surgery in 
primary high risk rectal cancer compared to standard chemoradiotherapy and surgery 
and optional adjuvant chemotherapy 
 
 
 
You have been asked to participate in a medical research study on new treatment for 
high risk rectal cancer. The following written information is intended as an addition to 
the information you have already received from your doctor in attendance. If, however, 
this information is unclear or insufficient you can always request additional information. 
Discuss the information with your partner, family, friends, or doctor/general practitioner. 
There is also the possibility to consult an impartial person, the details of which will be 
provided in this document. This person is knowledgeable on the research matter though 
is not in any way involved in the research. You will be given at least 2 days and up to 
one week, to consider your participation. 
This international study is initiated by University Medical Center Groningen (UMCG) in 
the Netherlands. The study will be performed according to national and international 
rules and laws.  
 
 
 
Background of this study 
Surgery is the most important type of treatment of cancer of the rectum. In some 
patients with high risk rectal cancer it is not possible to remove the whole tumour during 
surgery. Additional treatments both before and after the operation are applied as an 
attempt to reduce the chance of recurrence of the disease and thus increase the chance 
of cure. To this end, various kinds of chemotherapy (cell-killing drugs) and radiotherapy 
(radiation) have been applied in the past. 
 

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Current standard treatment consists of long term (5 to 6 weeks) radiotherapy combined 
with chemotherapy before surgery (also called neoadjuvant chemoradiotherapy). This 
neoadjuvant chemoradiotherapy is mainly aimed to prevent your cancer of the rectum 
from returning in the area around the tumour (this is called a local recurrence)., 
Neoadjuvant chemoradiotherapy does not adequately treat micro metastases that may 
be present at the time of surgery in places far from the rectum such as in the liver or 
lungs.. If cancer grows in places like the liver or lungs after surgery, this is known as a  
distant recurrence. Treatment with chemotherapy immediately after surgery may not 
adequately avoid or prevent distant recurrent disease. Possibly this is because many 
patients are not fit enough to start chemotherapy in time or not at all, after recovering 
from relatively tough surgery.  
In this study we hope to test a new experimental treatment to see if it is more effective 
than standard treatment in decreasing the risk of local and distant recurrence. In the 
experimental arm of the study, prior to surgery, we will give short term radiotherapy (5 
days), after which the size of the rectal tumour often decreases. During this waiting time 
before surgery  we will  give chemotherapy to treat possible micro metastases and to 
possibly decrease the risk of distant recurrence.. We will comparethis experimental 
treatment to the standard treatment of neoadjuvant chemotherapy (6 weeks) and then 
surgery. According to the opinion of the doctors in your local hospital post-operative 
chemotherapy can also be given. In your hospital post-operative chemotherapy <is / is 
not> standard treatment. 
 
 
Object of this study 
The aim of this study is to find out whether the experimental treatment can be tolerated 
better by the patients and has at least the same effect on survival as the standard 
treatment. To be able to judge the effect of the treatment, all patients will be followed up 
for three years to assess recurrence of disease. Results of patients with experimental 
and standard treatment will be compared. In order to avoid the investigators being 
influenced with regard to their choice in favour of one of the treatment types, the 
participants will be divided into two equal groups randomly. It is a matter of chance to 
which group you are assigned. This ensures that both patient and doctor are not able to 
influence the treatment choice.   
 
Chemotherapy consists of two types of drugs; capecitabine tablets (Xeloda) and 
oxaliplatin (Eloxatin) which is given by infusion. Both drugs have been evaluated 
positively on efficacy and safety by International and National Health Authorities. 
About 920 patients from Sweden, the Netherlands, Spain, Slovenia, Norway,  Denmark, 
USA and Canada . 
 
 
What does the research involve? 
Standard treatment: 
 Pre-operative chemoradiotherapy: 25 to 28 radiations will be given in a period of 
5 to 6 weeks. Simultaneously twice daily tablets of capecitabine have to be 
ingested. 
 8±2 weeks after the last radiation the rectum tumour will be removed during 
surgery. 

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 (depending on local policy) 6-8 weeks after the operation 8 cycles of post-
operative chemotherapy will be given. In each cycle of 3 weeks, a course 
consisting of infusion with oxaliplatin will be given on day 1. During the first two 
weeks of each course, you must take capecitabine tablets twice daily; but not 
during the third week (“free week”). 
 
Experimental treatment: 
 Radiation will be given during 5 workings days of a week. 
 11 to 25 days after last radiation, 6 cycles of pre-operative chemotherapy will be 
given. In each cycle of 3 weeks, a course consisting of infusion with oxaliplatin 
will be given on day 1. During the first two weeks of each course, you must take 
capecitabine tablets twice daily; but not during the third week (“free week”). 
 2-4 weeks after the last chemotherapy, the rectum tumour will be removed during 
surgery. 
 
 
 
Content of the study 
Prior to the start of the treatment you will be asked to sign for informed consent. During 
the screening several examinations will be carried out and visits to the involved 
specialists will take place to conclude whether you meet with all criteria to participate in 
this study. If not, participation in this study is not possible, your doctor will discuss other 
treatment options with you. The study looks like this: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
Screening 
Rando 
misation 
Radiotherapy + 
Chemotherapy 
(capecitabine, 
daily) 
5-6 weeks 
Surgery 
(optional) Chemotherapy 
capecitabine + oxaliplatin  
8 cycles 24 weeks 
Radiotherapy   
1 week 
Chemotherapy 
capecitabine + 
oxaliplatin  
6 cycles 18 weeks 
Surgery 
8±2 
weeks 
6-8 
weeks 
2-4 
weeks 
11-19 
days 
STANDARD TREATMENT 
EXPERIMENTAL TREATMENT 
or 

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Participating in a study often means extra tests and extra visits to the hospital. That is 
not the case in this study. Before surgery you will need to visit the hospital and /or 
radiotherapy center about 25 times in 14 weeks time (standard); in case of the 
experimental treatment this is about 12 times during a period of about 22 weeks. So the 
experimental treatment means that you will need to make fewer visits, but the time till 
surgery takes longer. Both study groups will be asked to fill out quality of life 
questionnaires three years after surgery, this will take you about fifteen minutes. If this 
is standard treatment in your hospital, patients in standard treatment group will receive 
8 cycles of chemotherapy (8 visits in 24 weeks) after surgery. 
 
Screening: 
 Medical history, concomitant medication and medical complaints 
 Physical examination 
 Rectoscopy and / or colonoscopy. A biopsy of the tumour might be taken 
 If significant for the study an X-ray of the colon will be taken 
 CT of lungs, abdomen and pelvis and a MRI of the pelvis will be performed to 
examine size and spread of the tumour. 
 
Each visit (screening, treatments and follow up) 
 Discussion of complaints 
 Blood samples for testing general health condition and effects of study treatment 
(about 10 ml per visit).   
 
Periodically (during and after treatment) 
 Physical examination (2-4 times) 
 CT of lungs, abdomen and pelvis (twice) and a MRI of the pelvis (2-3 times) will 
be performed to examine size and spread of the tumour. 
 
After surgery: 
 After the operation you will be followed up for at least five years. Follow-up visits 
will take place at 6, 12, 24, 36 and 60 months after surgery. Periodically blood 
samples and examinations will be performed. 
 3 Years after the operation questionnaires  to assess your quality of life.  
 
 
 
What do we expect from you? 
 Swallow the capecitabine tablets as prescribed. Do not take any drugs without 
consulting your doctor 
 Inform your doctor or his study personnel of any health changes or if you 
consider quitting study participation. 
 Report to your doctor or his personnel if you have a fever (temperature of 38,5 oC 
or more) or if you suffer from diarrhoea or vomiting. 
 
 
 

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Potential advantages and disadvantages of participation  
All drugs can cause side-effects, this also counts for capecitabine and oxaliplatin.  
Capecitabine: The side effects of capecitabine have been extensively described: 
nausea, (rarely) painful damage to the mucosa in the mouth (mucositis) or bowels, 
resulting in diarrhoea, and redness and pain in the skin of hands and feet (the hand-foot 
syndrome).  
Oxaliplatin: Common side effects include bruises, bleedings, signs of infections like sore 
throat and raised temperature, diarrhoea and vomiting, mucositis, dry cough, numbness 
and “pins and needles” in fingers and toes. 
Radiotherapy: The side effects of radiotherapy usually increase towards the end of the 
treatment. The complaints usually consist of fatigue, loss of appetite, nausea and pain 
behind the sternum if this area overlaps the field of irradiation. Pain during swallowing 
may also occur. 
When you are assigned to standard treatment, there is no difference with the treatment 
that you would have received outside study participation. It can be expected that side 
effects of the experimental treatment will be tolerated better. 
 
Contraception 
Chemotherapy and radiation results in damage to the unborn child. Therefore, patients 
may not become pregnant or father children during the treatment. Reliable 
contraception is therefore essential. Please discuss this with your doctor. 
 
Refusal to participate or withdrawal from participation 
Participation in this treatment in a study setting will only occur if you provide your explicit 
consent. Naturally, your participation is entirely voluntary. Therefore, you are free to 
decide not to participate in this study. If you wish to stop during the treatment, your 
doctor in attendance will discuss the best options for your further care with you. 
 
Privacy 
All information that will be gathered during this study, will be kept in confidence and 
processed anonymously. 
 
Insurance 
Conformable to the requirements of the Wet Medisch Onderzoek bij mensen (Dutch 
Decree on Compulsory Insurance in Medical Research Involving Human Subjects), a 
compulsory insurance has been taken out for this scientific study. You can find 
information about this in the enclosure. 
  
Approval 
This study has been approved by the Ethical Review Board of the UMC Groningen (NL)  
  
Questions 
If you have any questions regarding the treatment in the context of this study, please 
contact your doctor in attendance: ....... 
 

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Or the national coordinator of the RAPIDO Study in your country: ..... 
 
Questions concerning the study may be addressed to the independent doctor of this 
study Prof. dr. H.J.M. Groen  
 

 Version 3.2, 13 June 2019 
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Patient information on extra blood and tissue collection (RAPIDO trial) 
 
If you agreed to participate in the RAPIDO trial, we would also like to ask you to 
participate in a side study. This extra study will not be of direct benefit to you personally, 
but might provide information to improve treatment for future patients with rectal cancer. 
We would like to save a fragment of the tumour tissue obtained during the operation for 
scientific research. This tissue will be analysed with a microscope by the pathologist, 
who will also provide a description of his/her findings. Moreover, an extra sample of the 
tissue will be stored, in order to be able to predict in the future, using tissue analysis 
which treatment is most suitable for each individual patient with rectal cancer. We would 
also like to take some extra blood samples to store for this scientific research. If you 
agree, three extra samples will be taken twice at a moment default blood samples are 
taken to test your general health (before radiotherapy and before surgery). 
In principle, the result of this research will have no consequences for your treatment. 
You will therefore not be informed regarding the results of this research. The chance 
that the results of research into characteristics will be of importance for you personally is 
small. In this case, you can indicate on the consent form whether or not you would like 
to know the results after all. Your doctor is willing to help you to make a decision in this 
case. 
Participation in this part of the study is not obligatory, and you are requested to 
sign a separate part of the consent form for this. If you decide not to participate in 
this part of the study, you are still able to participate in the rest of the study. 
 
Your blood and tissue will be stored up to 15 years. It will be destructed after use. 

 Version 3.2, 13 June 2019 
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INFORMED CONSENT FORM RAPIDO STUDY 
 
Randomized Multicentre Phase III study of short course radiation therapy followed by prolonged 
pre-operative chemotherapy and surgery in primary high risk rectal cancer compared to 
standard chemoradiotherapy and surgery (and adjuvant chemotherapy). 
 
I have read and understood the patient information concerning the RAPIDO study of which I got 
a copy and I have had the opportunity to ask questions. I have understood the answers and 
these answers were clear. 
I confirm that I had time to think about it, and I know that I can ask for more information from my 
doctor and stop my participation in the study and that this will not influence the care given to 
me. 
I allow that the study coordinator and his assigned personnel should be able to look at the 
medical file to check study-related data. They will not be used for any other purpose. My name 
will not appear in any report. I agree my data will be kept for 15 years. 
I allow that my doctor may give information to my general practitioner concerning my 
participation in this study and other information which might be important. In addition, I allow 
that he might ask information about my current or past illnesses and treatment. 
I agree to participate in the study 
YES 
 
NO 
 
I allow that tumour tissues will be collected and will be used for future 
research 
YES 
 
NO 
 
I allow that extra blood samples will be taken from me and will be 
collected for future research 
YES 
 
NO 
 
 
Name patient ………………………………………………… Signature…………………… 
 
Date 
 
…… / …… / …………    
The undersigned declares that the above person has been informed with regard to the above 
study. 
Name doctor ………………………………………………… Signature……………………. 
 
Date 
 
…… / …… / ………… 
NB.  The original informed consent document must be stored in the medical records of 
the patient; de patient will receive a copy. 

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Appendix F - Radiation therapy 
 
Target dose 
All patients will receive 28 daily fractions of 1.8 Gy up to a total dose of 50.4 Gy or 25 fractions 
of 2.0 Gy up to a total dose of 50.0 Gy to the pelvic field including the tumour bed with a margin 
and the regional lymph nodes. A field reduction after 45 (1.8 Gy schedule) or 46 (2.0 Gy 
schedule) is recommended. The last fractions will then be given to the tumour bed with a margin.  
An extra boost is possible to deliver towards the primary tumour area with 1.8-2.0 Gy x 2 – 4. 
The treatment is given in combination with chemotherapy (capecitabine).  
In group B, the experimental arm, the target dose to the pelvic PTV is 25 Gy with 5 Gy in 5 
fractions during one week. The boost volume is included. An extra boost of 2 Gy x 2 – 3 is also 
possible to deliver in certain circumstances.  
 
Target volumes 
Boost GTV 
Gross tumour volume (GTV) is the visible primary tumour and visible pathological lymph 
nodes.  
CTV boost 
GTV boost plus a margin of 2 cm within the same anatomical compartment as the tumour is in, 
for the dose from 45 to 50.4 Gy, also around radiologically engaged lymph nodes! If the tumour 
is entirely within mesorectum with no threatened MRF, the 2 cm extension for uncertainties in 
tumour spread does not need to go outside the fascia. The margin of 2 cm will thus chiefly be 
added cranially and caudally. If the tumour e.g. grows into the sacral bone or the urinary bladder, 
the 2 cm margin does apply within those organs.  
GTV boost plus a margin of 1 cm within the same anatomical compartment  if an additional 
boost is given above 50.4 ( or 50.0) or 25 Gy. 
 
Pelvic CTV 
1. The primary tumour  
2. Primary lymph nodes in the bowel wall and within mesorectum. Mesorectum is composed 
of the surrounding fat around the bowel and extends dorsally towards sacrum. Distally, only 
lymph nodes or tumour deposits up to 4 cm are included. For tumours in lower rectum this 
means that the entire mesorectum down to the pelvic floor is included whereas in tumours 
high up in rectum, the most distal part of mesorectum is not included. The reason for this is 
to diminish radiation towards the sphincters. 

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3. The closest secondary lymph node stations consisting of presacral nodes and nodes along the 
rectal superior artery. These lymph nodes are partly overlapping with the primary mesorectal 
lymph nodes and they are important for all tumours within the rectum. Since local 
recurrences are very unusual above S1 – S2, lymph nodes above this level should not be 
included unless there are signs of pathological lymph nodes presacrally. If this is the case, 
the cranial limit of CTV should be at least 1 cm above the most cranial pathological lymph 
node. 
4. The lateral lymph node stations along the medial rectal and obturator arteries until they 
reach the level of the obturator canal should be included if the primary tumour is below the 
peritoneal reflection or up to about 8 to 10 cm from the anal verge. In higher tumours, these 
nodes are rarely involved.  
5. The lateral lymph node stations also include lymph nodes along the internal iliac artery up to 
the bifurcation from the external iliac artery. The cranial border for the CTV is in most cases 
just below the bifurcation of the internal and external iliac arteries. In most patients this is at 
the level of S1 – S2. In certain individuals, the bifurcation can be above L5 – S1. In these 
instances the cranial CTV border is at the level of S1-S2, unless lymph nodes along the 
internal iliac artery is seen. Then a margin of at least 1 cm above the most cranial lymph 
nodes must be drawn. 
6. Inguinal lymph nodes are included in CTV only if the tumour grows into the anal canal and 
distal to the dentate line or if it grows into the distal part of vagina.  
7. The entire ischio-rectal fossa, the anal canal and peritoneum is included in pelvic CTV only 
if the tumour grows into the levators or down into the anal canal. In these instances, rectal 
excision is always required.  
8. Lymph nodes along the external iliac artery are included if the tumour grows into anterior 
organs like the prostate, urinary bladder, cervix, vagina or uterus to such an extent that the 
external nodes are at risk for metastases. Therefore, napping or minimal overgrowth dorsally 
is not sufficient. 
 
PTV 
The above description relates to the CTV. A PTV should normally be defined and includes CTV 
and internal target volume (ITV) and a margin necessary for the setup. These margins are 
depending upon several factors that are related to the equipment at each radiotherapy centre.  
 
Treatment verification 
Treatment verification should be performed at least twice during the first treatment week, 
preferably according to a NAL or SAL procedure, and weekly thereafter for the 
chemoradiotherapy. For the 5x5 Gy schedule online correction is strongly recommended. 
Acceptable deviations should be in line with the chosen CTV-PTV margin. 
 
 

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Appendix G - Magnetic resonance imaging 
 
Requirements 
 
1.5T or 3T equipments 
Phased-array reciever coils for pelvic-/body imaging 
No obligatory preparations.  
(Four hours fasting) allowed 
Antispasmodic agents allowed 
No endoluminal or intravenous contrast agents 
 
Image sequences 
T2-weighted high resolution sequences in at least three different planes (Sagittal, transaxial and 
oblique planes) where one imaging sequence is perpendicular to the rectum at the level of the 
tumour interleaved with maximum 3 mm section thickness (1). If low tumours, additional 
oblique sequences including the tumour parallel and perpendicular to the anal canal are 
performed. 
 
T1-weighted axial images of the pelvis and diffusion weighted images of the pelvis allowed but 
can only be performed if the quality of the T2-weighted images have been guaranteed. 
 
 
MRI reporting 
 
Level of the tumour 
The distance of the tumour from the anorectal junction and/or from the anal verge is measured 
by electronic calipers on sagittal images. The length of the tumour is measured and reported.  It 
is also stated whether the tumour is above, at or below the level of the peritoneal reflection. For 
low tumours it is stated whether the tumour is within a mm from the levator muscles or not, 
whether there is involvement of the intershpincteric plane and the external sphincter. 
 
Morphology  
of the tumour is described whether the tumour is polypoid, (semi)annular. If there is evidence of 
a mucinous tumour indicated by typical high signal intensity on T2-weighted images, this is also 
reported. 
 

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Depth of extramural spread 
The maximum depth of extramural depth from the outer edge of the muscle layer to the outer 
edge of the tumour is measured on high resolution images perpendicular to the rectum at the 
level of the tumour (1) 
 
Extramural vascular invasion  
is recorded when there is tumour extension along a vessel as a serpintiguous extension of tumour 
signal within a vascular structure (2) 
 
Mesorectal Fascia 
Involvement of the potential circumferential margin is defined as tumour extending within 1 mm 
of the mesorectal fascia or closer. 
 
Perforation of the peritoneal reflection by tumour  
Is reported when nodular extension of tumour beyond the peritoneal reflection is found (3) 
 
Mesorectal lymph node metastases 
The total number of mesorectal lymph nodes is reported and the number of lymph nodes 
regarded as metastatic according to morphological criteria by G. Brown et al. A suspicion of 
mesorectal lymph node metastases is high if two or more of the following morphological criteria 
can be appreciated on high resolution T2-weighted sequences – round, irregular border and 
heterogeneous signal intensity (4).  
In addition to the morphological criteria. The following criteria are also used 
Mesorectal lymph nodes with a short axis diameter of more than 10 mm and round shape are 
regarded as metastatic. Mesorectal lymph nodes between 5-9 mm and at least two of the ciriteria 
round shape/irregular border/heterogeneous signal intensity are also regarded as metastatic. 
 
Extramesorectal lymph node metastases 
Presence of suspected metastatic inguinal, lateral pelvic lymph nodes should be reported. 
Metastatic extramesorectal lymph nodes or pelvic sidewall lymph nodes are defined by 
morphological criteria similar as for mesorectal lymph nodes: irregular border and/or 
heterogeneous signal intensity and/or round (not-oval) lymph nodes with short axis diameter of 
more than 10 mm. 
 
Evaluation post chemoirradiation 
When MRI is performed after neoadjuvant treatment, the post treatment MRI is compared with 
MRI at baseline. Viable tumour (high signal intensity) is separated from post treatment fibrosis 
(low signal intensity) on T2-weighted images. For mucinous tumours, remaining or increasing 
pure mucin pools may not necessary indicate progressive disease.  
 
Length of tumour and tumour and fibrosis if these are not clearly separated is measured as in 
baseline on sagittal T2-weighted images. 

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The minima distance of tumour (and fibrosis) is measured and the transaxial direction noted 1-12 
O´clock. 
Regarding lymph nodes, the short axis diameter of mesorectal and extramesorectal lymph nodes 
is measured. Lymph nodes with malignant morphological features pre treatment and a short axis 
diameter post treatment of equal to or more than 5 mm are considered malignant.  
A clinical complete response (CR) or near CR is defined as presence no visible tumour on T2-
weighted images with normal bowel wall layers or presence of residual fibrosis that is confined 
to the bowel wall. 
 
References: 
 
1. Taylor FG, Swift RI, Blomqvist L, Brown G. 
A systematic approach to the interpretation of preoperative staging MRI for rectal cancer.  
AJR Am J Roentgenol. 2008 Dec;191(6):1827-35. Review. 
 
 2. Smith NJ, Shihab O, Arnaout A, Swift RI, Brown G. MRI for detection of extramural 
vascular invasion in rectal cancer. AJR Am J Roentgenol. 2008 Nov;191(5):1517-22. Review. 
 
3. Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, Bourne MW, Williams GT. 
Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic 
resonance imaging. 
Br J Surg. 2003 Mar;90(3):355-64. 
 
4.  Brown G, Richards CJ, Bourne MW, Newcombe RG, Radcliffe AG, Dallimore NS, Williams 
GT. 
Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution 
MR imaging with histopathologic comparison. Radiology. 2003 May;227(2):371-7. 
 
5. Engelen SM, Beets-Tan RG, Lahaye MJ, Kessels AG, Beets GL.  Location of involved 
mesorectal and extramesorectal lymph nodes in patients with primary rectal cancer: preoperative 
assessment with MR imaging.  Eur J Surg Oncol. 2008 Jul;34(7):776-81. 
 
6. Lahaye MJ, Beets GL, Engelen SM, Kessels AG, de Bru√Øne AP, Kwee HW, van 
Engelshoven JM, van de Velde CJ, Beets-Tan RG. Locally advanced rectal cancer: MR imaging 
for restaging after neoadjuvant radiation therapy with concomitant chemotherapy. Part II. What 
are the criteria to predict involved lymph nodes? Radiology. 2009 Jul;252(1):81-91.  
 
7. MERCURY Study Group. Relevance of magnetic resonance imaging-detected pelvic sidewall 
lymph node involvement in rectal cancer. Br J Surg. 2011 Sep 16. 
 

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Appendix H - EORTC  Quality of Life 
Questionnaire, Colorectal Module and 
chemotherapy induced peripheral neuropathy 
 
EORTC C30 instrument is a copyrighted instrument, which has been translated and validated 
into 81 languages and is used in more than 3,000 studies worldwide. Presently QLQ-C30 
Version 3.0 is the most recent version and should be used for all new studies. 
It is supplemented by disease specific modules for e.g. Breast, Lung, Head & Neck, 
Oesophageal, Ovarian, Gastric, Cervical cancer, Multiple Myeloma, Oesophago-Gastric, 
Prostate, Colorectal Liver Metastases, Colorectal and Brain cancer which are distributed from 
the EORTC Quality of Life Department. Other disease specific modules are under development 
but not yet validated 
The C30 questionnaire will be provided by the LUMC Datacenter. 
While the EORTC QLQ-C30 is an important tool to assess the generic aspects of QOL, it has 
limitations and therefore a modular approach was adopted for disease specific treatment 
measurements. An essential aspect of the "modular" approach to QOL assessment adopted by the 
EORTC QLG (Quality of Life Group) is the development of modules specific to tumour site, 
treatment modality, or a QOL dimension, to be administered in addition to the core questionnaire 
(EORTC QLQ-C30). The modules, like the core questionnaire, are designed for use in cancer 
clinical trials. The CR 29 module is developed for colorectal cancer patients. 
QLQ-CR29: the colorectal module to assess the quality of life and the functional outcome. To 
optimally evaluate the sexual functioning, for male patients questions 56 and 57 from QLQ CR-
29 have been replaced by questions 50 to 55 from QLQ PR-25, whereas for female patients 
questions 58 and 59 from QLQ CR-29 have been replaced by questions 49 to 54 from QLQ EN-
24. 
QLQ-CIPN20: the module to assess the chemotherapy induced peripheral neuropathy  

 Version 3.2, 13 June 2019 
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Appendix J - National coordinators 
 
The Netherlands: 
Geke Hospers, medical oncology,  
UMC Groningen 
g.a.p.hospers@umcg.nl  
Sweden: 
Bengt Glimelius, radiation- & clinical-oncology,  
Akademiska sjukhuset, Uppsala 
Bengt.Glimelius@igp.uu.se 
Norway: 
Marianne Grønlie Guren, clinical oncology 
Oslo Universitetssykehus, Oslo 
UXARUR@ous-hf.no 
Spain: 
Andrés Cervantes, hematology and medical oncology, 
INCLIVA Health Research Institute, University of Valencia 
andres.cervantes@uv.es  
Slovenia 
Ibrahim Edhemovic, surgical oncology,  
Onkološki Inštitut, Ljubljana 
Ibrahim.Edhemovic@mf.uni-lj.si  
Denmark: 
Per Pfeiffer, clinical oncology 
Odense Universitetshospital 
per.pfeiffer@rsyd.dk 
Unites States: 
 
Michael Roach, Radiation oncology, Washington University 
School of Medicine, Siteman Cancer Center, St. Louis 
mroach@wustl.edu   
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix K – Local principal investigators 
Country 
Hospital 
City 
Investigator 
Department 
DENMARK 
Aalborg Universitets Hospital  AALBORG 
Laurids 
Østergaard 
clinical oncology 
DENMARK 
Odense University Hospital 
ODENSE C 
Per 
Pfeiffer 
clinical oncology 
NETHERLANDS  Noordwest Ziekenhuisgroep 
ALKMAAR 
Mathijs 
Hendriks 
medical oncology 
NETHERLANDS 
Amsterdam Universitair 
Medische Centra (AMC) 
AMSTERDAM 
Pieter 
Tanis 
medical oncology 
NETHERLANDS 
NKI/Antoni van 
Leeuwenhoekziekenhuis 
AMSTERDAM 
Monique 
van Leerdam 
medical oncology 
NETHERLANDS  Onze Lieve Vrouwe Gasthuis 
AMSTERDAM 
Emile 
Kerver 
medical oncology 
NETHERLANDS 
Amsterdam Universitair 
Medische Centra (VUMC) 
AMSTERDAM 
Anna 
Bruynzeel 
radiotherapy 
NETHERLANDS  Wilhelmina Ziekenhuis 
ASSEN 
Peter 
Nieboer 
medical oncology 
NETHERLANDS  Amphia Ziekenhuis 
BREDA 
Bert Jan 
ten Tije 
medical oncology 
NETHERLANDS  Reinier de Graaf Groep 
DELFT 
Addy 
van Luijtgaarden 
medical oncology 
NETHERLANDS  HagaZiekenhuis 
DEN HAAG 
Patricia 
Quarles van Ufford  medical oncology 
NETHERLANDS 
Haaglanden Medisch 
Centrum 
DEN HAAG 
Heleen 
Ceha 
medical oncology 
NETHERLANDS  Deventer Ziekenhuis 
DEVENTER 
Alex 
Imholz 
medical oncology 
NETHERLANDS  Catharina Ziekenhuis 
EINDHOVEN 
Hetty 
van den Berg 
medical oncology 
NETHERLANDS  Het Groene Hart Ziekenhuis 
GOUDA 
Wendy 
van der Deure‐Gielisse 
medical oncology 
NETHERLANDS 
Universitair Medisch 
Centrum Groningen 
GRONINGEN 
Geke 
Hospers 
medical oncology 
NETHERLANDS  Martini Ziekenhuis 
GRONINGEN 
Johan 
van Rooijen 
medical oncology 
NETHERLANDS  de Tjongerschans 
HEERENVEEN 
Jaap 
de Boer 
medical oncology 
NETHERLANDS  Ziekenhuisgroep Twente 
HENGELO 
Ester 
Siemerink 
medical oncology 
NETHERLANDS  Spaarne Gasthuis 
HOOFDDORP 
Bart 
de Valk 
medical oncology 
NETHERLANDS 
Medisch Centrum 
Leeuwarden 
LEEUWARDEN  Marco 
Polée 
medical oncology 
NETHERLANDS 
Radiotherapeutisch Instituut 
Friesland 
LEEUWARDEN  Annerie 
Slot 
radiotherapy 
NETHERLANDS 
Leids Universitair Medisch 
Centrum 
LEIDEN 
Corrie 
Marijnen 
radiotherapy 
NETHERLANDS  Alrijne Ziekenhuis 
LEIDERDORP 
Peter 
Neijenhuis 
surgery 
NETHERLANDS 
Radboud Universitair 
Medisch Centrum 
NIJMEGEN 
Sandra 
Radema 
medical oncology 
NETHERLANDS  Antonius Ziekenhuis 
SNEEK 
Gert Jan 
Veldhuis 
medical oncology 
NETHERLANDS 
Dr. Bernard Verbeeten 
Instituut 
TILBURG 
Tom 
Rozema 
radiotherapy 
NETHERLANDS  Diakonessenhuis 
UTRECHT 
Daan 
ten Bokkel Huinink 
medical oncology 
NETHERLANDS 
Universitair Medisch 
Centrum Utrecht 
UTRECHT 
Onne 
Reerink 
radiotherapy 
NETHERLANDS  Isala Klinieken 
ZWOLLE 
Metin 
Tascilar 
medical oncology 
NORWAY 
Sørlandet Sykehus 
Kristiansand 
KRISTIANSAND  Christian 
Kersten 
clinical oncology 
NORWAY 
Oslo Universitetssykehus 
OSLO 
Marianne 
Grønlie Guren 
clinical oncology 

 Version 3.2, 13 June 2019 
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SLOVENIA 
Institute of Oncology 
Ljubliana 
LJUBLJANA 
Ibrahim 
Edhemovic 
surgery 
SPAIN 
Vall d'Hebron Institut 
d’Oncologia 
BARCELONA 
Jaume 
Capdevila 
medical oncology 
SPAIN 
ICO Hospitalet. Hospital 
Duran I Reynals 
L'HOSPITALET 
de LLOBREGAT  Ramon 
Salazar 
medical oncology 
SPAIN 
Hospital Ramón y Cajal 
MADRID 
Vanessa 
Pachón 
medical oncology 
SPAIN 
Hospital Clínico Universitario 
de Valencia 
VALENCIA 
Andrés 
Cervantes 
medical oncology 
SPAIN 
Consorcio Hospital General 
Universitario Valencia 
VALENCIA 
Maria José 
Safont 
medical oncology 
SPAIN 
Hospital Universitari i 
Politècnic la Fe 
VALENCIA 
Jorge 
Aparicio 
medical oncology 
SWEDEN 
Södra Älvsborgs Sjukhus 
BORÅS 
Lena 
Malmberg 
clinical oncology 
SWEDEN 
Mälarsjukhuset 
ESKILSTUNA 
Helene 
Hörberg 
clinical oncology 
SWEDEN 
Falu Lasarett 
FALUN 
Ake 
Berglund 
clinical oncology 
SWEDEN 
Gävle Sjukhus 
GÄVLE 
Katalin 
Kovacs 
clinical oncology 
SWEDEN 
Sahlgrenska 
Universitetssjukhuset 
GÖTEBORG 
Susanne 
Ottosson 
clinical oncology 
SWEDEN 
Kalmar Hospital 
KALMAR 
Charlotte 
Bratthäll 
clinical oncology 
SWEDEN 
Centralsjukhuset i Karlstad 
KARLSTAD 
Britta 
Lödén 
clinical oncology 
SWEDEN 
Linköpings Universitet 
LINKÖPING 
Ingrida 
Verbiene 
clinical oncology 
SWEDEN 
Universitetssjukhuset i Lund 
LUND 
Anders 
Johnsson 
clinical oncology 
SWEDEN 
Universitetssjukhuset 
ÖREBRO 
Kenneth 
Villman 
clinical oncology 
SWEDEN 
Skaraborgs Sjukhus Skövde 
SKÖVDE 
Jan Henry 
Svensson † 
clinical oncology 
SWEDEN 
Karolinska 
Universitetssjukhuset 
STOCKHOLM 
Tone 
Fokstuen 
clinical oncology 
SWEDEN 
Sundsvalls Sjukhus 
SUNDSVALL 
Petra 
Flygare 
clinical oncology 
SWEDEN 
Norrlands 
Universitetssjukhus 
UMEÅ 
Brigitta 
Lindh 
clinical oncology 
SWEDEN 
Akademiska Sjukhuset 
UPPSALA 
Bengt 
Glimelius 
clinical oncology 
SWEDEN 
Västmanlands Sjukhus 
VÄSTERÅS 
Andrzej 
Piwowar 
clinical oncology 
SWEDEN 
Central Hospital Växjö 
VÄXJÖ 
Ulrika 
Palenius 
clinical oncology 
USA 
Washington University 
Medical School 
SAINT LOUIS 
Michael 
Roach 
radiotherapy 
 

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Appendix L  - Collection of blood samples  
Investigator study laboratory manual 
 
 
RAPIDO study 
 
Randomised Multicentre Phase III study of short course radiation therapy followed 
by prolonged pre-operative chemotherapy and surgery in primary high risk rectal cancer 
compared to standard chemoradiotherapy and surgery (and adjuvant chemotherapy) 
Protocol code: RAPIDO 
 
 
 
EudraCT registration number: 
2010‐023957‐12 

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1. CONTACT DETAILS  
For this study, DNA, RNA and proteomics samples are stored at the Uppsala Clinical Research 
Center, Sweden.  
Contact  
 
Birgitta Högberg  
+46 70 6124550 
UCR/Uppsala  Clinical  Research  Center, 
Uppsala Biobank/UCR Lab 
Uppsala Science Park, Hubben, Level 1 
Dag Hammarskjölds väg 38 
751 85 Uppsala  
 
 
 
 
 
 

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2. LABORATORY TESTING SCHEDULE 
The schedule for sample collection is included below.  
 
Sample collection time points 
Before radiotherapy 
14 till 0 days 
Before operation 
7 till 1 days 
 
 
3. SAMPLE COLLECTION AND HANDLING 
Blood  samples  will  be  collected  on  two  time  points:  before  start  (chemo)radiotherapy  and 
before operation. On each time point two 10 ml (or one 10 ml and two 5 ml) EDTA containing 
tubes  will  be  filled  with  whole  blood  and  afterwards  directly  processed  according  to  this 
protocol. After processing there are four to five Eppendorf tubes with 2 ml full blood in EDTA 
and two Eppendorf tubes with 2 ml blood plasma per timepoint per patient. To minimize the 
patient’s burden the blood sampling shall be combined with other laboratory tests.  
Complete the patient details on the sample tubes. Adhere a completed tube label to each tube 
prior to collection. Ensure that these details are consistent with the patient details you have 
recorded on the Clinical Requisition Form. Each tube should be marked with a waterproof pen 
with the study number, center number, patients code, date of birth (day/month/year), sample 
date  and  sample  description  (t=0  before  radiotherapy;  t=1  before  operation).  Phlebotomy: 
perform a standard venipuncture and allow a tube to fill completely under vacuum. 
Note: Blood collection may proceed according to local procedures. 
 
3.1 Full blood sample collection and freezing procedure 
Tube used  
One standard 10 ml EDTA containing tube (preferred) OR two standard 5 ml EDTA containing 
tubes. The EDTA tube type can be chosen by the center. 
 

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Handling of sample for whole blood  
‐ 
After whole blood is drawn, pipette the 10 ml of fresh whole blood into four or five 2.0 ml 
Eppendorf tubes.   
‐ 
Discard the empty EDTA tube. 
‐ 
Mark  the  Eppendorf  tubes  with  a  waterproof/cryoproof  label  and  pen  with  the  study 
number, center number, patient code, date of birth (day/month/year), sample date, sample 
description (t=0/t=1).  
 
Storage 
Store the Eppendorf tubes with full blood directly at ‐20 or ‐80 degrees Celsius.  
 
Note: It is preferred to aliquot 10 ml of fresh whole blood into four to five 2.0 ml Eppendorf 
tubes before storing at ‐20 or ‐80 degrees. If this is not feasible, it is possible to draw whole 
blood into two 5 ml EDTA containing tubes, and store these at ‐20 or ‐80 degrees Celsius.    
 
Purpose 
DNA will be isolated from the blood for genotyping. RNA will be isolated from the blood to 
determine expression patterns. 
 
3.2 Blood plasma sample collection and freezing procedure  
Tube used 
One standard 10 ml EDTA containing tube.  
 
Handling of sample for plasma 
‐ 
After  whole  blood  is  drawn,  spin  the  tube  in  a  balanced  centrifuge  at  1500  x  g  for  10 
minutes at 4 degrees Celsius. 
‐ 
Remove the tube from the centrifuge after spinning and pipette all the plasma (top layer) 
into two 2.0 ml Eppendorf tubes. 
‐ 
Discard the EDTA tube with the remaining debris. 

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‐ 
Mark  the  Eppendorf  tubes  with  a  waterproof/cryoproof  label  and  pen  with  the  study 
number, center number, patient code, date of birth (day/month/year), sample date, sample 
description (t=0/t=1). 
 
Storage 
Store  the  Eppendorf  tubes  with  the  supernatant  directly  at  ‐20  or  ‐80  degrees  Celsius  until 
collection and analysis.  
 
Purpose 
The samples will be used for proteomics. 
 
3.3 Sending samples  
The samples have been collected and are stored in Uppsala. Contact person Birgitta Högberg 
can be reached at +46 70 6124550. 
UCR/Uppsala Clinical Research Center, Uppsala Biobank/UCR Lab 
Uppsala Science Park, Hubben, Level 1 
Dag Hammarskjölds väg 38 
751 85 Uppsala  
  

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Appendix M - LARS score 
 
Bowel function questionnaire 
The aim of this questionnaire is to assess your bowel function. 
Please tick only one box for each question. It may be difficult to select only one answer, as we know that for 
some patients symptoms vary from day to day. We would kindly ask you to choose one answer which best 
describes your daily life. If you have recently had an infection affecting your bowel function, please do not take 
this into account and focus on answering questions to reflect your usual daily bowel function. 
 
 The LARS Score ‐ Scoring Instructions  
Add the scores from each 5 questions to one final score.  
 
Do you ever have occasions when you cannot control your flatus (wind)?  
□ No, never  
 
 
 
0  
□ Yes, less than once per week  
 
4  
□ Yes, at least once per week  
 
7  
 
Do you ever have any accidental leakage of liquid stool?  
□ No, never  
 
 
 
0  
□ Yes, less than once per week  
 
3  
□ Yes, at least once per week  
 
3  
 
How often do you open your bowels?  
□ More than 7 times per day (24 hours)  
4  
□ 4‐7 times per day (24 hours)  
 
2  
□ 1‐3 times per day (24 hours)  
 
0  
□ Less than once per day (24 hours)  
5  
 
Do you ever have to open your bowels again within one hour of the last bowel opening?  
□ No, never  
 
 
 
0  
□ Yes, less than once per week  
 
9  
□ Yes, at least once per week  
 
11  
 
Do you ever have such a strong urge to open your bowels that you have to rush to the toilet?  
□ No, never  
 
 
 
0  
□ Yes, less than once per week  
 
11  
□ Yes, at least once per week  
 
16  
 
Total Score:  
Interpretation:  
0‐20: No LARS  
21‐29: Minor LARS  
30‐42: Major LARS 

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Appendix N - English Patient Information and 
Informed Consent  RAPIDO TRIAL (with 
FOLFOX4 treatment) 
 
 
A study investigating the difference in effect of short term radiotherapy and 
chemotherapy followed by surgery compared to standard treatment of high risk rectal 
cancer. 
 
Original title in English: Randomised Multicentre Phase III study of short course 
radiation therapy followed by prolonged pre-operative chemotherapy and surgery in 
primary high risk rectal cancer compared to standard chemoradiotherapy and surgery 
and optional adjuvant chemotherapy 
 
 
 
You have been asked to participate in a medical research study on new treatment for 
high risk rectal cancer. The following written information is intended as an addition to 
the information you have already received from your doctor in attendance. If, however, 
this information is unclear or insufficient you can always request additional information. 
Discuss the information with your partner, family, friends, or doctor/general practitioner. 
There is also the possibility to consult an impartial person, the details of which will be 
provided in this document. This person is knowledgeable on the research matter though 
is not in any way involved in the research. You will be given at least 2 days, and up to 
one week, to consider your participation. 
This international study is initiated by University Medical Center Groningen (UMCG) in 
the Netherlands. The study will be performed according to national and international 
rules and laws.  
 
 
 
Background of this study 
Surgery is the most important type of treatment of cancer of the rectum. In some 
patients with high risk rectal cancer it is not possible to remove the whole tumour during 
surgery. Additional treatments both before and after the operation are applied as an 
attempt to reduce the chance of recurrence of the disease and thus increase the chance 
of cure. To this end, various kinds of chemotherapy (cell-killing drugs) and radiotherapy 
(radiation) have been applied in the past. 
 

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Current standard treatment consists of long term (5 to 6 weeks) radiotherapy combined 
with chemotherapy before surgery (also called neoadjuvant chemoradiotherapy). This 
neoadjuvant chemoradiotherapy is mainly aimed to prevent your cancer of the rectum 
from returning in the area around the tumour (this is called a local recurrence). 
Neoadjuvant chemoradiotherapy does not adequately treat micro metastases that may 
be present at the time of surgery in places far from the rectum such as in the liver or 
lungs. If cancer grows in places like the liver or lungs after surgery, this is known as a  
distant recurrence. Treatment with chemotherapy immediately after surgery may not 
adequately avoid or prevent distant recurrent disease. Possibly this is because many 
patients are not fit enough to start chemotherapy in time or not at all, after recovering 
from relatively tough surgery.  
In this study we hope to test a new experimental treatment to see if it is more effective 
than standard treatment in decreasing the risk of local and distant recurrence. In the 
experimental arm of the study, prior to surgery, we will give short term radiotherapy (5 
days) after which the size of the rectal tumour often decreases.. During this waiting time 
we will then give chemotherapy to treat possible micro metastases and to possibly 
decrease the risk of distant recurrence. We will compare this experimental treatment to 
the standard treatment of neoadjuvant chemotherapy (6 weeks) and then surgery. 
According to the opinion of the doctors in your local hospital post-operative 
chemotherapy can also be given. In your hospital post-operative chemotherapy <is / is 
not> standard treatment. 
 
 
Object of this study 
The aim of this study is to find out whether the experimental treatment can be tolerated 
better by the patients and has at least the same effect on survival as the standard 
treatment. To be able to judge the effect of the treatment, all patients will be followed up 
for three years to assess recurrence of disease. Results of patients with experimental 
and standard treatment will be compared. In order to avoid the investigators being 
influenced with regard to their choice in favour of one of the treatment types, the 
participants will be divided into two equal groups randomly. It is a matter of chance to 
which group you are assigned. This ensures that both patient and doctor are not able to 
influence the treatment choice.   
 
Chemotherapy in the experimental arm will consist of three types of drugs; folinic acid, 
fluorouracil, and oxaliplatin , which are all given by infusion. These drugs have been 
evaluated positively on safety by International and National Health Authorities. 
About 920 patients from Sweden, the Netherlands, Spain, Slovenia, Norway,  Denmark, 
USA and Canada will participate. 
 
 
What does the research involve? 
Standard treatment: 
 Pre-operative chemoradiotherapy: 25 to 28 radiations will be given in a period of 
5 to 6 weeks. Simultaneously twice daily tablets of capecitabine have to be 
ingested. 
 About 8 weeks after the last radiation the rectum tumour will be removed during 
surgery. 

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 (depending on local policy) 6-8 weeks after the operation 12 cycles of post-
operative chemotherapy will be given. In each cycle of 2 weeks, a course 
consisting of infusion with folinic acid, fluorouracil, and oxaliplatin will be given on 
day 1. On day 2 there will be additional infusion with folinic acid and fluorouracil. 
 
Experimental treatment: 
 Radiation will be given during 5 workings days of a week. 
 11 to 25 days after last radiation, 9 cycles of pre-operative chemotherapy will be 
given. In each cycle of 2 weeks, a course consisting of infusion with folinic acid, 
fluorouracil, and oxaliplatin will be given on day 1. On day 2 there will be 
additional infusion with folinic acid and fluorouracil. 2-4 weeks after the last 
chemotherapy, the rectum tumour will be removed during surgery 
 
 
Content of the study 
Prior to the start of the treatment you will be asked to sign for informed consent. During 
the screening several examinations will be carried out and visits to the involved 
specialists will take place to conclude whether you meet with all criteria to participate in 
this study. If not, participation in this study is not possible, your doctor will discuss other 
treatment options with you. The study looks like this: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating in a study often means extra tests and extra visits to the hospital. That is 
not the case in this study. Before surgery you will need to visit the hospital and /or 
radiotherapy center about 25 times in 14 weeks time (standard); in case of the 
experimental treatment this is about 23 times during a period of about 22 weeks. So the 
experimental treatment means that you will need similar number of visits, but the time till 
surgery takes longer. Both study groups will be asked to fill out quality of life 
questionnaires, three years after surgery. If this is standard treatment in your hospital, 
patients in standard treatment group will receive 12 cycles of chemotherapy (24 visits in 
24 weeks) after surgery. 
Informed 
consent 
Screening 
Rando 
misation 
Radiotherapy + 
Chemotherapy 
(capecitabine, 
daily) 
5-6 weeks 
Surgery 
(optional) Chemotherapy 
folinic acid, fluorouracil+ 
oxaliplatin  
12 cycles 24 weeks 
Radiotherapy   
1 week 
Chemotherapy folinic 
acid, fluorouracil + 
oxaliplatin  
9 cycles 18 weeks 
Surgery 
8±2 
weeks 
8 weeks 
2-4 
weeks 
11-19 
days 
STANDARD TREATMENT 
EXPERIMENTAL TREATMENT 
or 

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Screening: 
 Medical history, concomitant medication and medical complaints 
 Physical examination 
 Rectoscopy and / or colonoscopy. A biopsy of the tumour might be taken 
 If significant for the study an X-ray of the colon will be taken 
 CT of lungs, abdomen and pelvis and a MRI of the pelvis will be performed to 
examine size and spread of the tumour. 
 
Each visit (screening, treatments and follow up) 
 Discussion of complaints 
 Blood samples for testing general health condition and effects of study treatment 
(about 10 ml per visit).   
 
Periodically (during and after treatment) 
 Physical examination (2-4 times) 
 CT of lungs, abdomen and pelvis (twice) and a MRI of the pelvis (2-3 times) will 
be performed to examine size and spread of the tumour. 
 
After surgery: 
 After the operation you will be followed up for at least five years. Follow-up visits 
will take place at 6, 12, 24, 36 and 60 months after surgery. Periodically blood 
samples and examinations will be performed. 
 3 years after the operation questionnaires to assess your quality of life. 
 
What do we expect from you? 
 Swallow the capecitabine tablets as prescribed. Do not take any drugs without 
consulting your doctor 
 Inform your doctor or his study personnel of any health changes or if you 
consider quitting study participation. 
 Report to your doctor or his personnel if you have a fever (temperature of 38,5 oC 
or more) or if you suffer from diarrhoea or vomiting. 
 
 
Potential advantages and disadvantages of participation  
All drugs can cause side-effects, this also counts for capecitabine and oxaliplatin.  
Capecitabine: The side effects of capecitabine have been extensively described: 
nausea, (rarely) painful damage to the mucosa in the mouth (mucositis) or bowels, 
resulting in diarrhoea, and redness and pain in the skin of hands and feet (the hand-foot 
syndrome).  
Oxaliplatin: Common side effects include bruises, bleedings, signs of infections like sore 
throat and raised temperature, diarrhoea and vomiting, mucositis, dry cough, numbness 
and “pins and needles” in fingers and toes. 
Folinic Acid: Side effects are uncommon with the drug. Allergic reactions happen rarely 
and result in a fever, rash, itchiness or even swelling of the face or throat.  

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Fluorouracil:  Common side effects include poor appetite, nausea and vomiting, 
diarrhea, and sometimes unusual bleeding or bruising, and fever or chills. You may also 
experience dry or red eyes, and your skin may be sensitive to sunlight.  
Radiotherapy: The side effects of radiotherapy usually increase towards the end of the 
treatment. The complaints usually consist of fatigue, loss of appetite, nausea and pain 
behind the sternum if this area overlaps the field of irradiation. Pain during swallowing 
may also occur. 
When you are assigned to standard treatment, there is no difference with the treatment 
that you would have received outside study participation. It can be expected that side 
effects of the experimental treatment will be tolerated better. 
 
Contraception 
Chemotherapy and radiation results in damage to the unborn child. Therefore, patients 
may not become pregnant or father children during the treatment. Reliable 
contraception is therefore essential. Please discuss this with your doctor. 
 
Refusal to participate or withdrawal from participation 
Participation in this treatment in a study setting will only occur if you provide your explicit 
consent. Naturally, your participation is entirely voluntary. Therefore, you are free to 
decide not to participate in this study. If you wish to stop during the treatment, your 
doctor in attendance will discuss the best options for your further care with you. 
 
Privacy 
All information that will be gathered during this study, will be kept in confidence and 
processed anonymously. 
 
Insurance 
Conformable to the requirements of the Wet Medisch Onderzoek bij mensen (Dutch 
Decree on Compulsory Insurance in Medical Research Involving Human Subjects), a 
compulsory insurance has been taken out for this scientific study. You can find 
information about this in the enclosure. 
  
Approval 
This study has been approved by the Ethical Review Board of the UMC Groningen (NL)  
  
Questions 
If you have any questions regarding the treatment in the context of this study, please 
contact your doctor in attendance: ....... 
 
Or the national coordinator of the RAPIDO Study in your country: ..... 
 
Questions concerning the study may be addressed to the independent doctor of this 
study Prof. dr. H.J.M. Groen.  
Patient information on extra blood and tissue collection (RAPIDO trial) 

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If you agreed to participate in the RAPIDO trial, we would also like to ask you to 
participate in a side study. This extra study will not be of direct benefit to you personally, 
but might provide information to improve treatment for future patients with rectal cancer. 
We would like to save a fragment of the tumour tissue obtained during the operation for 
scientific research. This tissue will be analysed with a microscope by the pathologist, 
who will also provide a description of his/her findings. Moreover, an extra sample of the 
tissue will be stored, in order to be able to predict in the future, using tissue analysis 
which treatment is most suitable for each individual patient with rectal cancer. We would 
also like to take some extra blood samples to store for this scientific research. If you 
agree, three extra samples will be taken twice at a moment default blood samples are 
taken to test your general health (before radiotherapy and before surgery). 
In principle, the result of this research will have no consequences for your treatment. 
You will therefore not be informed regarding the results of this research. The chance 
that the results of research into characteristics will be of importance for you personally is 
small. In this case, you can indicate on the consent form whether or not you would like 
to know the results after all. Your doctor is willing to help you to make a decision in this 
case. 
Participation in this part of the study is not obligatory, and you are requested to 
sign a separate part of the consent form for this. If you decide not to participate in 
this part of the study, you are still able to participate in the rest of the study. 
 
Your blood and tissue will be stored up to 15 years. It will be destructed after use. 

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INFORMED CONSENT FORM RAPIDO STUDY 
 
Randomized Multicentre Phase III study of short course radiation therapy followed by prolonged 
pre-operative chemotherapy and surgery in primary high risk rectal cancer compared to 
standard chemoradiotherapy and surgery (and adjuvant chemotherapy). 
 
I have read and understood the patient information concerning the RAPIDO study of which I got 
a copy and I have had the opportunity to ask questions. I have understood the answers and 
these answers were clear. 
I confirm that I had time to think about it, and I know that I can ask for more information from my 
doctor and stop my participation in the study and that this will not influence the care given to 
me. 
I allow that the study coordinator and his assigned personnel should be able to look at the 
medical file to check study-related data. They will not be used for any other purpose. My name 
will not appear in any report. I agree my data will be kept for 15 years. 
I allow that my doctor may give information to my general practitioner concerning my 
participation in this study and other information which might be important. In addition, I allow 
that he might ask information about my current or past illnesses and treatment. 
I agree to participate in the study 
YES 
 
NO 
 
I allow that tumour tissues will be collected and will be used for future 
research 
YES 
 
NO 
 
I allow that extra blood samples will be taken from me and will be 
collected for future research 
YES 
 
NO 
 
 
Name patient ………………………………………………… Signature…………………… 
 
Date 
 
…… / …… / …………    
The undersigned declares that the above person has been informed with regard to the above 
study. 
Name doctor ………………………………………………… Signature……………………. 
 
Date 
 
…… / …… / ………… 
NB.  The original informed consent document must be stored in the medical records of 
the patient; de patient will receive a copy.