Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers - An International, Multi-Center, Double Blind, Randomized Placebo Controlled Phase III Trial
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: National Cancer Centre, Singapore

 
ICR02 / ASCOLT 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers 
 
An International, Multi-centre, Double Blind, Randomised 
Placebo Controlled Phase III Trial 
 
 
 
Version 7.0: 09 May 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICR02 /ASCOLT 
 
 
 
 
 
 Version 7.0: 09 May 2018  
 
TRIAL OUTLINE  
 
Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers - An International, multi-centre, double 
blind, randomised Placebo controlled Phase III Trial 
 
 
 
Dukes C / high risk Dukes B colon cancer  
(or) 
Rectal cancer subgroups 
Surgery 
(Complete resection of tumour) 
Standard therapy 
(at least 3 months of Chemotherapy 
+ Radiotherapy) 
 
Eligible patient 
 
Randomisation 
Aspirin 
200 mg OD for 3 years 
Placebo 
200 mg OD for 3 years 
3 monthly follow-up for 3 years 
followed by 
6 monthly follow-up for 2 years 
3 monthly follow-up for 3 years 
followed by 
6 monthly follow-up for 2 years 

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Version 7.0: 09 May 2018 
 
TRIAL MANAGEMENT GROUP 
Study Co-Chair 
Dr John Chia Whay Kuang 
 
Division of Medical Oncology 
National Cancer Centre 
11 Hospital Drive 
Singapore 169610 
 
 
 
A/Prof Toh Han Chong  
 
Division of Medical Oncology 
National Cancer Centre 
11 Hospital Drive 
Singapore 169610 
 
 
 
Dr Raghib Ali 
 
 
Director, Public Health Research Center  
New York University Abu Dhabi  
Saadiyat Island. PO Box 129188 
Abu Dhabi. UAE   
 
Prof Eva Segelov 
 
 
Professor/Director of Oncology 
Monash Health and Monash University 
Lvl 7, MHTP building, Monash Health 246 Clayton Rd 
Clayton VIC 3168 Australia 
 
Trial Project Management 
 
 
Project Manager 
 
Division of Medical Oncology 
National Cancer Centre 11 Hospital Drive 
Singapore 169610 
 
Trial Biostatisticians 
 
 
SCRI Statistician 
 
 
Singapore Clinical Research Institute 
31 Biopolis Way, Nanos #02-01  
Singapore 138669 
 
Trial Study Pharmacist 
 
 
National Cancer Centre Trial Pharmacist 
 
 
National Cancer Centre 
Oncology Pharmacy Level 3 
11, Hospital Drive 
Singapore 169610 
 
 
 
 

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 Version 7.0: 09 May 2018  
 
TRIAL STEERING COMMITTEE 
Independent Member 
 
 
Professor Pierce Chow 
 
 
Division of Surgical Oncology 
National Cancer Centre 
11 Hospital Drive 
Singapore 169610 
 
 
Professor Peter M Rothwell 
 
 
 
Department of Clinical Neurology  
University of Oxford  
Level 6, West Wing, John Radcliffe Hospital 
Oxford, OX3 9DU, UK  
 
Non-Independent Members 
Dr John Chia Whay Kuang 
 
 
Division of Medical Oncology 
National Cancer Centre 
11 Hospital Drive 
Singapore 169610 
 
A/Prof Toh Han Chong  
 
 
Division of Medical Oncology 
National Cancer Centre 
11 Hospital Drive 
Singapore 169610 
 
 
Dr Raghib Ali 
 
 
Director, Public Health Research Center  
New York University Abu Dhabi  
Saadiyat Island. PO Box 129188 
Abu Dhabi. UAE   
Prof David J Kerr 
 
 
Department of Clinical Pharmacology  
University of Oxford 
Old Road Campus Research Building 
Oxford, OX3 7DQ 
 
Prof Eva Segelov 
 
 
Professor/Director of Oncology 
Monash Health and Monash University 
Lvl 7, MHTP building, Monash Health 246 Clayton Rd 
Clayton VIC 3168 Australia 
 
Prof R John Simes 
 
 
Director 
NHMRC Clinical Trials Centre 
Medical Foundation Building 
University of Sydney NSW  2006 Australia 
 
Estelle Foo Mei Jye 
 
 
Project Manager  
Division of Medical Oncology 
National Cancer Centre 11 Hospital Drive 
Singapore 169610 
Observer, Nonvoting member 
Elmar Detering  
Medical Affairs Physician (MD, PhD) 
Global Medical Lead Aspirin (low dose; CRC)  
 
 
 
Bayer AG 
Medical Affairs TA Pulmonology  & Established 
Products. 
Medical Affairs & Pharmacovigilance, 
Pharmaceuticals 
Building S101 / 07 / 156 
Muellerstrasse 178 
13353 Berlin, Germany 
 

ICR02 /ASCOLT 
 
 
 
 
Version 7.0: 09 May 2018 
 
Data Monitoring Committee 
 
Prof Ian F. Tannock 
 
Emeritus Professor of Medical Oncology, 
Princess Margaret Cancer Centre 
610 University Avenue, 
Toronto, ON M5G 2M9, Canada 
 
 Prof Andrew Chan 
 
Massachusetts General Hospital / Program Director of 
Gastroenterology Training Program 
 
Dr Sharon Love 
 
 
Centre for Statistics in Medicine  
Wolfson College Annexe  
Linton Road, Oxford  
OX2 6UD, UK 
 
SUPPORTED BY GRANT FUNDING  
 
SingHealth Foundation 
 
National Medical Research Council, Singapore 
 
National Cancer Centre Research Fund 
 
Rising Tide Foundation 
 
Lee Foundation 
 
Lee Kim Tah Foundation 
 
 
 
PHARMACEUTICAL SUPPORT 
 
Bayer AG (Provided study drugs) 
 
The list of participating sites will be supplied in the form of supplementary documents as requested. 
 
 
This protocol is intended for use by the investigators and collaborators of this study. It is otherwise available 
for information only. No part of this protocol may be reproduced or distributed in any form or by any means, 
or stored in a database or retrieval system without the prior written permission of steering committee. 
 
 
 
 
 

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 Version 7.0: 09 May 2018  
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................... 1 
SUMMARY ......................................................................................................................... 2 
1.  INTRODUCTION ........................................................................................................... 6 
1.1. 
Background .................................................................................................................................... 6 
1.2. 
Adjuvant agents for colorectal cancer ......................................................................................... 7 
1.3. 
Failure of targeted Agents ............................................................................................................. 8 
1.4. 
NSAIDS as adjuvant agents .......................................................................................................... 9 
1.5. 
Aspirin’s Secondary Role – Prevention of new polyps ............................................................ 11 
1.6. 
Primary Prevention of Colorectal Cancer .................................................................................. 12 
1.7. 
  Preclinical data and scientific rationale ................................................................................... 14 
1.8. 
  Optimal biologically effective dose for Aspirin....................................................................... 15 
2. 
STUDY OBJECTIVE ................................................................................................. 16 
3. 
STUDY ENDPOINTS ................................................................................................ 16 
4. 
TRIAL DESIGN ......................................................................................................... 16 
5. 
ELIGIBILITY CRITERIA ........................................................................................... 17 
5.1. 
Inclusion Criteria .......................................................................................................................... 17 
5.2. 
Exclusion Criteria ......................................................................................................................... 18 
6. 
RANDOMISATION ................................................................................................... 18 
7. 
STUDY DRUG .......................................................................................................... 19 
7.1. 
How to take the study drug ......................................................................................................... 19 
7.2. 
Supply and Resupply of study drug .......................................................................................... 19 
7.3. 
Description and contents of study drug and placebo drug ..................................................... 19 
7.4. 
Packaging information ................................................................................................................ 19 
7.5. 
Storage information ..................................................................................................................... 20 
7.6. 
Study drug labelling and handling ............................................................................................. 20 
7.7. 
Compliance of study drug ........................................................................................................... 20 
7.8. 
Anticipated side effects of Aspirin ............................................................................................. 20 
8. 
BLINDING ................................................................................................................. 21 
8.1. 
Blinding ......................................................................................................................................... 21 
8.2. 
Code-break envelopes ................................................................................................................. 21 
8.3. 
Unblinding ..................................................................................................................................... 21 
9. 
TREATMENT SCHEDULE ....................................................................................... 21 
9.1. 
Treatment groups ......................................................................................................................... 21 
9.2. 
Treatment modification ............................................................................................................... 22 
9.3. 
Treatment discontinuation .......................................................................................................... 23 
9.4. 
Study Withdrawal ......................................................................................................................... 24 
10. 
CONCOMITANT/CONTRAINDICATED MEDICATIONS ....................................... 24 
11. 
ASSESSMENTS AND FOLLOW-UP ..................................................................... 24 
11.1. 
Screening .................................................................................................................................. 24 
11.2. 
Baseline ..................................................................................................................................... 25 
11.3. 
3-monthly assessments .......................................................................................................... 25 

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11.4. 
6-monthly assessments .......................................................................................................... 26 
11.5. 
Unscheduled visits .................................................................................................................. 26 
11.6. 
Assessment of recurrence and salvage chemotherapy ...................................................... 26 
11.7. 
Assessment of Medical Events ............................................................................................... 27 
11.8 
Post Month 60 – Clinical Data ..................................................................................................... 27 
12 
STATISTICAL CONSIDERATIONS ....................................................................... 27 
12.1 
Sample size calculation ............................................................................................................... 27 
12.2 
Statistical analysis ....................................................................................................................... 28 
12.3 
Interim analysis ............................................................................................................................ 29 
13 
SAFETY ................................................................................................................. 29 
13.1 
Definitions ..................................................................................................................................... 30 
13.2 
Reporting of Adverse Event ........................................................................................................ 31 
13.3 
Reporting of Death ....................................................................................................................... 31 
14 
SUB-STUDIES (For Singapore and Selected Sites Only) .................................. 32 
14.1 
Blood Samples ............................................................................................................................. 32 
14.1 
Biomarkers, protein, lipid and leukocyte profiling ................................................................... 32 
14.2 
Germline DNA ............................................................................................................................... 32 
14.3 
Stool Samples............................................................................................................................... 32 
14.4 
Urine Samples. ............................................................................................................................. 32 
14.5 
Archival tumour specimens ........................................................................................................ 32 
15 
DIRECT ACCESS TO SOURCE DATA ................................................................. 33 
16 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 33 
17 
ETHICAL CONSIDERATIONS .............................................................................. 33 
18 
INSURANCE .......................................................................................................... 33 
19 
PUBLICATION POLICY ......................................................................................... 33 
20 
STUDY ORGANISATION ...................................................................................... 34 
21 
ARCHIVING ........................................................................................................... 34 
REFERENCES ................................................................................................................. 35 
APPENDIX 1 – TNM AND DUKES STAGING FOR COLORECTAL CANCER .............. 39 
APPENDIX 2 – ECOG PERFORMANCE STATUS ......................................................... 41 
APPENDIX 3 – STUDY VISIT SCHEDULES & ASSESSMENTS ................................... 42 
APPENDIX 4 – STUDY DRUG LABEL ........................................................................... 43 

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LIST OF ABBREVIATIONS 
 
5FU 
5-Fluorouracil 
AE 
Adverse Event 
ALP 
Alkaline phosphatise 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase 
BP 
Blood pressure 
CEA 
Carcinoembryonic antigen 
CIOMS  
Council for International Organisations of Medical Sciences 
CRA 
Clinical Research Associate 
CT 
Computed tomography 
DFS 
Disease Free Survival 
DMC 
Data Monitoring Committee  
DRE 
Digital rectal examination 
EC 
Ethics Committee 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
ERUS 
Endorectal ultrasound 
FA 
Folinic acid 
FAP 
Familial adenomatous polyposis 
FOLFOX 
FOLFOX is a chemotherapy regimen for treatment of colorectal cancer, made up of the 
drugs, folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX) 
GCP 
Good Clinical Practice  
GERD 
Gastroesophageal reflux disease 
Hb 
Haemoglobin 
HR 
Hazard Ratio 
IRB 
Institutional Review Board 
LFT 
Liver function tests 
MCRC 
Medical Clinical Research Committee 
NSAID 
Non-steroidal anti-inflammatory drugs 
OS 
Overall Survival 
PGE2 
Prostaglandin E2 
PPI 
Proton pump inhibitor 
PR 
Pulse rate 
RT 
Radiation therapy 
SCRI 
Singapore Clinical Research Institute 
SAE 
Serious Adverse Event 
TCF 
T-Cell Factor 
TME 
Total mesocolon excision 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
VEGF 
Vascular Endothelial growth factor 

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SUMMARY 
Protocol 
Identifier: 
Version Number: 
Title:  
Study Phase: 
ASCOLT/ ICR02 
Version 7.0:   09 May 2018   
Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers 
An International, Multi-centre, Double Blind, Randomized 
Placebo Controlled Phase III Trial 
III 
Rationale: 
The utility of Aspirin and NSAIDs in preventing cancer, especially 
colon cancer is the subject of intense pre-clinical and clinical interest 
and investigation.  Whereas high quality evidence (randomized 
controlled studies) indicates that aspirin is effective in reducing 
colorectal adenomatous polyps; and numerous studies point towards 
an ability to prevent colorectal cancer; the role of Aspirin as an 
adjuvant agent in patients with established cancers remains to be 
defined.  The analysis of a nested cohort study (Nurses Health Study) 
has suggested that the initiation of Aspirin after the diagnosis of colon 
cancer was able to reduce colorectal cancer specific mortality (HR 
0.53, CI 0.33-0.86).  Further, a preplanned analysis of patients in the 
CALGB 89810 adjuvant Irinotecan trial suggested that patients who 
used aspirin or a cox2 inhibitor regularly had half the risk of 
recurrence and death. More recently, a Scottish study showed post-
diagnosis aspirin use to be associated with a lower risk of death from 
CRC (HR 0.58, CI 0.45-0.75).  Similarly, a Dutch study demonstrated 
post-diagnosis aspirin use to associate with an improvement in 
overall survival (HR 0.70, CI 0.57-0.88).  Up to date, although this 
data is strongly supportive of Aspirin’s potential role in adjuvant CRC 
therapy, the findings do not cross the threshold required to change 
clinical practice – that of a prospective randomized clinical trial.  Two 
large randomized cox-2 inhibitor studies had been undertaken to 
answer the same question, but were suspended prematurely, due to 
concerns of cardiovascular toxicity.  In contrast, Aspirin is cardio-
protective and is one of the most widely used drugs with a well-
established safety profile.  We hypothesize through this randomized, 
placebo-controlled adjuvant study, that Aspirin in patients with dukes 
C or high risk dukes B colorectal cancer (ASCOLT) can improve 
survival in this patient population over placebo control.  If indeed 
found to be beneficial, because aspirin is cheap and easy to 
administer, it will positively impact the lives of many individuals in 
Asia and globally.   
Objectives:  
Primary Endpoint:          Disease Free Survival (DFS) 
Secondary Endpoint:     Overall Survival (OS) over 5 years 
Subjects and 
Centres: 
A total of up to 1587 patients will be randomized from multinational 
centres.  
Inclusion 
Criteria:  
 
 
 
 
 
 
 
 
Male or female outpatient of ≥ 18 years of age or ≥ country’s legal 
age for adult consent 
 
Dukes C colon cancer, high risk Dukes B colon cancer, Dukes B 
rectal cancer or Dukes C rectal cancer  
 
Undergone complete resection of primary tumour  
 
Completed standard therapy (at least 3 months of chemotherapy ± 
radiotherapy ) 
 
Within 120 days of completion of standard therapy  
 
(surgery, chemotherapy ± radiotherapy)  
 
ECOG performance status 0 to 2 
 
Satisfactory haematological or biochemical functions  
(Tests should be carried out within 8 weeks prior to randomisation:- 
ANC ≥ 1.0 x 109/L, Platelets ≥ 100 x 109/L, Creatinine clearance ≥ 
30 mL/min, Total bilirubin ≤ 2 x the upper limit normal, AST & ALT ≤ 5 
x the upper limit normal) 

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                                                                                           Version 7.0: 09 May 2018 
 
 
 
 
Completed the following investigations 
 Colonoscopy(or CT colonogram(within 16 months prior to 
randomization) 
 Imaging of abdomen (CT or CT colonogram or MRI or PET or 
Ultrasound) within 16 months prior to randomization 
 
Written informed consent  
Exclusion 
Criteria 
 
 
 
Pre-existing Familial adenomatous polyposis, inflammatory bowel 
disease or ulcerative colitis 
 
Active gastritis or active peptic ulcer  
 
History of continuous daily use of PPI more than 1 year prior to 
consent 
 
Gastrointestinal bleeding within the past one year 
 
Haemorrhagic diathesis (i.e. haemophilia) 
 
Uncontrolled hypertension (untreated systolic blood pressure > 160 
mmHg, or diastolic blood pressure > 95 mmHg) 
 
History of recent cancers (except for colorectal cancers, non-
melanoma skin cancers, basal cell carcinomas, squamous cell 
carcinomas) in the past 5 years 
 
History of stroke, coronary arterial disease, angina, or vascular 
disease 
 
Patients who are on current long term treatment (≥ 4 consecutive 
weeks) with Aspirin, NSAID or Cox-2 inhibitors 
 
History of erosive GERD or active erosive GERD on gastroscopy. 
 
Patient on active current treatment with antiplatelet agents (i.e. off-
study Aspirin, clopidogrel, ticlopidine)  
 
Patient receiving current treatment with anticoagulants (i.e. warfarin, 
low molecular weight heparins) 
 
Pregnant, lactating, or not using adequate contraception 
 
Patient having known allergy to NSAID or Aspirin 
 
Unexplained rise of CEA (i.e. smoker with elevated CEA will not be 
excluded) 
 
Patient on other investigational drug 
 
Patients with HNPCC (Lynch Syndrome) 
 
Treatment 
Groups and 
Randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
Study Duration 
 
 
 
 
 
 
Eligible patients will be randomized to two treatment arms, (either 
200mg Aspirin for 3 years or 200mg Placebo for 3 years) using the 
following stratification factors:  
 
Study centre 
 
Tumour type (Dukes C colon, high risk Dukes B colon cancer & 
rectal cancer sub-groups) and  
 
Type of adjuvant chemotherapy received (exposed/ not exposed 
to oxaliplatin) 
Eligible Patient
Aspirin Arm
200mg daily for 3 years
Placebo Arm
200mg daily for 3 years
Randomized
 
 
Patients will be receiving aspirin or placebo for 3 years after 
randomisation and followed up for 5 years after randomization. The 
study is expected to recruit the last patient by end of 2020, with the 
last patient potentially being followed up until 2025.  
NOTE– (these dates may need changing according to new 
estimated recruitment timelines) 

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Follow-Up 
 
 
After randomization, patient will have 3 monthly assessments for 3 
years (month 3 to month 36) followed by 6 monthly assessments for 
additional 2 years (month 42 to month 60). Subjects who consent to 
continue information collection after month 60 will have vital data 
captured via review of medical records or phone call.  Data capture for 
vital status, recurrence, NSAIDs consumption and medical events 
(e.g. stroke, acute mycocardial infarction [AMI], new cancers, and 
major bleeds) will occur every 12 months and up to the time of last 
patient last visit (month 60 or earlier) at the site.   
 
Statistics and 
Analysis Plan 
 
Based on recent studies of aspirin in colorectal cancer patients, we 
assumed a hazard ratio of 0.72 for disease free survival between the 
aspirin and the placebo groups (the corresponding absolute 
difference of disease free survival rate between the two treatment 
groups is about 8.5%, assuming that 3-year disease free survival 
rates for Dukes B colon cancer, Dukes C colon cancer and rectal 
cancer are 65% after standard adjuvant chemotherapy). A total of 
300 recurrences (or deaths) is required for a two-sided log-rank test 
of 5% type I error, 80% power and 15% attrition rate. This translates 
into a total sample size of 1200 patients if the disease free survival 
rate is 65% in the placebo group.  
A recent review of trial interim data, after enrollment of at least 1140 
patients and 3 year follow-up being completed in 430 patients, 
revealed a pooled disease free survival rate of 79% at 5 years, we 
subsequently recalculated the sample size to be 1587 patients 
(attrition rate reduced to 10%, the rest unchanged).  
In analyzing the Primary Endpoint: Disease Free Survival (DFS) and 
Secondary Endpoint: Overall Survival (OS), logrank test will be used 
to compare between groups. Hazard ratio and its 95% confidence 
interval will be estimated. Cox model will be further performed to 
adjust for potential confounding factors.  
 
Two interim analyses are scheduled. The first analysis is a safety and 
toxicity analysis planned to be done after 540 patients are recruited 
into the study or at the mid-point of the targeted recruitment period, 
whichever comes earlier. The second analysis will look at safety as 
well as DFS and OS, after 540 patients have been followed up for 3 
years, or when the cohort of patients included in the first analysis 
have completed follow up for 3 years..   
 
 
 
 

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Assessments 
Screening* 
 
Baselin
e 
Follow-up month (+/- 1 month) 
Follow-up month 
(+/- 1 month) After 
Recurrence 
Follow-up month (+/- 1 
month) After Early Study 
Drug Discontinuation and 
no recurrence 
Post Month 
60 
 
3, 9 ,15, 
21, 27, 33 
6,12, 18, 
24, 30, 36 
42, 48, 
54, 60 
3 to 60 
3 to 36 
Written informed consent 
 
x 
 
 
 
 
 
 
 
Demography, Tumour history, Medical 
history & family history 
 
 
x 
 
 
 
 
 
 
Record surgical measurements,(For 
rectal cancer only) 
 
 
x 
 
 
 
 
 
 
Adjuvant Therapy 
 
 
x 
 
 
 
 
 
 
Vital signs (Body weight, BP, height), 
ECOG 
 
 
x 
 
 
 
 
 
 
Hb 
(Within 8 weeks prior 
to randomisation) 
 
x 
 
x 
 
 
 
 
Platelet count, Creatinine, Serum 
Bilirubin, AST, ALT 
(Within 8 weeks prior 
to randomisation) 
x 
 
 
 
 
 
 
 
CEA 
 
 
x 
x 
x 
x 
 
x 
 
Imaging of abdomen (CT or CT 
colonogram or MRI or PET or 
Ultrasound) 
To be done if not done 
within 16 months prior 
to randomization 
x 
 
x  (Mth 6, 18 and 30) Optional; or frequency according to institutional practice 
 
Radiological examination of the Chest 
(including but not restricted to Chest x 
ray, CT thorax or PET scan) 
To be done if not done 
within 16 months prior 
to randomization 
x 
 
 
 
 
 
 
 
Colonoscopy/CT colonogram 
Full colonoscopy if not 
done within 16 months 
prior to randomization 
x 
 
x  (Mth 6 and 30) Optional; or frequency according to institutional practice 
 
AE and SAE 
 
 
 
x 
x 
 
 
 
 
Death 
 
 
 
x 
x 
x 
x 
x 
x 
Medical Events 
 
 
 
x 
x 
x 
x 
x 
x 
Concomitant NSAIDs 
 
 
 
x 
x 
x 
x 
x 
x 
Concomitant treatment/medication 
 
 
 
x 
x 
 
 
 
 
Recurrence, Salvage Chemotherapy 
 
 
 
x 
x 
x 
x 
x 
x 
Notes: 
*Screening can start after last dose of standard therapy;     

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1.  INTRODUCTION 
1.1. 
Background 
Colorectal cancer is the third most common cancer worldwide with almost 1 million new cases 
diagnosed each year.  It is now also the third leading cause of cancer mortality in men and women 
with more than half of diagnosed patients dying from the disease.1 Over the past 3 decades, the age-
standardized incidence rate for colorectal cancer has increased from two to fourfold in Asian countries 
such as China, Japan, South Korea and Singapore.  Mortality rates in Asian countries have risen 
concomitantly and in Singapore rates have doubled over the same period, .2  now with incidence rates 
amongst the highest in Asia; colon cancer has recently surpassed lung cancer as the commonest 
cancer diagnosed in Singapore. 3  
With the rising rates of cancer, a fundamental shift of the cancer burden has also occurred between 
the developed and underdeveloped world. This problem, highlighted in the 2008 WHO World Cancer 
Report, warned of a disproportionate number of cancer deaths occurring in developing countries.  
Currently of the annual 12 million new cancer cases diagnosed and the 7.6 million cancer deaths 
worldwide; 5.6 million new cases and 4.7 million cancer deaths occurred in developing countries.4   By 
the year 2020, it is predicted that changes in the demographics of the population in  developing 
nations will lead to approximately 70% of all new cancers occurring in lower income countries.5  
Efforts therefore will have to be made to develop novel therapies that are not only effective but also 
accessible to the people who need them.6 
 
 
Fig. 1 Time trends of ASR of colorectal cancer of males from    
Western and Asian cancer registries showing increasing rates.  
WHO/IARC database 2000.  
 
 
 
 
Fig 2. Trends in Age standardised Incidence 
for selected cancer sites in Singapore Males 
(1968-2002) 

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1.2. 
Adjuvant agents for colorectal cancer  
The 5 FU Era 
Adjuvant chemotherapy has been proven to improve relative overall survival in duke’s C colon cancer 
by approximately 25-35%, in a series of landmark clinical trials conducted over the past 3 decades 
(table 1).  The first trial to show benefit was NSABP-C01 conducted in the 1980s.  Post-surgical 
patients randomised to Semustine, Vincristine and 5FU (MOF) chemotherapy were found to be 30% 
less likely to develop recurrences or death compared with those receiving surgery alone.7  
Two subsequent studies further established 5FU based chemotherapy as the standard of care.  In the 
study by Moertel et al, post-operative intravenous 5FU combined with levamisole reduced the relative 
risk of recurrence and death by 40% and 33%, and the absolute risk of death by 12%, compared with 
standard surgery alone.8  For the North Central Cancer Treatment Group (NCCTG) study, colon 
cancer relapse and death was significantly lower in patients receiving intravenous 5FU/leucovorin 
compared with surgery alone -  27% versus 41% and 28% versus 40% respectively.9 
Over the next two decades, due to a lack of effective new agents, development continued to focus on 
5FU based regimens comparing duration, schedules, and administration route.  For example, 12 
month was compared with 6 month duration of chemotherapy and continuous infusion 5FU (via pump) 
was compared with bolus 5FU in 3 large randomised studies.  Although toxicity was lower for 
infusional 5FU, overall survival was not improved.10-12   Finally, in 2005, the landmark X-ACT study, 
demonstrated oral 5FU (capecitabine) to be non-inferior to IV 5FU. (Twelves et al).13   
Trial Name 
No. 
of 
Subjects  
Intervention Arms 
Results 
Reference 
 
NSABP C03 
 
 
 
1166 
 
MOF  versus 
BCG   versus 
Observation 
 
 
Improved DFS and 
OS 
 
J Natl Cancer Inst 1988;80(1):30-
6. 
Intergroup  
 
 
929 
5FU/ levamisole 
vs 
levamisole alone 
 
Improved DFS and 
OS 
Ann Intern Med 1995;122(5):321-
6 
NCCTG 
 
 
317 
5FU/Leucovorin 
vs 
Observation 
 
Improved DFS and 
OS 
J Clin Oncol 1997 Jan;15(1):246-
50 
X-ACT 
 
1987 
Capecitabine (oral 5FU) vs 
Bolus 5FU (mayo regimen) 
No 
difference 
between IV and 
oral 5FU 
N Engl J Med 2005;352:2696-704 
 
Table 1.  Clinical Trials - Adjuvant chemotherapy for colon cancer (1988 – 2005) 
 
Oxaliplatin and Irinotecan 
A year before X-ACT, the MOSAIC study was able to establish a new standard of care.  For the first 
time in two decades, a new agent (oxaliplatin), was shown to improve 3 year disease free survival 
(DFS) over infusional 5FU alone.14   After 7 years of follow up, oxaliplatin was associated an absolute 
2.5% survival gain for Dukes C colon cancer.  Although Oxaliplatin-5FU combinations have become 
the new standard of care for Dukes C colon cancer; neurotoxicity and thrombocytopenia continue to 
remain significant challenges in the clinic, and the higher cost of oxaliplatin still represents a 
substantial barrier to its routine adoption in many countries including Singapore. 
Since the MOSAIC study was published in 2004, no other new agents have been shown to improve 
colon cancer outcomes (Table 2). For example, although highly effective in the metastatic setting, 

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Irinotecan chemotherapy has failed in three large randomised adjuvant studies – the EORTC 
PETACC-3, ACCORD and CALGB 89803.15-17   The failure of irinotecan is particularly disappointing, 
since there are so few agents with a similar track record of efficacy in the metastatic setting.  
However, the consistent negative results in these high profile studies, means that further trials with 
Irinotecan will unlikely be undertaken in the future.18  With conventional chemotherapy combinations 
appearing to be approaching their therapeutic index and limit, much hope is now centred on 
combinations using biologic agents, for example bevacizumab and cetuximab.   
Trial Name 
No 
of 
Subjects  
Intervention Arms 
Results 
Reference 
 
Oxaliplatin 
MOSAIC 
 
 
1123 
Infusional 
5FU 
/ 
Oxaliplatin 
Vs 
Infusional 5FU alone 
Improved DFS 
N Engl J Med 2004;350:2343-51 
Irinotecan 
PETAAC 3 
 
 
2124 
Irinotecan/5FU  
Vs 
5FU 
No difference 
J Clinl Oncol, 2005;23, (16S): 8 
ACCORD 
 
 
2014 
Irinotecan/5FU  
Vs 
5FU 
No difference 
J Clin Oncol. 2005;23(16S):3502. 
CALGB 89803 
 
1264 
Irinotecan/5FU  
Vs 
5FU 
No difference 
J Clin Oncol. 2004;22(14S):3500. 
Table 2.  Clinical Trials - Oxaliplatin and Irinotecan Chemotherapy  
1.3. 
Failure of targeted Agents 
Bevacizumab The idea of using anti-VEGF monoclonal antibodies such as Bevacizumab, upfront in 
the adjuvant setting is one that carries particular scientific merit. The concept of the “angiogenic 
switch” means that tumours more than 1mm would need to eventually grow their own blood supply in 
order to survive.19  Consequently , bevacizumab should be theoretically even more effective, when 
used to treat tumours that are small, and particularly vulnerable to vascular disruption.  Two large 
adjuvant bevacizumab studies have been undertaken to prove this concept (table 3) – the NSABP 
C08 trial and the AVANT study.20 The results of the C08 study was presented at ASCO 2009 and was 
negative for its primary endpoint21.  2632 patients were randomised to either 5FU/Oxaliplatin or the 
same chemotherapy with Bevacizumab and after a median follow up of 3 years, there was no 
significant difference in disease free survival between the 2 populations.  The failure of bevacizumab 
in the adjuvant setting has forced a serious re-evaluation of our current understanding of tumour 
dormancy and treatment of micrometastasis disease free survival.  
 
Table 3.  Adjuvant Bevacizumab studies 
Trial Name 
No. of 
Subjects 
 
Intervention Arms 
Results 
Reference/ Comments 
 
NSABP-C08 
 
 
 
 
 
2632 
 
Oxaliplatin/5FU/ 
Bevacizumab 
Vs 
Oxaliplatin/5FU alone 
 
 
Negative  
 
J 
Clin 
Oncol 
27:18s, 
2009 
(supple; abstr LBA4) 
 
 
AVANT 
 
3450 
Oxaliplatin/5FU/ 
Bevacizumab 
Vs 
Oxaliplatin/Capecitabine/  
Bevacizumbab 
Vs 
Oxaliplatin/5FU alone 
Pending 
www.clinicaltrials.gov: 
NCT00112918 

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Cetuximab, a chimeric human-mouse monoclonal antibody to VEGF receptor is currently under 
development as an adjuvant agent for colon and rectal cancers (table 4). 22-23 Although Cetuximab is 
highly effective in the metastatic setting, the preliminary results of the NCCTG Intergroup 0147 study 
evaluating its use in the adjuvant setting indicates that it  improves neither disease free survival nor 
overall survival.24   
 
Table 4.  Adjuvant Cetuximab studies 
1.4. 
NSAIDS as adjuvant agents 
Cox 2 specific inhibitors.  Since the discovery that cox-2 enzyme was consistently over-expressed 
in colon cancer; a large body of pre-clinical scientific evidence has emerged implicating cox and 
PGE2 in cancer initiation and propagation.25-26 This has culminated in two large randomised trials 
evaluating Cox-2 specific inhibitors as specific adjuvant agents in colon cancer (table 5) – VICTOR 
and the EORTC PETAAC 5.  Both these trials have however been discontinued following concerns 
about the cardiovascular safety for these agents when in extended use.  PETAAC 5 was a double 
blind randomised placebo controlled study, and evaluated celecoxib or placebo for 3 years and used 
DFS as a primary endpoint.27  Unlike ASCOLT, celecoxib was administered concurrently with 
chemotherapy (this is not possible with aspirin due to the risk of chemotherapy induced 
thrombocytopenia) and the population under study was restricted to Duke C colon cancer patients 
only.   
Launched in 2001, VICTOR randomised patients with stage II or III colon and rectal cancer that had 
completed standard adjuvant therapy to 2 years of rofecoxib, 5 years of rofecoxib or placebo, before it 
was prematurely suspended in 2005 when rofecoxib was withdrawn from the market.28   In contrast to 
the EORTC study, VICTOR only randomized patients after completion of standard adjuvant therapy 
and it also included rectal cancers and stage II disease.  In the analysis of 2300 patients who had 
been treated with study drug for a median of 7 months, there was no difference observed between the 
two treatment groups in terms of disease free survival and overall survival.29 However due to the short 
median exposure to study medication (7mths versus the planned 2 and 5 years), and the failure to 
achieve accrual target, it is not possible to make any conclusion concerning efficacy.  Of note 
however, survival during the first year was significantly superior in favour of rofecoxib, during the first 
year of study (when patients were exposed to study drug), but the difference was insignificant at 5 
years. 
Study Name 
No of  
Subjects 
Intervention 
Results 
Reference 
 
 
 
 
 
EORTC 
PETAAC5 
1450 
Celecoxib vs Placebo 
Suspended 
www.clinicaltrials.gov 
NCT00085163 
VICTOR 
 
 
7000 
Rofecoxib vs Placebo 
Suspended 
Annals 
of 
Oncology 
19 
(Supplement 8):2008, LBA3 
Table 5:  Adjuvant Cox-2 Inhibitor studies  
Trial Name 
No 
of. 
Subjects 
 
Intervention Arms 
Results 
Reference/ Comments 
 
NCCTG Trial 
 
2600 
 
Chemotherapy with or without 
5FU 
 
Negative 
 
www.clinicaltrials.gov  
NCT00079274 
 
French Study 
(FFCD) 
 
 
2000 
 
Ox/5FU/Cetuximab 
Vs 
Ox/5FU 
 -  
 
www.clinicaltrials.gov NCT00265811 

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Aspirin. The first suggestion that NSAIDs/ Aspirin may be beneficial in the adjuvant setting derives 
from a pre-planned review of patients in the CALGB 89803 study.  This study randomised stage III 
colon cancer patients to 5FU chemotherapy with or without irinotecan, and in addition to the primary 
study, incorporated a pre-planned analysis to compare outcomes of patients who were on Aspirin or 
cox2 inhibitors.  Of the 830 patients surveyed, 75 patients and 41 patients used Aspirin and Cox-2 
inhibitors regularly.  Amongst Aspirin and Cox2 users, the hazard ratio for disease recurrence was 
0.45 (95% CI 0.21-0.97) and recurrence and/or death 0.48 (95%CI 0.24-0.99).  No difference however 
was noted with paracetamol use.30    
A nest cohort study (Nurses’ Health Study) suggested that the initiation of Aspirin after the diagnosis 
of colon cancer was able to reduce colorectal cancer specific mortality (HR 0.53, CI 0.33-0.86) on 
multivariate analysis31.  Regular aspirin use after diagnosis was associated with an impressive 
lowering of colorectal cancer−specific mortality among participants in whom primary tumours 
overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76).  This is in contrast to patients with 
tumours that had weak or absent cox2 expression where aspirin use was not associated with lower 
risk (multivariate HR, 1.22; 95% CI, 0.36-4.18).  This suggests a biologically plausible mechanism for 
aspirin’s activity.   
The California Teachers Study conducted by Zell et al was a prospective cohort study comprising 
133,479 female public school teachers and administrators32. Aspirin and ibuprofen use was assessed 
by a self-administered questionnaire, and incident diagnosis of CRC was identified through the 
California Cancer Registry database. Amongst 621 participants who developed CRC, regular NSAID 
(aspirin or ibuprofen) use pre-diagnosis was found to decrease overall risk of death and death from 
CRC. Amongst regular pre-diagnosis aspirin or NSAID users (approximately a third of the study 
cohort), the multivariate HR for CRC-specific mortality was 0.62 (95% CI 0.41–0.94), and for overall 
survival was 0.74 (95% CI 0.54–1.01). When analysed for duration of use, 5 or more years of aspirin 
use was associated with an even greater benefit for CRC-specific survival (RR = 0.33; 95% CI 0.18–
0.63) and for overall survival (HR = 0.53; 95% CI 0.34–0.83). 
More recently, Bastiaannet et al published the largest observational study evaluating the benefit of 
post--diagnosis ‘adjuvant’ aspirin33. In total, 4,481 patients with CRC were identified from a population 
cancer registry in the Netherlands, and aspirin use was assessed from a centralized prescription 
database.  Frequent aspirin use post CRC diagnosis was associated with significant survival gain 
(adjusted HR 0.70; 95%CI 0.57–0.88).  Aspirin dose in this Dutch study was 80mg daily.      
Most recently McCowen et al analysed 2990 CRC patients in a Scottish cohort34.  Aspirin use post-
diagnosis was associated with lower risk of all-cause mortality (HR =0.67, 95%CI 0.57–0.79) and 
colorectal cancer-specific mortality (HR 0.58; 95%CI 0.45–0.75).  Majority of patients in this study 
used low dose Aspirin (75mg daily). 
Although the results from these studies are extremely exciting and have the potential to open up new 
avenues in our understanding of cancer biology; because they are observational, the results will have 
to be proven in a prospective randomized placebo-controlled study.  The ASCOLT study is the first 
study to evaluate this. 
 

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Study Name 
No of 
subjects 
Study Type 
 
Intervention 
Results 
Reference 
 
CALGB 89803 
(Fuchs et al) 
 
 
 
 
830 
 
Nested 
case-control 
study 
 
 
5FU/Leu +/- Irinotecan 
 
Patients prospectively 
surveyed for Aspirin 
/Cox2 use  
 
Lower recurrence 
for patients on  
Aspirin and cox2 
inhibitors (RR 
0.48). No benefit 
for paracetamol 
 
 
J Clin Oncol 2005;23S: 
3530 
 
Nurses Health 
Study 
(Chan et al) 
 
1279 
Nested 
case-control 
study 
 
Analysis of outcomes 
with regards to aspirin 
use 
Reduced 
colorectal cancer 
specific mortality 
(HR 0.53) 
JAMA 2009;302(6):649-
659 
 
California 
Teachers 
Study  
(Zell et al) 
 
621 
 
Nested 
case-control 
study 
 
 
Analysis of outcomes 
with regards to pre-
diagnosis aspirin use   
 
Reduced CRC-
specific mortality 
(HR 0.62) 
 
Cancer 2009; 115: 5662–
5671 
 
Dutch Study 
(Bastiaannet 
et al) 
 
4481 
 
Cancer 
Registry 
Study 
 
 
Analyzed according to 
Post-CRC diagnosis 
aspirin use 
 
Reduced overall 
mortality 
(HR 0.70) 
 
Br. J. Cancer 2012; 106: 
1564–1570. 
 
Scottish Study 
(McCowen et 
al) 
 
2990 
 
Cancer 
Registry 
Study 
 
 
Analyzed according to 
Post-CRC diagnosis 
aspirin use 
 
Reduced CRC-
specific mortality 
(HR 0.58) 
 
Eur J Cancer 2012. 
http://dx.doi.org/10.1016/j
.ejca.2012.10.024 
 
Table 6.  Evidence supporting role for Aspirin in Established Colon Cancer 
 
1.5. 
Aspirin’s Secondary Role – Prevention of new polyps 
There is currently high quality evidence from a series of prospective placebo-controlled randomized 
studies that Aspirin and NSAIDs reduced the incidence of colorectal adenomas (table 7).  Therefore 
since patients with resected colorectal cancer are at increased risk of developing a second 
metachronous cancer (up to 3% of patients in the first 5 years), they may derive secondary benefit 
from the use of aspirin.   
In the study by Sandler et al, a total of 635 patients were randomised to receive Aspirin 325 mg daily 
or placebo. One or more adenomas were found in 17% of patients in the Aspirin group and 27 % of 
patients in the placebo group (P=0.004). The relative risk of any polyp in the Aspirin group was 0.65 
(95%CI 0.46-0.91) and the time to detect the first adenoma was longer in the Aspirin group than in the 
placebo group.35 In the Baron study, patients were randomised to receive Aspirin at 81 mg, 325 mg or 
placebo. For advanced neoplasm (adenomas measuring at least 1 cm, or with villous, tubulovillous 
features, severe dysplasia or invasive cancer) the relative risks were 0.59 (95% CI 0.38-0.92) for the 
81 mg arm and 0.83 for the 325 mg Aspirin arm.36  In a third trial by Logan et al, 945 patients were 
randomised to Aspirin, Folate supplementation or placebo.  Whereas no benefit was found for folate, 
Patients on Aspirin had a significant reduction in polyp burden.37  More recently, a 375 patient 
randomised study demonstrated that patients treated with Sulindac and Difluoromethylornithine 
(DMFO), a drug also used to treat trypanosomiasis, reduced the risk of recurrent adenomas by 72% 
and high risk adenomas by 92%.38    This magnitude of reduction was much larger than expected and 
in fact was the greatest seen for any chemoprevention trial to date and this has sparked off a renewed 
interest in the use of NSAID combination agents for chemoprevention.39  Cox2 inhibitors studies (i.e. 
APC, PreSAP, APPROVe) have also shown this class of agents to be effective in reducing polyps, 40-
42 however their adverse cardiovascular profile precludes their long term use for this indication.  
Aspirin however is cardio-protective and can be safely administered over prolonged periods of time.43-
44   

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Study / 
Author 
 
No of 
Subjects 
Intervention 
Results 
Reference 
Baron et al 
 
 
1121 
Aspirin 81mg  
vs 
Aspirin 325mg  
vs 
Placebo 
RR 0.59 for high risk polyps in 81mg 
Aspirin arm 
N Engl J Med 2003;348:891 
Sandler et al 
 
 
517 
Aspirin  vs 
Placebo 
RR 0.65 for any adenoma in 325mg 
Aspirin arm. 
N Engl J Med 2003;348:883 
Logan et al 
 
 
945 
Aspirin 300mg  
Vs 
Folate 0.5mg 
Vs  
Placebo 
RR 0.79 for any adenoma and 0.63 
for high risk adenoma in Aspirin arm 
Gastroenterology 2008; 
134:29 
Meyskens et al 
 
 
 
375 
Sulindac + DMFO  
Vs 
Placebo 
RR 0.3 for any adenoma and RR 
0.085 for high risk adenoma 
Cancer Prev Res 2008;1:32 
APC study 
 
 
1364 
Celecoxib vs 
Placebo 
RR 0.67 for 200mg bd dose and RR 
0.55 for 400mg bd dose 
 
N Engl J Med. 2006;355:873 
PreSAP study 
 
 
1561 
Celecoxib vs 
Placebo 
RR 0.64  for adenomas and RR 0.59 
for high risk adenomas 
N Engl J Med. 2006;355:885 
APPROVe 
Study 
2587 
Rofecoxib vs 
Placebo 
RR 0.76 for adenomas. RR 0.65 for 
advanced adenomas  
Gastroenterology 
2006;131:1674 
 
Table 7.  NSAIDs and Polyp prevention 
 
1.6. 
Primary Prevention of Colorectal Cancer 
A large number of epidemiological and clinical studies have shown a strikingly consistent 40 to 50 
percent reduction in the risk of colorectal neoplasia, in patients on regular aspirin, despite the 
differences in study designs, populations, and patterns of Aspirin use.45    
In a retrospective Australian case control study performed in the 1980s, Kune et al noticed that there 
was a significant deficit of heart disease, stroke and arthritis in patients who had colon cancer who 
used regular aspirin amongst 715 colon cancer cases matched against 727 controls.  On multivariate 
analysis, controlling for heart disease and stroke, the association between aspirin use and incidence 
of colon cancer persisted and remained highly significant across gender and disease site.46 
Later, in a prospective mortality study of 662,424 individuals who provided information on the 
frequency and duration of their aspirin use, Thun et al noted that death rates from colon cancer 
decrease with more frequent aspirin use.  The relative risk among persons who used aspirin 16 or 
more times per month for at least one year was 0.60 in men (95% CI 0.40 - 0.89) and 0.58 in women 
(95% confidence interval, 0.37 - 0.90).  Adjustment for dietary factors, obesity, physical activity, and 
family history did not alter the findings significantly and no association was found between the use of 
acetaminophen and the risk of colon cancer.47 
Further support comes from the analysis of the results of the National Health and Nutrition 
Examination Survey I (NHANES I) and the NHANES I Epidemiologic Follow-up Studies (NHEFS).  
Amongst 12 668 responding subjects who were followed up an average of 12.4 years, 1,257 were 
eventually diagnosed with cancer.  The relative risk of colorectal cancer amongst younger men who 
were regular users of aspirin was 0.35 (95% CI 0.17-0.73).48 
In the Nurses Health Study, women were surveyed using 3 consecutive questionnaires in 1980, 1982 
and 1984.  Incidence of colorectal cancer in women who were consistent users of aspirin, defined as 

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2 or more tablets a week, were compared with non-users.     In total, 331 new cases of colorectal 
cancer diagnosed during 551,651 person-years of follow-up.  Although there was no difference at 4 
years; after 20 years of consistent aspirin use, there was a statistically significant reduction (relative 
risk, 0.56; 95% CI  0.36 to 0.90; P for trend = 0.008).49. 
More recently, a combined analysis of two randomised aspirin trials (The British Doctors Aspirin Trial 
and the UK-TIA  Aspirin Trial), demonstrated that Aspirin reduced the incidence of colorectal cancer 
with a Odds Ratio (OR) of 0.74 (95% CI 0.56-.97). Subjects in these studies were randomised 
prospectively to aspirin or placebo, but with a vascular outcome as the primary endpoint.  In compliant 
patients who received Aspirin for 5 years or more, the OR for incidence of new colorectal cancer at 
10-14 years was 0.26 (95% CI 0.12-0.56, p=0.0002).  A systemic review of published observational 
studies performed by the same authors showed that in 19 case-control studies (20,815 cases) and 11 
cohort studies (1,136,110 individuals), regular use of Aspirin or NSAID was consistently associated 
with a reduced risk of colorectal cancer.50 
In the Women’s Health Study,  39 876 women were randomised in a 2x2 factorial trial design to 
aspirin 100mg every other day, vitamin E and placebo.   After an average 10 yrs of follow up, 2865 
new cases of invasive cancers were diagnosed however there was no effect of Aspirin on the 
incidence of all cancers or colorectal cancer.   This study was however limited by the low dose and 
(alternate-day) schedule of aspirin administration.51  
Study / Author 
 
Study Type 
No of 
Subjects 
Results 
Reference 
 
Kune et al. 
 
 
 
Case-Control 
 
715 colon 
cases vs 
727 controls 
 
 
significant deficit of colon cancer 
amongst aspirin users 
 
Cancer Res 1988 
;48:4399 
Thun et al. 
 
 
 
 
 
Nested Case-Control 
662,424 
Death rate from gastrointestinal 
cancer  40% lower amongst 
individuals who used Aspirin 16 
times/ mth or more. 
Cancer Res 1993; 15; 
53 (6): 1322-7 
NHANES I and 
NHEFS study 
 
 
 
Nested Case-Control 
12,668 
Lower incidence risk across 
several cancers with the lowest 
risk amongst young male aspirin 
users 
Epidemiology 1994; 
5(2):138-46 
Nurses Health 
Study 
 
Nested Case-Control 
551,651 
person yrs of 
follow up 
 
Lower risk of colon cancer with 
prolonged aspirin use 
N Engl J Med 1995; 
333 : 609-14 
US Physician 
Health Study 
 
 
Randomised trial 
evaluating aspirin in 
vascular disease 
22,071 
No Benefit 
N Engl J Med 1989; 
321:129 
Women’s Health 
study 
 
Randomised trial 
evaluating aspirin in 
vascular disease 
 
39,876 
No Benefit 
JAMA 2005;294:47 
Flossman et al 
 
 
 
Randomised trials 
evaluating aspirin in 
vascular disease 
7588  
Overall lower incidence of 
colorectal cancer HR 0.74, (95% 
CI 0.56-0.97) in Aspirin users. 
 
Amongst compliant patients with 
prolonged (>5 yrs) use, HR 0.26 
(95CI 0.12-0.56) 
Lancet. 2007 May 
12;369(9573):1603-13 
 
Table 8.  Aspirin and Primary prevention of colorectal cancer 
 
 
 

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1.7. 
  Preclinical data and scientific rationale 
The pathways and mechanisms in which aspirin/ NSAIDs inhibit colon cancer cell growth are multiple, 
and complex.52,53  Aspirin and Indomethacin have been shown in numerous animal studies to reduce 
the incidence, multiplicity and size of chemically induced gastrointestinal cancers54-56 and in APC min 
mice.57  Aspirin has also been shown to have anti-angiogenic properties in vitro and is able to potently 
inhibit endothelial cell migration and endothelial capillary tube formation.58  Sulindac and cox2 
inhibitors have also been shown to reduce microvascular density, cell proliferation index and increase 
apopotosis in-vivo, in athymic xenograft mouse models.59    Recently in an aggressive ovarian clear-
cell cancer mouse model, mice treated with aspirin were noted to have markedly lower ascitic volume, 
smaller area of diaphragmatic tumor coverage, and a longer time to disease progression and distant 
metastatasis.60 Through a series of experiments, the authors were able to show that increased local 
and systemic inflammation always accompanied tumor progression and the extent of inflammation 
also corresponded with disease progression.  By modulating inflammation via macrophage depletion, 
researchers were able to alter rate of cancer progression in the mice – thus demonstrating that 
aspirin’s activity was dependent on the adaptive immune system.  This is particularly interesting 
because inflammation stands at the nexus of the adaptive immune response, and the latter is an 
extremely powerful prognostic marker in human colon cancer.61   
Whilst it is well known that chronic inflammation predisposes to certain malignancies, it has only 
recently recognized that a maladaptive inflammatory response is required for malignant 
transformation and metastasis.62  Indeed Hanahan and Weinberg have included tumor promoting 
inflammation as one of the key hallmarks of cancer.  63  Inflammation has been shown to induce 
widespread epigenetic changes in ileum of mice (i.e. methylation of polycomb target genes) leading to 
silencing of multiple genes required for the development of cancer.64  Studies have also linked 
proinflammatory PGE2 (a downstream product of cox activation) with colon cancer carcinogenesis via 
complex interactions with stem cell pathways.65,66 Indeed mice which lack the ability to produce PGE2 
have resistance to colon cancer.67   The evidence from preclinical studies is also finding some support 
from several human studies. For example, a very large cohort study in China found a strong 
association between urine PGE2 and the risk of developing colon cancer68 and another Scottish 
study, noted that high pre-operative CRP levels correlated with poor tumor specific survival.69   Low 
doses of Aspirin has been shown to be highly effective in reduce rectal mucosal PGE2 levels in 
human subjects70,71 and this may be one reason to explain its anti-cancer effect.   
Aspirin is a non-selective inhibitor of cox and binds to both cox-1 and cox-2 in an irreversible fashion.  
Whereas cox-1 is constitutively activated in all tissues, cox-2 represents an inducible isoform that is 
only expressed in inflamed tissues.  Cox-2 is not normally expressed in normal colonic epithelial 
tissue, however it is over-expressed in 40-50% of adenomatous polyps and in 85% of colon cancers.72  
Further, the intensity of cox over-expression is higher in metastasis when compared to the primary 
colonic tumor.  Cox-2 has been shown to play an important role in tumor growth and studies of cox-2 
knock-out mice have demonstrated inhibition of tumor growth versus wild type mice.  Conversely, 
when wild type mice were treated with cox-2 inhibitors, it also demonstrated a similar ability to retard 
tumor growth.73 It is currently believed that NSAIDs and cox-2 inhibitors also act on additional 
pathways apart from cox.  Invitro studies in some instances seem to indicate NSAIDs do not require 

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the presence of cox-2 to prevent cancer and are able to demonstrate an ability to inhibit cell 
proliferation, angiogenesis and to induce apoptosis, even in the absence of cox-1 and/or cox-2.74.  
Indeed, most recent analysis of colorectal cancer patients in the Nurses Health Study indicate that 
tumor PIK3CA mutational status may help select for patient who would benefit from aspirin 
treatment.75   
1.8. 
  Optimal biologically effective dose for Aspirin 
The optimal dose of Aspirin as an adjuvant agent for colorectal cancer is not known. There have 
been, to date, no randomised Aspirin trials exploring secondary prevention as an endpoint. Non-
randomised studies evaluating Aspirin as a primary prevention agent have suggested that a dose of 
300 mg a day for 5 years is effective 31,50. In the analysis of the Nurses Health Study, regular use of 
Aspirin (325 mg) twice or more per week was shown to reduce the incidence of colorectal cancers 
that over express Cox-2 but not the incidence of cancers with weak or absent expression of Cox-2.   
In the polyp prevention study by Baron J A et al, a lower dose (81 mg) of Aspirin appeared to be at 
least equally as effective as an intermediate dose (325 mg) in preventing recurrence of polyps36. In 
addition, dose escalation studies in normal human subjects using mucosal PGE2 as a biomarker have 
suggested that 81 mg Aspirin dose was sufficient to significantly suppress rectal mucosal PGE2 levels 
and did so to an equivalent extent as higher doses70,71 .     
In both the CALGB 89803 analysis30, and the study by Chan et al,31 the majority of participants were 
taking Aspirin at 325 mg per day (personal communication, Charles Fuchs and Andrew Chan).  In 
contrast, subjects in the studies by Bastiaannet et al and McCowen et al utilized low-dose aspirin 
(75mg to 80mg).32,33 
Our study uses a 200 mg daily dose, which falls directly in the middle of the dose range used by 
patients in the various cohort studies.  We believe this intermediate dose will most optimally define the 
trade-off between efficacy and tolerability.  
 
 

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2. 
STUDY OBJECTIVE 
To assess the effectiveness of Aspirin against placebo control in patients with dukes C or high risk 
dukes B colorectal cancer in terms of Disease Free Survival (DFS) and Overall Survival (OS)    
3. 
STUDY ENDPOINTS 
Primary endpoints 
- 
DFS among all eligible subjects (high risk Dukes B colon cancer, Dukes C colon cancer and rectal 
cancer patient sub-groups); 
- 
DFS among patients with colon cancer (high-risk Dukes B and Dukes C colon cancer). 
Secondary endpoints 
- 
Overall survival (OS) over 5 years 
- 
DFS and OS in 
 
Chinese, Malay, Indian and other ethnic groups 
 
Resected high risk Dukes B colon cancer, Dukes C colon cancer and rectal cancer sub-
groups, individually 
 
Compliant versus non-compliant subjects 
 
PIK3CA mutated tumors (where samples are available) 
Endpoint definitions 
Disease recurrence is defined as any one of the followings: 
1. Unequivocal radiological evidence of colorectal cancer recurrence 
2. Recurrence detected by Digital rectal examination (DRE) 
3. Positive histology or cytology (i.e. peritoneal or pleural cytology) 
4. Colonoscopic evidence of local cancer recurrence at the previous operation site 
5. Detection of a new colon or rectal primary tumour 
Disease free survival is defined as the time from randomisation to the time of documentation of 
disease recurrence or death from any cause. If there is no disease recurrence or death by the time 
when a patient is last followed up, it will be censored at that time.  
Overall survival is defined as the time from randomisation to the time of death from any cause. If 
there is no death by the time when a patient is last known to be alive, it will be censored at that time. 
Compliant subject is defined as a subject who takes the study drug for more than 70% of days for 
the study period during which the patient is on treatment, up to the time of discontinuation. 
4. 
TRIAL DESIGN 
Dukes C colon cancer, high risk Dukes B colon cancer, Dukes B rectal cancer or Dukes C rectal 
cancer patients who have completed the resection of primary tumour will be treated with standard 

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therapy (chemotherapy ± radiotherapy). Adjuvant chemotherapy is not specified but should consist of 
at least 3 months of a 5FU based chemotherapy – for example, weekly 5FU/FA (Roswell Park 
regimen), monthly 5FU/FA (Mayo Clinic regimen), infusion of 5FU, oral capecitabine, FOLFOX or 
Capecitabine/Oxaliplatin regimens.  Rectal cancers may additionally have adjuvant radiotherapy 
administered in either adjuvant or neoadjuvant fashion. During the last cycle of standard therapy, 
prospective patients would be invited to participate in this study. Once informed consent is taken & 
within 120 days of completion of the standard therapy, they would be checked for trial eligibility.  
An eligible subject will be randomised to the study in 1:1 ratio to either 
- 
Aspirin arm: 200 mg Aspirin once a day for 3 years 
- 
Placebo arm: 200 mg matching placebo once a day for 3 years. 
After randomisation, patient will have 3 monthly assessments for 3 years (month 3 to month 36) 
followed by 6 monthly assessments for additional 2 years (month 42 to month 60). All subjects will be 
approached to seek consent for survival information (DFS, OS) after 5 years post randomization will 
have data collected via review of medical records or by phone contact, every 12 months until, and at  
the last patient last visit (month 60 visit or earlier) at the site. 
The purpose of 5 year follow up is to evaluate- 
1. The long term survival outcomes and 
2. Persistence of effect after completion of treatment. 
5. 
ELIGIBILITY CRITERIA 
5.1. 
Inclusion Criteria 
- 
Male or female outpatient of ≥ 18 years of age or ≥ country’s legal age for adult consent 
- 
Dukes C colon cancer, high risk Dukes B colon cancer, Dukes B rectal cancer or Dukes C rectal 
cancer (see Appendix 1 for definition of High Risk Dukes B)  
- 
Undergone complete resection of primary tumour 
- 
Completed standard therapy ( at least 3 months of chemotherapy ± radiotherapy ) 
- 
Within 120 days of completion of standard therapy (surgery, chemotherapy ± radiotherapy)  
- 
ECOG performance status 0 to 2 
- 
Satisfactory haematological or biochemical functions (tests should be carried out within 8 weeks 
prior to randomisation): Results of clinical investigations carried out within 8 weeks prior to 
randomisation can be used in place of the required screening investigations. Patients with mild 
laboratory abnormalities can be included at the discretion by the site principal investigator,  and 
after approval by ASCOLT Trial Management Group 
- 
ANC ≥ 1.0 x 109/L 
- 
Platelets ≥ 100 x 109/L 
- 
Creatinine clearance ≥ 30 mL/min 

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- 
Total bilirubin ≤ 2.0 x the upper limit normal 
- 
AST & ALT ≤ 5 x the upper limit normal 
- 
Completed the following investigations 
- 
Colonoscopy(or CT colonogram(within 16 months prior to randomization) 
- 
Imaging of abdomen (CT or CT colonogram or MRI or PET or Ultrasound) within 16 
months prior to randomization 
- 
Written informed consent  
5.2. 
Exclusion Criteria 
- 
Pre-existing Familial adenomatous polyposis, inflammatory bowel disease or ulcerative colitis 
- 
Active gastritis or active peptic ulcer  
- 
History of continuous daily use of PPI more than 1 year prior to consent 
- 
Gastrointestinal bleeding within the past one year 
- 
Haemorrhagic diathesis (i.e. haemophilia) 
- 
Uncontrolled hypertension (untreated systolic blood pressure > 160 mmHg, or diastolic blood 
pressure > 95 mmHg) 
- 
History of recent cancers (except for colorectal cancers, non-melanoma skin cancers, basal cell 
carcinomas, squamous cell carcinomas) in the past 5 years 
- 
History of stroke, coronary arterial disease, angina, or vascular disease 
- 
Patients who are on current long term treatment (≥ 4 consecutive weeks) with Aspirin, NSAID or 
Cox-2 inhibitors 
- 
History of erosive GERD or active erosive GERD on gastroscopy. 
- 
Patient on active current treatment of antiplatelet agents (i.e. off-study Aspirin, clopidogrel, 
ticlopidine)  
- 
Patient receiving active treatment of anticoagulants (i.e. warfarin, low molecular weight heparins) 
- 
Pregnant, lactating, or not using adequate contraception 
- 
Patient having known allergy to NSAID or Aspirin 
- 
Unexplained rise of CEA (i.e. smoker with elevated CEA will not be excluded) 
- 
Patient on other investigational drug 
- 
Patients with HNPCC (Lynch Syndrome) 
6. 
RANDOMISATION 
Randomization will occur within 120 days of completion of standard therapy. After informed consent is 
signed and subject’s eligibility is confirmed, the subject can be randomised in a 1:1 allocation ratio, 
stratified by  

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- 
Study centre 
- 
Tumour type (Dukes C colon, high risk Dukes B colon cancer, and  rectal cancer sub-groups) 
and  
- 
Type of adjuvant chemotherapy received (exposed/ not exposed to oxaliplatin)  
to receive either Aspirin or a matched placebo for 3 years. 
Randomisation will be done via direct web randomisation: Authorized study centre personnel will 
randomise the patient via a password-protected internet web site. The randomisation system will then 
determine the treatment arm and provide the subject number to be used for the patient. The site 
monitor/ project coordinator will be informed immediately in the event that the web randomisation is 
not successful.  
7. 
STUDY DRUG 
7.1. 
How to take the study drug 
The study subject will take two tablets of study drug orally daily for 3 years or as instructed by 
investigator.  
7.2. 
Supply and Resupply of study drug 
The investigator or designated person at the study centre will dispense the study drug to the patient at 
baseline visit and each assessment/ follow-up visit. Patients are required to return the used and 
unused bottles at each visit for drug accountability.  
Each subject will be given sufficient supply at each follow-up visit to the study centre according to the 
specified protocol schedule during the first 3 years after randomisation. If the subject requires 
treatment modification (dose reduction), study drug supply will be adjusted and dispensed as 
appropriate. 
The manufacturer of study drug, Bayer AG, will provide the required study drugs for this study. These 
are being shipped from Bayer AG to the central drug depot. The central drug depot will then be 
responsible for the distribution to the individual study centres. The study centre PI is responsible to 
ensure that there are adequate supplies for the study subjects at the centre. 
7.3. 
Description and contents of study drug and placebo drug 
Each tablet contains 100 mg enteric-coated Aspirin (Acetylsalicylic acid) or placebo. Excipients of 
Aspirin Cardio placebo include: microcrystalline cellulose, citric acid anhydrous, dibasic hydrogen 
phosphate, lactose monohydrate, magnesium stearate of vegetable origin, maize starch, silica 
colloidal anhydrous, methacrylic acid-ethyl acrylate copolymer, talc, triethylcitrate. 
7.4. 
Packaging information 
Each tablet contains 100 mg enteric-coated Aspirin (Acetylsalicylic acid) or placebo. Study drug will 
be supplied in screw capped bottles with 100 tablets per bottle and two bottles of study drug will be 
packed in a secondary packaging box. This would be sufficient for 100 days for one subject.  

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7.5. 
Storage information 
Study drugs at each centre must be stored in a secure and locked facility and in a dry place, at room 
temperature (25 degree centigrade and below). Any temperature deviation must be reported once 
known, to the site monitor or project coordinator who will in turn report to the project manager of the 
trial at NCCS. 
Following exposure to a temperature deviation, study drugs will not be used until approval is given by 
the manufacturer through the trial project manager via the site monitor or project coordinator. 
7.6. 
Study drug labelling and handling 
The primary label of the study drugs will be labelled through Bayer AG centrally and delivered to the 
allocated depots. The kit numbers will be labelled by unblinded personnel at the allocated depots 
before delivering to the individual study centres in batches. 
The label will include the following particulars (Appendix IV – Study Drug Label): 
a) the study protocol code 
b) batch number 
c) Manufacture date, expiry date or retest date of study material 
d) the subject number for whom the study material is intended 
e) The study site code 
f) 
Dosage and administration instruction 
g) the storage conditions, as indicated by the manufacturer 
h) the words : “ For clinical trial use only” 
i) 
the name and address of the manufacturer 
The study drug at site should be handled only by authorised personnel at site. The study drug 
accountability will also be done by authorised personnel and all the procedures will be documented. 
The authorised personnel at site is also responsible of the destruction of the unused or returned study 
drug as per institution practice after the study drug accountability is documented checked. 
The investigator at each study centre should ensure that the investigational product(s) are used only 
in accordance with the approved protocol. 
7.7. 
Compliance of study drug 
Noncompliance is defined as omission of more than 30% of days for the study period during which the 
patient is on the study drug. The reason for non-compliance will be documented. 
7.8. 
Anticipated side effects of Aspirin 
Side effects that occasionally occur are gastrointestinal disorders such as nausea, vomiting, 
diarrhoea, and slight gastrointestinal blood loss which is exceptional cases can lead to anaemia. 
Gastrointestinal ulcers may rarely develop, in some circumstances with haemorrhaging and 

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perforation. Dizziness and ringing in the ear can occur as symptoms of over dosage, especially in 
children and elderly patients.  
Rare cases of hypersensitivity reactions (e.g. difficulty in breathing, skin reaction) can occur. 
Isolated cases of liver and kidney function disturbances, and severe skin reactions have been 
reported. 
The absolute annual increase risk attributable to Aspirin for major bleeding, major gastrointestinal 
bleeding and intracranial haemorrhage is estimated at 0.13%, 0.12% and 0.03% respectively. 
(McQuaid KR et al) 
8. 
BLINDING 
8.1. 
Blinding 
This is a double-blind study. The patient, the study team including the investigator(s) and the sponsor 
will be blinded. However, study statistician who prepares the randomisation list and the designated 
unblinded personnel who are involved in the procedures of study drug packaging and labelling will not 
be blinded.  
8.2. 
Code-break envelopes 
The study statistician will prepare the sealed emergency code-break envelopes and distribute to the 
study centres accordingly. The envelopes will contain the treatment assignment, with the 
corresponding subject number printed on it. The sealed emergency code-break envelopes will be 
collected before site closure or when necessary to return to the study statistician for destruction.   
8.3. 
Unblinding 
The emergency code-break envelopes provided by the study statistician will be kept at site by 
investigator or designated person. In case of medical emergency, unblinding should be done to the 
required subject only, where the study code needs to be known prior to the further management of 
subject. At such, the study centre investigator or designated person will unblind the treatment given to 
the subject. The investigator will discuss the purpose of unblinding with the study co-chair, if possible, 
prior to unblind the study patient. The study statistician and monitor/project coordinator will be 
informed of the occurrence and reason for unblinding. In the event of unblinding, only the investigator 
treating the patient will be unblinded of the treatment code & it is his primary responsibility to keep the 
rest of the study team at his centre blinded of the treatment code. 
9. 
TREATMENT SCHEDULE 
9.1. 
Treatment groups 
The study drug, oral Aspirin 200 mg/ placebo 200 mg OD should be started immediately but no later 
than 2 weeks after randomisation/baseline visit. The patient will be treated with the same study drug 
for 3 years.  

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9.2. 
Treatment modification 
The treatment modifications listed in this section are for reference only. The investigator should 
modify the treatment according to clinical judgement and best medical practices. 
Event 
Severity 
Action 
Angioedema 
Any 
Stop study drug permanently 
Anaphylaxis 
Any 
Stop study drug permanently 
Generalized Rashes 
Any 
- Stop study drug for two weeks 
- Consider to rechallenge at next follow up/ assessment if the rash 
is mild, or unlikely to be related to study drug 
Epigastric discomfort 
Mild 
- Reduce dose to 100 mg of study drug 
- Start PPI  
- Review in one month. If symptoms persist, consider stopping 
study drug and gastroscopy ( Treat as per Gastroscopic findings) 
Epigastric discomfort 
Moderate 
- Stop study drug 
- Start PPI 
- Review in one month 
- Rechallenge with lower dose (i.e. 100 mg) of study drug if 
symptoms resolved and continue long term PPI therapy. 
- Consider gastroscopy if symptoms persist 
Epigastric discomfort 
Severe 
- Stop study drug 
- Start PPI 
- Gastroscopy 
- Treat as per Gastroscopic findings 
Haematamesis 
 
 
- 
- Stop study drug permanently 
- Start PPI 
- Gastroscopy 
- Treat as per Gastroscopic findings 
Melenic stools 
 
 
- 
- Stop study drug permanently 
- Start PPI 
- Gastroscopy with/without colonoscopy 
- Treat as per Gastroscopic findings 
Asymptomatic drop in 
haemoglobin of > 2 
g/dL from baseline 
 
- 
 
 
- Stop study drug 
- Start PPI 
- Gastroscopy/Colonoscopy 
- Treat as per Gastroscopic findings 
Gastroscopic Findings 
Event 
Severity 
Action 
Gastritis 
Mild/ 
Moderate 
- Stop study drug 
- Start PPI 
- Rechallenge with lower dose (i.e. 100 mg) of study drug 2- 4 
weeks after therapy with PPI 
- Helicobacter pylori eradication if present 
Gastritis 
Severe  
- Stop study drug (for 4-8 weeks) 
- Start with PPI  

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- Consider rechallenge with lower dose (i.e. 100 mg) of study drug 
4-8 weeks after therapy with PPI if symptoms resolved 
completely 
- Helicobacter pylori eradication if present 
Peptic ulcer  
 
- 
- Stop study drug permanently 
- Start PPI  
- Helicobacter pylori eradication if present 
Oesophageal or Gastric 
Varices 
 
- 
- Stop study drug permanently 
- Continue on follow up as per institutional practice 
- Helicobacter pylori eradication if present 
Normal findings in a 
symptomatic patient 
 
 
- 
- Consider other cause of symptoms 
- Continue study drug at lower dose ( i.e. 100 mg) together with 
PPI 
- Consider to stop  study drug if symptoms are severe and 
persistent despite treatment with PPI  
Patients who are unable to tolerate 200 mg of study drug may have the dose reduced to 100 mg of 
study drug. The reason and date of dose reduction will be clearly documented. PPIs will be used in 
patients who have symptoms of epigastric discomfort. They should be given at adequate doses and 
continued for at least 3 months. PPIs are preferable to H2 antagonists. Antacids (i.e. magnesium 
trisilicate, magnesium carbonate) should not be given in place of PPIs; however, they may be used to 
supplement these agents. Patients who undergo gastroscopy should be screened for helicobacter 
pylori. Positive helicobacter pylori should be treated accordingly.  
Patients who develop anaphylaxis, angioedema or gastrointestinal bleeding should stop the study 
drug immediately and should not undergo rechallenge to study drug. 
Patients who need to undergo elective surgery or other interventional procedures may stop the study 
drug 5 days prior to surgery and recommence the study drug upon recovery (when haemostasis is 
secured or when the patient is able to take orally). 
9.3. 
Treatment discontinuation 
The investigator has the right to discontinue study treatment if he/she feels that it is in the best 
interests of the patient or due to safety concerns.  
Study drug will be stopped immediately if there is disease recurrence confirmed by CT, histology or 
cytology, and in the event of an SAE unequivocally related to study drug (or at the discretion of the 
investigator if the relationship of SAE to the study drug cannot be established with certainty at the time 
of reporting ). 
The reasons for treatment discontinuation will be documented. Patients with their treatment 
discontinued will continue to be followed up until 5 years after randomisation.  
Even if a patient chooses not to adhere to the treatment assignment or data collection schedule, every 
effort should be made to follow patient for the protocol objectives until the end of the study. 
 

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9.4. 
Study Withdrawal  
All patients, including patients discontinued from study treatment, will continue to be followed up for 5 
years after randomisation, unless the patient withdraws consent, is lost to follow up or death. The 
reason for withdrawal should be documented.  
10. 
CONCOMITANT/CONTRAINDICATED MEDICATIONS 
Patients are not permitted to take the following medications concurrently with the study drug. If 
required, patient should be removed from the study treatment with the reason clearly documented: - 
- 
Other investigational drugs while on treatment with study drug 
- 
Any anticancer treatment while on treatment with study drug 
- 
Antiplatelet agents (off-study Aspirin, clopidogrel, ticlopidine) concurrently with study medication 
- 
Anticoagulants (warfarin, unfractionated heparin or low molecular weight heparin) concurrently 
with study medication   
Patients should be encouraged to use paracetamol or codeine phosphate for analgesia and to avoid 
NSAID whenever possible. Although short term intermittent NSAID use is allowed, NSAID should not 
be prescribed with study drug for more than 2 consecutive weeks. The use of NSAID must be clearly 
documented throughout the study. 
Patients will be allowed concurrent PPIs, H2 antagonists or antacids. 
Ongoing concomitant medication will be recorded from baseline visit date until 30 days after treatment 
discontinuation. Patients receiving study drug should maintain adequate contraception.  
11. 
ASSESSMENTS AND FOLLOW-UP  
11.1. Screening 
Within 8 Weeks prior to randomisation 
- Haematology: platelet count  
- Creatinine  
- LFT: serum bilirubin, AST, ALT  
Within 16 months prior to randomization 
- Full colonoscopy(or CT colonogram).   
- Imaging of abdomen (CT or CT colonogram or MRI or PET or Ultrasound)    
- Radiological examination of the Chest (including but not restricted to Chest x ray, CT thorax or 
PET scan) 
 
 

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11.2. Baseline 
- 
Medical history: asthma, diabetes, ischaemic heart disease, stroke, gastrointestinal ulcers or 
bleeding, alcohol history, smoking 
- 
Tumour History: stage, risk factors, treatment, and tumour response grade (for patients with 
neoadjuvant chemoradiation only)  
- 
Family history of Colorectal cancer 
- 
Record ongoing medication  
- 
Vital signs: body weight, height, BP 
- 
Haematology: haemoglobin (within 8 weeks prior to randomisation) 
- 
CEA(latest reading)  
- 
Randomization performed and study treatment commence 
11.3. 3-monthly assessments  
3-monthly patient assessments will be done at month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36.  
Assessments ± 1 month window will be allowed for each 3-monthly visit. Phone assessments are 
allowed at alternate 3-monthly assessments if patient is unable to return for site follow-up.  The 
following will be performed at each assessment: 
- 
CEA  
- 
Hb (for month 6, 12, 18, 24, 30, 36 only) 
- 
Record AE and SAE (See Section 13.2)   
- 
Concomitant medication 
- 
Concomitant NSAIDs 
- 
Medical Events : (acute myocardial infarction, transient ischemic attack, stroke, new cancers and 
gastrointestinal bleeding) 
- 
Recurrence and Salvage Chemotherapy  
The following will be performed at each specified interval: 
- 
Surveillance Colonoscopy/ CT colonogram at month 6 and 30 (optional) *  
- 
Surveillance CT scan (abdomen ± pelvis) / or CT colonogram at  month 6, 18 and 30 (optional)* 
Off-site investigations (for example surveillance CEA, CT scan, colonoscopy) will be allowed and data 
from unscheduled investigations (for example CT scan or colonoscopy due to symptoms or during 
hospitalisations) may be recorded.   
* The policy of surveillance CT scan and Colonoscopy (as described above) will be decided at the 
study centre level, by the study centre PI. However, these procedures wherever implemented, should 
be consistently applied to all trial subjects within a particular study centre.   

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Early Treatment Discontinuation follow-up  
- 
Subjects with early treatment discontinuation (e.g. for toxicity) but without recurrence will continue 
with the same 3 monthly assessments except Hb that is not required after study drug treatment is 
discontinued.   
- 
Subjects with recurrence (who may be receiving salvage treatment or palliative care) may be 
assessed at 6 monthly intervals in the clinic or via phone assessments if they are unable to return 
for 3 monthly clinic follow up.  Hb, CEA, and concomitant medication data are not required after 
recurrence date.  
11.4. 6-monthly assessments  
6-monthly assessments will be done at month 42, 48, 54 and 60. 
Assessments ± 1 month window will be allowed for each 6-monthly visit. The following will be 
performed at each assessment: 
- 
CEA 
- 
Death and related information if any 
- 
Medical Events: ( AMI, transient ischemic attack, stroke, new cancers and gastrointestinal 
bleeding) 
- 
Concomitant NSAIDs 
- 
Recurrence and salvage chemotherapy 
- 
Subjects with recurrence (who may be receiving salvage treatment or palliative care) may be 
assessed via phone assessments if they are unable to return for clinic follow up.  CEA  is not 
required after recurrence date.  
11.5. Unscheduled visits 
Any additional visit to the scheduled follow-ups will be considered as unscheduled visit if it is of 
medical significance in the opinion of the treating physician or investigator. 
At such visits, the patient will be assessed for: 
- 
Recurrence 
- 
AE and SAE  
- 
Medical Events: (acute myocardial infarction, transient ischemic attack, stroke, new cancers and 
gastrointestinal bleeding) 
11.6. Assessment of recurrence and salvage chemotherapy 
For the patient with unequivocal radiological documented recurrence, the date of CT scan or any 
other radiological modality documenting unequivocal recurrence will be taken as the date of 
recurrence. Patients who have disease recurrence confirmed with histology or cytology, the date of 
recurrence will be taken as the date of biopsy or cytology collection. 

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For patients with local recurrence detected through colonoscopy/CT colonogram or digital rectal 
examination (DRE), without CT scan or histology, the date of colonoscopy or DRE will be taken as the 
date of recurrence. 
An elevated CEA level or abnormal LFT will not be considered as acceptable evidence of colorectal 
cancer recurrence. However, a rising CEA trend should prompt the search for possible tumour 
recurrence.  
At the time of colorectal cancer recurrence, the investigator should clearly indicate the site of tumour 
recurrence and the method of diagnosis.  
Patients with tumour recurrence and commencing salvage chemotherapy will have the names and 
initiation date of each new chemotherapy regimen recorded. 
11.7. Assessment of Medical Events 
Medical events such as acute myocardial infarction, ischemic stroke (including transient ischemic 
attack), hemorrhagic stroke or new non-colorectal cancers will be recorded.  Major gastrointestinal 
bleeding (requiring blood transfusion) will also be recorded.     
11.8  Post Month 60 – Clinical Data 
Subjects who have consented to allow data collection after month 60, will have their medical records 
reviewed every 12 months (or via phone contact), up to and at the time of the last patient last visit 
(month 60 or earlier) - at the site.    
The following will be recorded: 
- 
Death related information; if any 
- 
Medical Events: ( AMI, transient ischemic attack, stroke, new cancers and gastrointestinal 
bleeding) 
- 
Concomitant NSAIDs 
- 
Recurrence and salvage chemotherapy 
12 STATISTICAL CONSIDERATIONS  
12.1 Sample size calculation 
Initial sample size calculation 
The initial total trial size was 2660 patients, 1330 randomised to Aspirin group and 1330 randomised 
to Placebo group. In the sub-groups, there should be at least 2000 high risk Dukes B or Dukes C 
colon cancer patients, others are rectal cancer patients  
It was assumed that 3-year disease free survival rate for Dukes B colon cancer, Dukes C colon 
cancer and rectal cancer are 65% after standard adjuvant chemotherapy; and the attrition rate is 5%.  
The total trial size (2660) would be sufficient to detect an 6% absolute difference of disease free 
survival rate for all subjects between the two treatments, with a two-sided logrank test of 5% type I 
error and 90% power; For the main sub-group analysis, the 3-year DFS rate for colon cancer patients 

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was assumed to be 65% under standard care, which is similar to the entire group as a whole, the size 
of colon cancer (n=2000) will be sufficient to detect an 6% absolute difference of disease free survival 
rate for colon cancer between the two treatments, with a two-sided logrank test of 5% type I error and 
80% power.  
Subsequent sample size calculation 
Based on recent studies31,33,34 of aspirin in colorectal cancer patients, with a reported hazard ratio 
(HR) or risk ratio ranging from 0.67 to 0.77, we assumed a hazard ratio of 0.72 for disease free 
survival between the aspirin and the placebo groups. The corresponding  absolute difference of 
disease free survival rate between the two treatment groups is about 8.5% instead of 6% for a 3 year 
disease free survival rate of 65% in the placebo group. To detect a HR of 0.72, a total of 300 
recurrences (or deaths if occur without recurrence) is required for a two-sided logrank test of 5% type 
I error and 80% power. This translates into a total sample size of 1200 patients if the disease free 
survival rate is 65% in the placebo group and attrition rate is 15%.  
Latest sample size calculation 
A recent review of trial interim data, after enrollment of at least 1140 patients and 3-years follow-up 
being completed in 430 patients, revealed a pooled disease free survival rate of 79% at 5 years. We 
estimated that only 240 recurrences would be observed with a total sample size of 1200, a shortfall of 
60 recurrences to maintain the study power at 80%. We subsequently recalculated the sample size to 
be 1587 patients such that we would expect to observe 300 recurrences (or deaths) at the end of 
study (attrition rate reduced from 15% to 10%, the rest unchanged). 
12.2 Statistical analysis 
All statistical analyses will be carried out on an intention-to-treat basis.  
In the analysis of disease free survival, an event of interest is considered to have occurred if a patient 
relapses or dies during the study period. The starting point for disease free survival is the date of 
randomisation and the end point is the date of first disease recurrence or date of death, whichever 
occurs first. Patients in whom there has been no evidence of disease after treatment are censored at 
the date of last follow-up. Similarly, the overall survival time is censored at the date when the patient 
is last known to be alive. 
Each primary endpoint will be analysed as follows. Survival curves will be constructed using the 
Kaplan-Meier method.  Life table estimates of 3 and 5 year survival rates will be calculated.  The 
efficacy of Aspirin will be evaluated by the Hazard Ratio (HR) and its corresponding 95% CI. A Cox 
proportional hazard model will be used to estimate HRs adjusting for the trial stratification factors (site, 
type of tumour and type of adjuvant chemotherapy).  Stratified analysis and other non-proportional 
hazard models (which allow for the effects of covariates to vary over time) would be considered when 
proportional hazards assumption is not valid.  
The secondary endpoint of overall survival will be analysed in a similar manner to the primary 
endpoints. For the subgroup analyses, tests for interaction for the colon cancer subgroups and other 
subgroups will be conducted first.  Similar analyses of DFS and OS as presented above will be 
repeated within the subgroups respectively defined by ethnicity, tumour type, and patients’ 

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compliance and according to patient’s PIK3CA mutational status. The percentage of patients with 
different PIK3CA mutational status will be compared by Chi-square test in the Aspirin and Placebo 
groups. 
As an exploratory analysis, cumulative incidence function will be estimated and the two treatment 
arms will be compared using Gray’s method when considering competing risks of first recurrence with 
different causes of death due to colorectal cancer, other cancers or other causes. 
12.3 Interim analysis 
An independent DMC will be established to review the interim results of the study. Two interim 
analyses are scheduled. Ideally, the first interim analysis should be done after 540 patients have been 
recruited (estimated to take between two to three years) or at the mid-point of the targeted recruitment 
period (end of Year 2012), whichever comes earlier. The second interim analysis should be done 
once 540 patients or the same cohort of patients from the first interim analysis, have been followed up 
for 3 years (approximately between fifth to sixth year).   
The aim of the first interim analysis is toxicity. Safety will be the main issue reviewed in the first DMC 
meeting. A report containing non-confidential data should be sent to the Study Steering Committee. 
Randomisation, compliance, CRF received and processed, AE and SAE should be included in this 
DMC report. 
The study endpoints to be reviewed in the second interim analysis are disease free survival and 
overall survival, in addition to toxicity profiles. Statistical analysis method for the primary endpoint will 
be the same as 12.2. The analysis results of the interim analyses will not be the sole criteria for 
deciding whether to terminate accrual or report the results early. Rather they will provide a guideline 
to aid in the decision, which will also take into account the characteristics of the patients, nature of 
toxicities, relevant external results. Another goal of this monitoring is to identify if the study is 
underpowered and sample size needs to be adjusted. Apart from the reason of safety, which may 
caution otherwise, the minimum trial size will remain as 1200 as initially planned. 
In addition to the two interim analyses above, periodic review of safety data (in the same format of the 
first interim analysis) will be performed for annual DMC meetings. Efficacy data will not be included 
unless requested by DMC.   
The results of the interim reviews will remain confidential to the study statistician and the DMC 
members. After reviewing the efficacy and safety data, the DMC will make recommendations to the 
Study Steering Committee on changes to the protocol. 
13 SAFETY 
The site investigator of each study centre is responsible for monitoring the safety of subjects for that 
study centre.   
Immediate medical attention should be provided to resolve any SAE which occurs during the study. All 
AEs and SAEs occurring after any administration of the study drug will be followed until resolution or 
are clearly determined to be due to the patient’s stable or chronic condition or intercurrent illness.  
 

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13.1 Definitions 
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) product.   
All AEs, including observed or volunteered problems, complaints, or symptoms are to be recorded.  
Each AE is to be evaluated for duration, intensity and causal relationship with the study medication or 
other factors. 
The most anticipated AEs associated with Aspirin use are gastrointestinal related, majority of which 
are minor and resolved without any medical intervention. In rare cases, more serious effects, such as 
bleeding can be occurred in patient with long-term Aspirin use. Even less, haemorrhagic stroke can 
occur. 
Adjuvant chemotherapy related toxicities can occur, however they are not regarded as AE for this 
study.  
Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that: 
- 
Results in death 
- 
Is life-threatening 
- 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
- 
Results in persistent or significant disability/incapacity, or 
- 
Is a congenital anomaly/birth defect 
A medical event that may not be immediately life-threatening or result in death or hospitalisation but 
may jeopardise the patient or may require intervention to prevent a serious outcome may also be 
considered serious (e.g. intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development 
of drug dependency or drug abuse).  Medical and scientific judgement must be exercised when 
classifying events as serious. 
When SAE occurs, the subject will be reassessed and investigator will consider whether to continue 
or discontinue study medication. 
Unexpected adverse drug reaction (UADR) 
An UADR is defined as an adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g. investigator’s brochure for an unapproved investigational product 
or package insert/summary of product characteristics for an approved product). 
 

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13.2 Reporting of Adverse Event 
All AEs will be recorded on the AE form in the subject’s case report form.   
The site investigator (international site or local site) is responsible to report all SAEs with de-identified 
relevant reports within 1 working day of the knowledge of the event to all of the following:  
- Attention to monitor or project coordinator 
- Investigational Product Manufacturer (Bayer AG) 
The site investigator  is also responsible to report all SAEs to relevant ethics committee or institutional 
review board within the required timeline. All SAEs will be followed up until resolution with updated 
information reported whenever available to the relevant parties as per initial reporting procedure. 
The study monitor/project coordinator will notify the study co-chair and study project manager with the 
submitted SAE report by the site. The study co-chair will review the SAE report and recommendations 
will be sent to the site investigators if any. 
The study co-chair is responsible to ensure any serious and unexpected adverse drug reaction 
occurring in the study is notified to all participant sites for reporting to ethics committee(s) or 
institutional review board(s) of all study centres and regulatory body (ies) of the country (ies) where 
the study is conducted by using the CIOMS Form. Fatal or life-threatening unexpected adverse drug 
reaction must be notified immediately but no later than 7 calendar days after the first knowledge by 
the study co-chair, followed by a complete report within 8 additional calendar days. All other serious, 
unexpected adverse drug reactions that are not fatal or life threatening must be reported within 15 
calendar days after first knowledge by the study co-chair. The CIOMS Form will be sent to Bayer AG 
for review before distributing to all participating sites.  
After discontinuation of treatment, patients should be carefully monitored for the occurrence of new 
adverse events up to 30 calendar days (follow-up period) after the administration of the last dose of 
aspirin.  Adverse events are to be assessed in terms of their seriousness, severity, and relationship to 
the study drug. Only serious adverse (SAEs) should be reported to Bayer AG.    
AEs and SAEs will be recorded from the time of entry into the study until 30 days after the full 
completion of study treatment, or in instances of early drug termination 30 days after the final 
cessation of study drug.  
13.3 Reporting of Death 
The site investigator is responsible for reporting all deaths that happen after 30 calendar days of study 
drug discontinuation until study completion date within 14 days of first knowledge by the Site 
Investigator to the study monitor/project coordinator.  Date of death, cause and related information - 
will be documented as specified by the Trial Management Group.    
The study monitor/project coordinator will notify the study co-chair and study project manager with the 
submitted report by the site. The report will be reviewed by the study co-chair and recommendations 
will be sent to the site investigators if any. 
 

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14 SUB-STUDIES (For Singapore and Selected Sites Only) 
14.1 Blood Samples 
Only patients who consent for research bloods will have 30 mls of blood collected at the time of 
consent and at 6 and 12 months after randomisation.  The blood will be spun down and the buffy coat 
and serum aliquoted and stored separately in liquid nitrogen and at minus 80 degrees 
respectively.   Each sample will be coded by a study number with no patient identifiers. 
14.1 
Biomarkers, protein, lipid and leukocyte profiling 
Biomarkers will be investigated for possible association with clinical outcomes (disease free survival, 
overall survival) and for the effects of the study medication. Protein biomarkers related to inflammation 
and adaptive immunity will be profiled using standardised high throughput techniques. Lipid 
biomarkers derived from the metabolism of fatty acids which may be affected by COX activity will be 
profiled using HPLC. Leukocyte subsets and their function will be characterised by flow cytometry.   
14.2 
Germline DNA 
DNA will be extracted using standardised methods and stored for subsequent genotyping. Genotyping 
for polymorphisms in drug targets and metabolising enzymes of relevance to aspirin and susceptibility 
to or prognosis of colon cancer will be performed using previously described techniques. Known 
functional SNPs of COX 1 and COX2, Prostaglandin syntheses, and CYP2C9 will be characterized 
using high throughput sequencing techniques.   
14.3 
Stool Samples 
Stool Samples will be collected once at the following time points: Before initiation of study drug or any 
time points after initiation of study drug.  Stool will be collected in a sterile specimen container and 
approximately one gram will be sealed in cryovials and snap frozen in liquid nitrogen before storage at 
-80 degrees Celsius.   Stools will be analyzed in batches for Streptococcus bovis and other colonic 
flora.  Association analysis will be made between colonic flora and clinical outcomes.  
14.4 
Urine Samples.   
Urine specimens will be collected at the time of entry into the study before initiation of aspirin, and at 6 
and 12 months after randomisation.  Urine will be collected in a sterile specimen container and aliquot 
into vials to be stored at -80 degrees.   Urine will be analysed for prostaglandin metabolites levels that 
will be correlated with aspirin treatment and outcomes. 
14.5 
Archival tumour specimens  
In consenting patients, where samples are available, archived paraffin embedded tumour tissues will 
be retrieved, annotated, and stored till the end of the study where they will then be reviewed for 
immunohistocytochemical COX 1/ 2 staining and graded according to intensity of staining.  Correlation 
will be made between intensity of Cox 1/ 2 staining and aspirin benefit. Archived tumour tissue will be 
stained for leukocyte subsets and correlation made with COX staining, survival and aspirin benefit.  

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DNA will also be extracted from archival paraffin tumour samples and tumour PIK3CA mutational 
status will also be assessed and analysed according to Aspirin exposure. 
15 DIRECT ACCESS TO SOURCE DATA 
The investigator will permit study related monitoring, audits, MCRC and/or EC review and regulatory 
inspection(s), providing direct access to the source data/ documents.  
16  QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be monitored by delegated monitors according to its standard operating procedures. All 
protocol amendments will be in collaboration with SCRI. All administrative changes and regulatory 
reports/ approvals will be reported to Trial Management Group. The Investigator at each study centre 
must ensure that the study is conducted in compliance to the approved study protocol at the 
respective centre. 
17 ETHICAL CONSIDERATIONS 
This study shall be conducted in accordance to the principles of ICH E6 and any relevant research 
requirements. The study protocol should be reviewed and approved by the institutional review board 
or ethics committee of each participating centre.  This will be the responsibility of each participating 
investigator. 
The patient's written informed consent to participate in the study should be obtained after a full 
explanation has been given of the treatment options, including the conventional and generally 
accepted methods of treatment and the manner of treatment allocation.  
The right of the patient to refuse to participate without giving reasons must be respected.  After the 
patient has entered the study, the clinician remains free to give alternative treatment to that specified 
in the protocol at any stage if he/she feels it to be in the patient's best interest.  However, the patient 
will need to remain within the study for the purpose of follow-up and data analysis.  Similarly, the 
patient remains free to withdraw at any time from protocol treatment without giving reasons and 
without prejudicing his/her further treatment. 
Records identifying the patient will be kept confidential and will not be made publicly available. If the 
results of the study are presented or published, the patient’s identity will be kept confidential. The 
monitor(s), auditor(s), the Ethic Committee/ Institutional Review Board, and the regulatory authority 
(ies) will be granted direct access to patient’s original medical records for verification of clinical study 
procedures and/or data, without violating the patient confidentiality. 
18 INSURANCE 
Study related injury would be determined by the institution insurance policy of the centre.  
19 PUBLICATION POLICY 
The results from all participating centres will be analysed together and published as soon as possible. 
Individual clinicians must not publish data concerning their patients that are directly relevant to 

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questions posed by the study until the main study report is published. The study results will be 
published under the ASCOLT Study Group.  
20 STUDY ORGANISATION 
The day-to-day running of the ASCOLT study will be managed by the Trial Management group. 
However, the ASCOLT study will also be subject to review by the Trial Steering Committee, Data 
Safety Monitoring Committee and Trial Management Group. Each committee will comprise of a 
mixture of independent members, study principal investigators, representatives from Trial 
Management Group, project manager and statisticians.  For a full breakdown of committee members, 
please refer to the beginning of the protocol. 
Data Monitoring Committee 
The Data Monitoring Committee (DMC) is an independent group of individuals who are appropriately 
qualified and experienced in clinical trials. These individuals will be responsible for overseeing the 
safety aspects of the trial. The detailed plan of DMC review is stated under protocol 12.3 interim 
analysis. The DMC members will be confirmed within one year of study kick-off. 
Trial Steering Committee 
The Trial Steering Committee (TSC) is responsible for assessing the trial’s overall progress, sample 
use, sanctioning or proposing any protocol changes, reviewing and approve publication data and 
abstracts, review trial endpoints, efficacy data, site performance, approving any proposals made by 
the TMG to change the design of the trial. This committee will receive and act upon reports from both 
the Trial Management Group and the DMC. 
Trial Management Group 
The Trial Management Group (TMG) is responsible for acting on the advice and recommendations of 
the DMC, and TSC. They will be responsible for acting on the advice and proposals given by the TSC 
and DMC committees, putting procedures in place, planning the course of action for the trial, problem 
solving any major issues and overall trial coordination.  
21 ARCHIVING 
The investigator of each centre must securely retain study documentation and secure access to the 
source data for a period of 15 years or as specified by the local IRB/ regulatory policy.  

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APPENDIX 1 – TNM AND DUKES STAGING FOR COLORECTAL CANCER 
TNM and Dukes Staging for Colorectal Cancer 
 
Primary Tumour (T) 
Tx  
Primary tumour cannot be assessed 
T0 
No evidence of primary tumour 
Tis 
Carcinoma in situ: intraepithelial or invasion of lamina propria* 
T1 
Tumour invades submucosa 
T2 
Tumour invades muscularis propria 
T3 
Tumour invades through the muscularis propria into the subserosa, or into non-peritonealized 
pericolic or perirectal tissues 
T4 
Tumour directly invades other organs or structures, and/or perforates visceral peritoneum** , *** 
 
* Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or 
lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. 
 
**  Note : Direct invasion in the 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.  The V and L 
substaging should be used to identify the presence or absence of vascular or lymphatic invasion. 
 
 
Regional Lymph Nodes (N)   
Nx 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in 1 to 3 regional lymph nodes 
N2 
Metastasis in 4 or more regional lymph nodes 
 
Note: A tumour nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic 
evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph 
node.  If the nodule has an irregular contour, it should be classified in the T category and also coded 
as V1(microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong 
likelihood that it represents venous invasion. 
 
Distant Metastasis (M) 
Mx 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 

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APPENDIX 1(Continued)  
TNM AND DUKES STAGING FOR COLORECTAL CANCER 
Stage grouping 
 
T 
N 
M 
TNM 
Dukes 
Tis 
N0 
M0 
0 
- 
T1 
T2 
N0 
N0 
M0 
M0 
I 
I 
A 
A 
T3 
T4 
N0 
N0 
M0 
M0 
IIA 
IIB 
B 
B 
T1-T2 
T3-T4 
Any T 
N1 
N1 
N2 
M0 
M0 
M0 
IIIA 
IIIB 
IIIC 
C 
C 
C 
Any T 
Any N 
M1 
IV 
- 
 
Adapted from: 
AJCC Cancer Staging Manual.  Sixth Edition. Springer 2002. 
 
 
Criteria for high risk Dukes B (any of the following) 
 
 
 
High grade (3 or 4) tumours 
 
Lymphatic invasion 
 
Vascular invasion 
 
Less than 12 lymph nodes examined 
 
Bowel obstruction 
 
Perforation 
 
T4 tumour 
 
Elevated CEA 
 
 
 
 
 
 
 

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APPENDIX 2 – ECOG PERFORMANCE STATUS 
 
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 
 
 
* As published in Am. J. Clin. Oncol.: 
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.  

                                                                                                             ICR02 /ASCOLT 
 
 
 
Version 7.0: 09 May 2018                                                                                  
                           Page -42-  
APPENDIX 3 – STUDY VISIT SCHEDULES & ASSESSMENTS  
Assessments 
Screening* 
 
Baseline 
Follow-up month (+/- 1 month) 
Follow-up month (+/- 
1 month) After 
Recurrence 
Follow-up month (+/- 1 
month) After Early Study 
Drug Discontinuation and no 
recurrence 
Post Month 60 
 
3, 9 ,15, 21, 
27, 33 
6,12, 18, 24, 
30, 36 
42, 48, 54, 60 
3 to 60 
3 to 36 
Written informed consent 
 
x 
 
 
 
 
 
 
 
Demography, Tumour history, Medical 
history & family history 
 
 
x 
 
 
 
 
 
 
Record surgical measurements,(For rectal 
cancer only) 
 
 
x 
 
 
 
 
 
 
Adjuvant Therapy 
 
 
x 
 
 
 
 
 
 
Vital signs (Body weight, BP, height), 
ECOG 
 
 
x 
 
 
 
 
 
 
Hb 
(Within 8 weeks prior 
to randomisation) 
 
x 
 
x 
 
 
 
 
Platelet count, Creatinine, Serum 
Bilirubin, AST, ALT 
(Within 8 weeks prior 
to randomisation) 
x 
 
 
 
 
 
 
 
CEA 
 
 
x 
x 
x 
x 
 
x 
 
Imaging of abdomen (CT or CT 
colonogram or MRI or PET or Ultrasound) 
 
To be done if not 
done within 16 
months prior to 
randomization 
x 
 
x  (Mth 6, 18 and 30) Optional; or frequency according to institutional practice 
 
Radiological examination of the Chest 
(including but not restricted to Chest x 
ray, CT thorax or PET scan) 
To be done if not 
done within 16 
months prior to 
randomization 
x 
 
 
 
 
 
 
 
Colonoscopy/CT colonogram 
Full colonoscopy if 
not done within 16 
months prior to 
randomization 
x 
 
x (Mth 6, 18 and 30) Optional; or frequency according to institutional practice 
 
AE and SAE 
 
 
 
x 
x 
 
 
 
 
Death 
 
 
 
x 
x 
x 
x 
x 
x 
Medical Events 
 
 
 
x 
x 
x 
x 
x 
x 
Concomitant NSAIDs 
 
 
 
x 
x 
x 
x 
x 
x 
Concomitant treatment/medication 
 
 
 
x 
x 
 
 
 
 
Recurrence, Salvage Chemotherapy 
 
 
 
x 
x 
x 
x 
x 
x 
Notes: 
* 
Screening can start after last dose of standard therapy 

ICR02 /ASCOLT 
 
 
 
Page -43 -                                                                                            Version 7.0: 09 May 2018 
 
APPENDIX 4 – STUDY DRUG LABEL   
Study code :ICR02/ASCOLT 
 
Date of Dispensing 
 
Subject No: 
 
Subject Initial 
 
Kit No: 
 
Pack Batch No:  
 
Expiry date 
 
2 bottles x 100 tablets Aspirin/Placebo 100mg 
For Oral Use Only 
Take as directed/  
Do not store  above 25°C 
FOR CLINICAL TRIAL USE ONLY 
 
KEEP OUT OF REACH OF CHILDREN 
Manufactured by Bayer Pharma AG D-51368 
Leverkusen, Germany