Next Generation STAR-TREC: A Prospective Multicenter Study Evaluating Organ Preservation With Mesorectal Chemoradiotherapy in Early Rectal Cancer
Phase: PHASE4
Conditions: Rectal Cancer
Sponsor: Vastra Gotaland Region

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1 
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SAVE THE RECTUM BY WATCHFUL WAITING AFTER 
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(CHEMO)RADIOTHERAPY OR TOTAL MESORECTAL EXCISION FOR 
7 
EARLY RECTAL CANCER? 
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-NEXT GENERATION STAR-TREC 
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2025-522955-25-00 
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A TRIAL WITHIN THE SCANDINAVIAN SURGICAL OUTCOMES 
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RESEARCH GROUP 
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Trial protocol 
 
Trial ID: 
NG-ST 
EU Trial number: 
2025-522955-25-00 
Version number: 
1.0 
Date: 
13-Oct-2025 
Sponsor: 
Västra Götalandsregionen 
Sahlgrenska University Hospital/Östra, Department of Surgery, 
Sponsor representative: 
Eva Angenete 
Co-sponsor: 
Department of Oncology, Sahlgrenska University Hospital/Östra 
 
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18 
TABLE OF CONTENTS 
19 
Revision history ............................................................................................................ 6 
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Signature page ............................................................................................................... 7 
21 
Contact information ..................................................................................................... 9 
22 
List of used acronyms and abbreviations ................................................................. 10 
23 
1.0 
Synopsis ........................................................................................................... 12 
24 
2.0 Background and rationale ................................................................................... 16 
25 
2.1 Rectal cancer and standard treatment ............................................................................. 16 
26 
2.2 Neoadjuvant (chemo)radiotherapy .................................................................................. 16 
27 
2.3 Neoadjuvant treatment in early rectal cancer with the aim to avoid surgery ................. 17 
28 
2.4 Rationale and design of the Next generation study awaiting the results from the STAR- 
29 
TREC study .......................................................................................................................... 18 
30 
2.1.5 Patient involvement ..................................................................................................... 19 
31 
3.0 Benefit-risk evaluation ......................................................................................... 19 
32 
3.1 Benefits ........................................................................................................................... 19 
33 
3.2 
Risks ......................................................................................................................... 19 
34 
4.0 Trial objectives ...................................................................................................... 20 
35 
4.1 Primary objective ............................................................................................................ 20 
36 
4.2 Secondary objectives ...................................................................................................... 20 
37 
4.3 Primary endpoint ............................................................................................................ 20 
38 
4.3. Secondary endpoint ....................................................................................................... 20 
39 
5 Trial design and procedures ................................................................................... 21 
40 
5.1 
Overall trial design ................................................................................................... 21 
41 
Time points for follow up and collection of data into CRF .............................................. 22 
42 
5.2 Procedures and flow-chart .............................................................................................. 22 
43 
5.3 Biological sampling procedures ..................................................................................... 25 
44 
5.3.1 Handling, storage and destruction of biological samples ............................................ 25 
45 
5.3.2. Total volume of blood per subject .............................................................................. 25 
46 
5.3.3 Biobank ........................................................................................................................ 25 
47 
5.4.1 Start of the clinical trial ............................................................................................... 25 
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5.4.2 Temporary halt or early termination ............................................................................ 25 
49 
5.4.3 End of clinical trial ...................................................................................................... 26 
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6.0 Subject selection .................................................................................................... 26 
51 
6.1 Inclusion criteria ............................................................................................................. 26 
52 
6.2 Exclusion criteria ............................................................................................................ 26 

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6.3 Screening and inclusion .................................................................................................. 27 
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6.4 Withdrawal criteria ......................................................................................................... 28 
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7.0 Trial treatments .................................................................................................... 28 
56 
7.1 Description of investigational medicinal product(s) ....................................................... 28 
57 
7.1.1. Dose and administration ............................................................................................. 28 
58 
7.1.2 Packaging, labelling, and handling of investigational medicinal products ................. 29 
59 
7.1.3 Drug accountability and treatment compliance ........................................................... 29 
60 
7.2 Auxiliary medicinal products ......................................................................................... 29 
61 
7.3 Concomitant treatment of radiotherapy .......................................................................... 29 
62 
7.3.1 Purpose and scope of radiotherapy guideline .......................................................... 29 
63 
7.3.2 Radiotherapy treatment planning ............................................................................. 29 
64 
7.3.3 Patient position and immobilisation ......................................................................... 29 
65 
7.3.4 Definition of treatment volumes .............................................................................. 29 
66 
7.3.5 Gross tumour volume (GTV) ................................................................................... 30 
67 
7.3.6 Clinical target volume (CTV) .................................................................................. 30 
68 
7.3.6.1 Superior limit .................................................................................................... 30 
69 
7.3.6.2 Inferior limit ..................................................................................................... 30 
70 
7.3.6.3 Anterior limit .................................................................................................... 30 
71 
7.3.6.4 Posterior limit ................................................................................................... 30 
72 
7.3.6.5 Lateral limits ..................................................................................................... 30 
73 
7.3.7 Planning target volume (PTV) ................................................................................. 30 
74 
7.3.8 Organs at risk (OAR) ............................................................................................... 30 
75 
7.3.9 Dose and volume guidelines .................................................................................... 31 
76 
7.3.10 Dose-volume objectives and constraints ................................................................ 31 
77 
7.3.11 Treatment verification ........................................................................................... 31 
78 
7.3.12 Radiotherapy Quality Assurance (RTQA) ............................................................ 32 
79 
7.3.12.1 Pre-trial QA .................................................................................................... 32 
80 
7.3.12.2 On-trial QA ..................................................................................................... 32 
81 
7.4 Surgery ........................................................................................................................... 32 
82 
7.5 Treatment after trial end ................................................................................................. 32 
83 
8 Methods for measurement of endpoints for clinical efficacy and safety ............ 33 
84 
8.1 Methods for measurement of endpoints for clinical efficiency ...................................... 33 
85 
8.1.1 Primary endpoint ..................................................................................................... 33 
86 
8.1.2 Secondary endpoints ................................................................................................ 33 
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8.1.3 Quality of life assessment ........................................................................................ 34 

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8.2 Methods for measurement of endpoints for clinical safety ............................................ 35 
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9.0 Handling of adverse events .................................................................................. 35 
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9.1 Definitions ...................................................................................................................... 35 
91 
9.1.1 Adverse Event (AE) ................................................................................................. 35 
92 
9.1.2 Serious Adverse Event (SAE) ................................................................................. 35 
93 
9.1.3 Suspected Unexpected Serious Adverse Reaction (SUSAR) .................................. 35 
94 
9.2 Assessment of Adverse Events (AE) .............................................................................. 36 
95 
9.2.1 Assessment of causal relationship ........................................................................... 36 
96 
9.2.2 Assessment of intensity ........................................................................................... 37 
97 
9.3 Reporting and registration of Adverse Events ................................................................ 37 
98 
9.3.1 Reporting of Adverse Events (AE) .......................................................................... 37 
99 
9.3.2. Reporting of Serious Adverse evets (SAE) ............................................................ 38 
100 
9.3.2. Reporting of Suspected Unexpected Serious Adverse Reactions (SUSAR) .......... 38 
101 
9.4 Follow-up of Adverse Events ......................................................................................... 38 
102 
9.5 Independent Data Monitoring Committee ...................................................................... 38 
103 
9.6 Annual Safety Report (ASR) .......................................................................................... 38 
104 
9.7 Procedures in case of emergencies, overdose or pregnancy ........................................... 38 
105 
10 Statistics .................................................................................................................. 39 
106 
10.1 Analysis population and statistical analyses including sample size calculations ......... 39 
107 
11 Quality Control and Quality Assurance .............................................................. 39 
108 
11.1 Quality Assurance and Sponsor oversight .................................................................... 39 
109 
11.2 Monitoring .................................................................................................................... 39 
110 
11.3 Source data ................................................................................................................... 39 
111 
11.4 Deviations, serious breaches and other reporting obligations ...................................... 40 
112 
11.5 Audits and inspections .................................................................................................. 40 
113 
12 Ethics ...................................................................................................................... 40 
114 
12.1 Compliance to the protocol, ICH-GCP and regulations ............................................... 40 
115 
12.2 Ethical review of the trial ............................................................................................. 40 
116 
12.3 Procedure for obtaining informed consent ................................................................... 41 
117 
12.4 Data protection ............................................................................................................. 41 
118 
12.5 Insurances ..................................................................................................................... 41 
119 
13 Substantial changes to the study .......................................................................... 41 
120 
14 Collection, handling and archiving of data ......................................................... 42 
121 
14.1 Case Report Form - eCRF ............................................................................................ 42 
122 
14.2 Data collection .............................................................................................................. 42 

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14.3 Data management plan ................................................................................................. 42 
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15 Notifications of trial completion, reporting and publication ............................. 44 
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16 Bibliography ........................................................................................................... 44 
126 
17. Appendix ............................................................................................................... 48 
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REVISION HISTORY 
 
Protocol version 
Date of issue 
Summary of changes 
1.1 
2025-12-10 
Addition of statistical considerations and 
sample size calculation 
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SIGNATURE PAGE 
133 
Sponsor 
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I am responsible for ensuring that this protocol includes all essential information to be able to 
135 
conduct this trial. I will submit the protocol and all other important trial-related information to 
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the responsible investigator(s) so that they can conduct the trial correctly. I am aware that it is 
137 
my responsibility to keep the staff members who work with this trial informed and trained. 
 
138 
 
139 
140 
 
4 Aug 2025 
141 
Eva Angenete 
 
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Principal Investigator 
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I have read this protocol and agree that it includes all essential information to be able to 
147 
conduct the trial. By signing my name below, I agree to conduct the trial in compliance with 
148 
this clinical trial protocol, the EU Regulation on clinical trials of medicinal products for 
149 
human use (EU 536/2014), the Declaration of Helsinki, ICH-GCP (Good Clinical Practice) 
150 
guidelines and the current national regulations governing the conduct of this clinical trial. 
151 
I will submit this protocol and all other important trial-related information to the staff 
152 
members and investigators who participate in this trial, so that they can conduct the trial 
153 
correctly. I am aware of my responsibility to continuously keep the staff members and 
154 
investigators who work with this trial informed and trained. 
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I am aware that quality control of this trial will be performed in the form of monitoring and 
156 
eventual audit and inspection. 
 
 
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4 Aug 2025 
 
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161 
CONTACT INFORMATION 
 
Responsibility in the clinical trial 
 
Sponsor representative/Principal Investigator 
Responsibility: 
• 
Study protocol 
• 
Adherence to GCP 
Eva Angenete, MD, PhD, Professor 
Västra Götalandsregionen 
Sahlgrenska University Hospital/Östra 
Department of Surgery 
+46-31-34210000 
e-mail: eva.angenete@vgregion.se 
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164 
LIST OF USED ACRONYMS AND ABBREVIATIONS 
 
Abbreviation 
Term/Explanation 
ADL 
Activities of Daily Living 
ALT 
Alanine Transaminase 
AE 
Adverse Event 
AR 
Adverse Reaction: any unfavourable and unintended reaction to an 
investigational medicinal product, regardless of dose 
ASR 
Annual Safety Report = the annual safety report for reporting to 
authorities. In Sweden this is the Swedish Medical Products Agency 
via CTIS 
Bd 
Bis Die (twice daily) 
CBCT Voltage 
Cone Beam Computed Tomography voltage. The voltage used in 
CBCT is usually in the range of 120-140 kV. 
CRP 
C-Reactive Protein 
CRT 
Chemoradiotherapy 
cCR 
clinical Complete Response 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTIS 
Clinical Trials Information System = Centralized EU database/portal 
for application and communication with authorities concerning clinical 
trials. In Sweden this includes the Swedish Medical Products Agency 
and the Swedish Ethical Review Authority. 
CTR 
EU Regulation 536/2014, also called CTR, Clinical Trials Regulation 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumour Deoxyribonucleic Acid 
DPYD 
Dihydropyrimidine Dehydrogenase 
DSUR 
Development Safety Update Report = the standard which should be 
used for annual safety reporting to authorities 
EMVI 
Extramural Vascular Invasion 
EORTC 
European Organization for Research and Treatment of Cancer 
FFPE 
Formalin Fixed Paraffin-embedded 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
Gy 
Grey, the unit of ionizing radiation dose in the International System of 
Units (SI), defined as the absorption of one joule of radiation 
H&E 
Haematoxylin and Eosin 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ITT 
Intention-to-treat = including all data from all subjects who have 
participated in the trial 
LARS 
Low Anterior Resection Syndrome 
Läkemedelsverket 
Swedish Medical Products Agency – the national authority responsible 
for regulation and surveillance of the development, manufacturing and 
sale of medicinal products 

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Member State 
European Union (EU) Member state where an application for 
authorisation of a clinical trial or of a substantial modification has been 
submitted. 
MDT 
Multidisciplinary Team 
MRI 
Magnetic Resonance Imaging 
OAR 
Organs at Risk 
PP 
Per Protocol analysis = including only data from subjects who have 
completed the trial completely in accordance with the protocol, with no 
deviations from the protocol 
QoL 
Quality of life (here often health related quality of life, but not 
excluding global quality of life) 
RSI 
Reference safety information. A list of all known serious adverse 
reactions for the investigational medicinal product, including severity 
and frequency of the adverse reaction. The RSI is contained in the 
Summary of Product Characteristics or IB and is used to determine 
which adverse reactions should be reported as suspected unexpected 
serious adverse reactions (SUSARs). 
SAE 
Serious Adverse Event: Any untoward medical occurrence that at any 
dose requires inpatient hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability or 
incapacity, results in a congenital anomaly or birth defect, is life-
threatening, or results in death 
SAR 
Serious Adverse Reaction 
SCRCR 
Swedish ColoRectal Cancer Registry 
SP or SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction: This is an event that 
is likely related to the investigational medicinal product but with 
unexpected occurrence. An adverse reaction is unexpected if its nature 
or seriousness is not consistent with the information on the product in 
the RSI. 
T1 
Tumour invading the submucosa 
T2 
Tumour invading the muscularis propria 
T3 
Tumour invades into subserosa or into non-peritonealised pericolic or 
perirectal tissues 
T4 
Tumour perforates visceral peritoneum (4a) and/or directly invades 
other organs or structures (4b) 
TEM 
Transanal Endoscopic Microsurgery 
TME 
Total Mesorectal Excision 
ULN 
Upper Limit of Normal 
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168 
1.0 SYNOPSIS 
 
EU Trial 
number: 
2025-522955-25-00 
Title: 
Next generation StaR-TREC 
-Save the rectum by watchful waiting after (chemo)Radiotherapy or Total 
mesorectal excision for early REctal Cancer? 
Trial ID: 
NG-ST 
Short 
background/ 
Rationale/Aim: 
In patients with a newly diagnosed early rectal cancer the primary 
treatment is surgery without previous neoadjuvant treatment. However, 
the surgical treatment is associated with complications and if surgery 
could be avoided maintaining curative intent it is possible that QoL could 
be improved. One way of achieving this goal is to treat patients with 
chemoradiotherapy prior to planned surgery. If the patient responds with a 
clinical complete response (cCR), leaving no visible tumour surgery could 
be avoided. This is often called organ preservation. 
In the international multicentre randomized study, STAR-TREC 
(NCT02945566), patients were offered the choice of choose surgical 
treatment or possible organ preservation. 
Those who preferred organ preservation were randomised 1:1 between (i) 
organ preservation with mesorectal Chemoradiotherapy (CRT) versus (ii) 
organ preservation with mesorectal Short Course Radiotherapy (SCRT). 
The trial closed patient entry in end of March 2024 after having 
randomized the planned number of patients (in the combined phase II and 
III a total of 344 patients). IN the experience with the experimental 
treatments were that they were well tolerated by patients. Many patients 
were interested in the possibility to participate in the study. One year 
follow-up indicates that CRT renders almost 60% of patients a clinical 
complete response (with the addition of local excision this number was 
increased to 79%). 
In light the emerging demand from patients to offer the possibility of a 
non-surgical option to patients with early tumours until the results from 
the STAR-TREC trial are available this study has been developed. Organ 
preservation without detailed specification is included as a possibility in 
the recent guidelines for treatment of colorectal cancer in Sweden. 
In consensus in the oncologic and surgical community in Sweden 
mesorectal chemoradiotherapy has been suggested as a treatment option 
to standard rectal resection. 
Primary 
objective: 
Can mesorectal chemoradiotherapy achieve clinical complete response in 
early rectal cancer that is sustainable so that patients defer/avoid surgery? 
Secondary 
objectives: 
Oncologic: Local recurrence, mortality and overall survival 
Surgical: Complications and hospital stay 
Patient reported outcomes: Quality of life, urinary function, sexual 
function, bowel and stoma function 

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Health economy 
Primary 
endpoint: 
Clinical complete response rate evaluated by MRI and endoscopy at one 
year (i.e. patients that have not undergone surgery) 
Secondary 
endpoint: 
• Oncologic: 
o Clinical complete response rate without surgical 
intervention at three years 
o Local recurrence at three years 
o Mortality at three years 
o Overall survival at three years 
• Surgical 
o Surgical morbidity measured as Comprehensive 
Complications index at 90 days after surgery (if 
performed) 
o Total length of hospital stay during the first year 
o Outcome after surgery (Histopathological assessment of 
the resected rectal specimen to report (a) Presence of clear 
margins (>1mm from excision border to tumour edge), (b) 
TNM staging.) 
• Patient reported outcomes (all measured Baseline, post treatment, 
at surgery if applicable and at one, two and three years) 
o Quality of life 
o Urinary function 
o Sexual function 
o Bowel and stoma function 
Health economic analysis at three years 
Trial design: 
National, multi-centre, open-label, prospective trial. 
Patients will choose possible organ preservation or standard surgery. 
Those who prefer possible organ preservation will be offered treatment 
according to the experimental arm of the STAR TREC trial: mesorectal 
Chemoradiotherapy (CRT). 
Those who prefer standard surgery or have no preference will undergo 
standard Total Mesorectal Excision (TME) surgery without neoadjuvant 
radiotherapy treatment. 
Trial 
population: 
Subjects referred to either a colorectal surgeon or the colorectal cancer 
multidisciplinary team (MDT) with suspected early stage rectal cancer 
(T1-T3bNx/N0). Diagnosis must be confirmed with a biopsy prior to 
study entry. 
Number of 
subjects: 
Due to the study design the number of patients to be included has not 
been fixed, but it is estimated to be at least 60-80 patients during the 
period until STAR-TREC data will be available 
Inclusion 
criteria: 
• Biopsy proven adenocarcinoma of the rectum < 12 cm 
• Magnetic Resonance Imaging (MRI)-staged TT1-3b, N0, MX/M0 
rectal tumour 
• MDT determines that the following treatment options are all 

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reasonable and feasible: TME surgery or CRT 
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 
• Willing and able to consent 
Exclusion 
criteria: 
• MRI node positive (≥N1, defined by protocol guidelines) 
• MRI extramural vascular invasion (mriEMVI) present (defined by 
protocol guidelines) 
• MRI defined mucinous tumour 
• Mesorectal fascia threatened by tumour (≤ 1mm on MRI or ERUS) 
• Maximum tumour diameter >40mm (either measured from everted 
edges on sagittal MRI or ERUS examination) 
• No residual luminal tumour following endoscopic mucosal resection 
or similar local excision 
• Prior pelvic radiotherapy 
• Definite evidence of regional or distant metastases (M1) in opinion of 
MDT 
• Uncontrolled cardiorespiratory comorbidity (inadequately controlled 
angina or myocardial infarction or arrhythmia within 6 months prior 
to trial entry) 
• Known complete Dihydropyrimidine Dehydrogenase deficiency 
• Known Gilbert’s disease 
• Medication with coumarin-derivative oral anticoagulants that cannot 
be stopped or substituted by low molecular weight heparin 
• Medication with metronidazole, phenytoin, sorivudine or its 
analogues, such as brivudine 
• Pregnancy or breast feeding 
• Age <18 years 
Intervention: 
This is a low intervention trial as the investigational medicinal product 
(Capecitabine) is already authorized, used according to the terms in its 
marketing authorization to the same diagnosis but at a different tumour 
stage than standard and the complementary diagnostic procedures do not 
contribute to the risk or burden to subject safety compared to normal 
clinical practice. 
Patients will choose organ preservation or standard surgery. Those who 
prefer organ preservation will be treated with mesorectal CRT 
 
Those who prefer standard surgery or have no preference, will undergo 
standard TME surgery without neoadjuvant treatment. They will be asked 
to participate in the QoL part of the study, while the remainder of the data 
will be extracted from the national quality registry, the Swedish 
ColoRectal Cancer Registry (SCRCR) 
 
Long course concurrent chemoradiation (CRT): 
Capecitabine: 825 mg/m² orally, b.d., on radiotherapy days 
Radiotherapy: A dose of 50 Gy applied to the primary tumour and 
surrounding mesorectum in 25 fractions of 2 Gy, 5 days a week. 

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The first assessment after treatment is at 6-8 weeks (from end of 
chemoradiotherapy) using composite clinical, endoscopic and MRI based 
assessment will identify the minority of non-responders who should 
convert to TME surgery. Patients demonstrating a clinical Complete 
Response (cCR) after chemoradiotherapy 6-8 weeks will be offered to 
enter the national watch and wait program and followed accordingly 
in the WoW study NCT03125343 (3, 6, 9, 12, 15, 18, 21 and 24 months 
and then every 6 months for another 3 years and then yearly for five 
more years). 
 
If near complete response there will be a re-evaluation after 12 weeks 
after chemoradiotherapy to determine if the criteria for clinical complete 
response (cCR) are met. 
Regardless of timepoint, patients who achieve CR may progress directly 
to active surveillance. Those who do not fulfil the criteria for CR will 
progress to TME-surgery. 
Investigational 
medicinal 
product(s), 
dosage, 
administration: 
Capecitabine: 825 mg/m² administered orally twice daily on radiotherapy 
days 
Radiotherapy: A dose of 50 Gy applied to the primary tumour and 
surrounding mesorectum in 25 fractions of 2 Gy, 5 days a week. 
Ethical 
considerations, 
benefit/risk: 
The treatment suggested has been evaluated at one year after finalized 
treatment with little known severe side effects. The benefit for the patients 
is that the treatment is offered as it is yet to be standardized in Sweden 
according to national treatment guidelines. Possible risks include 
increased risk for complications if surgery is deemed necessary, but 
according to previous publications this risk is small. 
Planned 
duration of the 
trial: 
About two-year inclusion, and at least three-year follow up after inclusion 
of the last patient. 
 
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2.0 BACKGROUND AND RATIONALE 
172 
2.1 Rectal cancer and standard treatment 
173 
Rectal cancer is a common cancer with about 2000 new patients diagnosed yearly in Sweden. 
174 
Survival and risk for local recurrence (5-9%) have improved over the last decades due to both 
175 
improved surgical technique and preoperative treatment (1-7). 
176 
Standard primary radical surgery (Total Mesorectal Excision (TME)) is the evidence-based 
177 
oncologically effective treatment for early-stage rectal cancer; only 2% and 12% of patients 
178 
experience local or distant failure respectively (2). It entails removing the bowel including the 
179 
surrounding fat and lymphatic tissue (mesorectum). However, resection of a low rectal 
180 
tumour may require a permanent stoma, and many more patients will need a temporary stoma, 
181 
some of which are not reversed. Complications associated with rectal cancer surgery include 
182 
anastomotic leakage, which is a common complication even in non-irradiated patients, as 
183 
clinical leaks amounted to 16% in the Dutch TME trial (8). Pelvic dissection may 
184 
inadvertently cause autonomic nerve damage leading to urinary incontinence or retention 
185 
(25%-34%) and sexual dysfunction (9-11). More than half of all patients experience some 
186 
form of faecal incontinence following primary TME surgery and 30-40% suffer daily 
187 
symptoms of urgency, incomplete emptying and stool frequency(12-14). 
188 
It is possible that radical surgery, may not be the optimal method of treatment for early 
189 
tumours. Early rectal tumours can be locally excised through the anus with low morbidity and 
190 
mortality using Transanal Endoscopic Microsurgery (TEM) or endoscopic submucosal 
191 
dissection (ESD) (15). Morbidity and mortality after local excision are lower than after radical 
192 
resection, but the long-term results have been inadequate with local recurrence rates ranging 
193 
from 5% to 28% for T1 lesions, and from 11% to 45% for T2 lesions (16, 17). The problem is 
194 
that these rates of recurrence are higher than would be expected with radical resection, 
195 
although some registry-based data indicate that appropriate right selection of patients might 
196 
improve these results(18). Omission of total mesorectal excision risks leaving behind 
197 
microscopic lymph node metastases, a potential cause of local failure. It is difficult to predict 
198 
the risk of lymph node involvement although there is data indicating that the risk increases 
199 
with depth of wall penetration, but there can be lymph node involvement even in patients with 
200 
only T1 tumours, risk factors for this includes lymphovascular invasion, tumour budding and 
201 
perineural invasion. The incidence of lymph node metastasis ranges from 6% to 14% for T1 
202 
tumours, 17% to 23% for T2 tumours, and 49% to 66% for T3 tumours (19). 
203 
2.2 Neoadjuvant (chemo)radiotherapy 
204 
Neoadjuvant (preoperative) radiotherapy has been shown to reduce local recurrence in several 
205 
randomized trials (20). The two most common schedules for this treatment are preoperative 
206 
chemoradiotherapy (45-50.4 Gy in combination with fluoropyrimidine based chemotherapy) 
207 
and short course hypofractionated radiotherapy (25Gy in five fractions). No significant 
208 
difference in local recurrence rates has been reported between the two types of schedules (21, 
209 
22). Short course radiotherapy with a delay to surgery has been studied in the Stockholm III 
210 
trial which demonstrated low toxicity and a 12.5% pathological complete response (pCR) rate 
211 
(23). 
212 
Although the main aim of neoadjuvant treatment firstly is to reduce the risk for local 
213 
recurrence after surgery, achieving a complete removal of the tumour, a pathological 

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214 
complete response (pCR) is sometimes possible. Data indicates that if a pathological complete 
215 
response is achieved disease-free survival is improved compared to patients with no or little 
216 
response to neoadjuvant treatment (24-26). 
217 
It has been suggested that if a clinical complete response (cCR) is achieved, surgery is not 
218 
necessary, and a strategy of organ preservation could be adopted. However, the neoadjuvant 
219 
must treatment eradicate all tumour tissue to achieve organ preservation. In more advanced 
220 
rectal cancer this occurs after neoadjuvant treatment in about 15-20% of all tumours, thus 
221 
making deferral of surgery possible. This is mainly referred to as opportunistic organ 
222 
preservation performed in Sweden only within the framework of a study protocol (the WoW 
223 
study, NCT03125343). 
224 
In Brazil this approach has been tested in selected cases since 2004 (27). It has since been 
225 
reported in selected cases from all over the world collected in an international watch and wait 
226 
registry, indicating that it can be possible to defer surgery if signs of cCR are seen after 
227 
neoadjuvant treatment (28). In a pooled dataset including 2323 patients a correlation was 
228 
found between the clinical T-stage and the pCR rate (cT1: 58%, cT2: 28%, cT3: 16% and 
229 
cT4: 12%) (25). Thus, the success rate of achieving a clinical complete response after 
230 
radiotherapy treatment will be highly dependent upon tumour stage. The data indicate that 
231 
with appropriate selection neoadjuvant treatment may be of particular benefit to patients with 
232 
early tumours. 
233 
2.3 Neoadjuvant treatment in early rectal cancer with the aim to avoid surgery 
234 
There have been some studies, mainly prospective, non-randomised phase II studies that have 
235 
evaluated use of (chemo)radiotherapy in the context of early-stage rectal cancer for the 
236 
purpose of achieving a clinical complete response and organ preservation. These studies 
237 
generally supplemented the neoadjuvant treatment with local transanal excision and or 
238 
radiotherapy boosts of the area of the bowel wall originally occupied by tumour. The studies 
239 
demonstrated high rates of organ preservation and infrequent pelvic cancer recurrence; but 
240 
often at the cost of treatment related toxicity (29-34). It has been suggested that modifying the 
241 
approach to local excision could improve results, either only performing local excision if 
242 
residual tumour is present as carried out in the recent STAR-TREC trial (35) or in all patients 
243 
(sometimes only removing a scar) as in the recently published TAUTEM (Chemoradiotherapy 
244 
and Local Excision vs Total Mesorectal Excision in T2-T3ab, N0, M0 Rectal Cancer). In the 
245 
TAUTEM study 17 hospitals in Spain participated and all but one patient in the 
246 
chemoradiotherapy arm underwent TEM(36). In the STAR-TREC trial both 
247 
chemoradiotherapy and short course radiotherapy with a delay to surgery was used(35) and 
248 
patients with incomplete response were treated with TEM if there were signs of a more 
249 
advanced tumour, these patients were referred to radical surgery. Three centres in Sweden 
250 
participated in the study and results presented at the ESTRO congress in Vienna report cCR 
251 
after 5x5 Gy of 27% compared to 57% after CRT. Addition of local excision after near 
252 
complete response resulted in a watch and wait strategy at one year of 61.5% after 56x5Gy 
253 
compared to 79.8% for patients treated with CRT. 
254 
Another option that has been suggested consists of an endoluminal brachytherapy approach 
255 
which might achieve better tumour response with lesser toxicity (37). The OPERA included 
256 
patients with T2-T3b tumours with minor lymph node involvement (N1<8 mm) and all 
257 
patients received chemoradiotherapy. They were then randomized to either a boost of external 

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beam radiotherapy (9 Gyx5) or brachy radiotherapy (90Gy/3 fractions). They found that 64% 
259 
of patients with external beam radiotherapy achieved a clinical complete response, compared 
260 
to 92% after brachy radiotherapy. The 5-year local regrowth was 39% vs 17%, and some 
261 
patients had their local regrowth after 3 years, indicating that long-term follow-up may be 
262 
necessary. There are indications that patients that undergo brachy radiotherapy and then have 
263 
incomplete response have very poor bowel function suggesting that studies are required to 
264 
ascertain that patients receive correct information for shared decision making (38). 
265 
In summary there seems to be sufficient evidence that some patients will achieve clinical 
266 
complete response after chemoradiotherapy with a long-term positive oncologic outcome 
267 
(25), but long-term morbidity is not sufficiently described to date. This treatment will increase 
268 
the risk for postoperative complications and increased risk for affected bowel function after 
269 
both local excision and TME-surgery. Local excision may not always be adequate to treat 
270 
insufficient response to chemoradiotherapy. Presently in Sweden there are no available 
271 
treatment options apart from radical surgery (as recommended in the Swedish National 
272 
Treatment Guidelines for Colorectal cancer) for patients with early rectal cancer while 
273 
waiting for the long-term results from the STAR-TREC trial. The CORRECT trial has 
274 
commenced in Stockholm and Uppsala in 2025 offering treatment options with contact 
275 
therapy (brachy radiotherapy). 
276 
2.4 Rationale and design of the Next generation study awaiting the results from 
277 
the STAR-TREC study 
278 
In light of the promising results from smaller studies, and the positive experience from 
279 
treatments centres within the STAR-TREC trial this study aims to offer at treatment option to 
280 
patients with early rectal cancer in a prospective phase II study to enable evaluation of results, 
281 
and to enable comparisons with results from present and future studies until results from the 
282 
STAR-TREC trial are published. The first results presented at ESTRO 2025 indicate that 57% 
283 
of patients that received CRT maintained a clinical complete response one year after treatment 
284 
compared to 27.3% in the arm with 5x5 Gy (https://user-swndwmf.cld.bz/ESTRO-2025- 
285 
Abstract-Book). The dosage of Capecitabine at 825mg/m2 for five days per week has been 
286 
chosen to mimic the STAR-TREC study. 
287 
The STAR-TREC trial included patients with a radiological staging Magnetic Resonance 
288 
Imaging (MRI)-stageTX/T1-3b, NX/N0, MX/M0 rectal tumour. Exclusion criteria were 
289 
designed to avoid including patients with known risk factors for locoregional relapse 
290 
following rectal cancer treatment. This study will use the same inclusion criteria, and similar 
291 
follow-up routine. Patients who choose standard treatment i.e. radical surgery (TME-surgery) 
292 
will be the control arm. 
293 
The choice to refrain from local surgical resection of a possible small regrowth or insufficient 
294 
response lies in a combination of clinical observations of morbidity and insufficient clinical 
295 
experience at the study sites. It may be reconsidered when the long-term results from the 
296 
STAR-TREC study are available, and the use of local excision is supported by the recent data 
297 
from the TAUTEM trial where mesorectal CRT and TEM were found non-inferior to standard 
298 
TME resection (36). 

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2.1.5 Patient involvement 
300 
The study has been discussed and modified in collaboration with patient representatives from 
301 
the Swedish stoma association ILCO. 
302 
3.0 BENEFIT-RISK EVALUATION 
303 
3.1 Benefits 
304 
The possible benefits for patients entering this study include 
305 
• 
avoiding surgery and surgery related complications including surgical infections, 
306 
small bowel obstruction, cardiopulmonary complications and others 
307 
• 
possibly improved bowel function due to deferring surgery 
308 
• 
possibility to avoid a stoma that may improve quality of life. 
309 
3.2Risks 
310 
Possible risks are: 
311 
• 
Patients enter the study hoping to avoid surgery, but many will still require surgery to 
312 
achieve cure. This could be difficult to accept and may lead to disappointment. The 
313 
best way to mitigate this is probably by informed consent and providing support. 
314 
• 
As some patients will require surgery it could be considered that they are over-treated 
315 
with chemotherapy and radiotherapy before surgery. This may increase the risk for 
316 
complications postoperatively. 
317 
• 
The rigid follow-up if surgery is avoided in a watch and wait setting might increase 
318 
the risk of fear of recurrence or anxiety, although data are scarce (39, 40). This is 
319 
mitigated by support and information. 
320 
• 
Chemotherapy may induce side-effects: hand-foot syndrome, diarrhoea, vomiting, 
321 
nausea, stomatitis, abdominal pain, anorexia, fatigue, and asthenia. Less common side 
322 
effects include cardiotoxicities, cytopenia, infections, thrombophlebitis, deep vein 
323 
thrombosis, pulmonary embolism, kidney failure, liver toxicity, skin reactions, 
324 
hypersensitivity reactions and toxic leukoencephalopathy. 
325 
• 
Radiotherapy of rectal cancer, 50 Gy/25 Gy, can cause acute and late side-effects such 
326 
as increased urinary and bowel frequency, pain in the lower abdomen and anus, anal 
327 
discharge, sexual dysfunction, infertility, colitis, pelvic stiffness/pain, secondary 
328 
malignancies. In this study, the treatment volume is significantly smaller compared 
329 
with radiotherapy given in advanced rectal cancer. The concept of reduced treatment 
330 
volume is new and previously tested only in the STAR-TREC trial, preceding this 
331 
study. Interim data from the STAR-TREC trial show minimal short-term treatment- 
332 
related toxicity. In patients that have a complete tumour response with radiotherapy 
333 
alone, the overall risk of late morbidity is assessed to be lower compared with the 
334 
patients undergoing up-front TME-surgery according to clinical routine. In patients 
335 
that will need TME surgery after radiotherapy the radiotherapy will add up to the 
336 
acute and late morbidity. Given the reduced treatment volumes and moderate 
337 
radiotherapy doses, the acute and late toxicity is assessed to be manageable. 

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338 
4.0 TRIAL OBJECTIVES 
339 
Investigate if using chemoradiotherapy 2 Gy x 25 with Capecitabine 825 mg/m2 and a limited 
340 
clinical target volume (CTV) will obtain a clinical complete response rate of 50% or more in 
341 
patients with TX/T1-3b, NX/N0, MX/M0 rectal tumours. 
342 
The aim is to provide a treatment option to surgery to patients with early rectal cancer that 
343 
fulfil the inclusion criteria for the now closed STAR-TREC study. This will enable a safe 
344 
implementation with a control of outcomes and treatment regimens. 
345 
4.1 Primary objective 
346 
The primary objective of this trial is to achieve a sustained clinical complete response rate in 
347 
patients 1 year after treatment. 
348 
4.2 Secondary objectives 
349 
The secondary objectives of this study include oncologic safety, treatment related safety and 
350 
functional outcome including quality of life (QoL). 
351 
4.3 Primary endpoint 
352 
Primary variable: clinical complete response rate. Measured as the ratio of patients with a 
353 
non-operative approach at onset that after evaluation by a combination of MRI, clinical and 
354 
endoscopic examination have a clinical complete response at 1 year. 
355 
4.3. Secondary endpoint 
356 
The secondary endpoints for the study are: 
357 
• 
Oncological: 
358 
o local recurrence 
359 
o local regrowth 
360 
o Survival (overall) 
361 
o Metastases 
362 
o Organ preservation rate 
363 
o clinical complete response rate 
364 
• 
Surgical 
365 
o morbidity measured with Comprehensive Complications Classification Index 
366 
(41) 
367 
o total length of hospital stay, 
368 
o radical resection (R0) after surgery 
369 
• 
Quality of life 
370 
Urinary function 
371 
o Sexual function 
372 
o Bowel function 
373 
o presence of a stoma 
374 
• 
Health economic evaluation. 

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375 
5 TRIAL DESIGN AND PROCEDURES 
376 
5.1 Overall trial design 
377 
The study design is a national multi-centre prospective non-randomized phase IV cohort 
378 
study. Planned centres are Sahlgrenska University Hospital, Skåne University Hostpital, 
379 
Stockholm South General Hospital. It is an initiative from the surgical and oncological 
380 
community in Sweden to offer patients a choice of treatment before solid scientific evidence 
381 
is present to support either treatment option. It is a low-intervention clinical trial as the 
382 
investigational medicinal product Capecitabine is authorized and used according to the terms 
383 
in its marketing authorization to the same diagnosis but at a different tumour stage than 
384 
standard. The complementary diagnostic procedures are not considered to contribute to the 
385 
risk or burden to subject safety compared to normal clinical practice. 
386 
Patients who meet inclusion criteria will be offered neoadjuvant treatment to defer/avoid 
387 
surgery or TME surgery upfront. 
388 
Those who prefer organ preservation will be treated with mesorectal chemoradiotherapy. 
 
389 
Those who prefer standard surgery or have no preference, will undergo standard TME surgery 
390 
without neoadjuvant treatment. They will be asked to participate in the QoL part of the study, 
391 
while the remainder of the data will be extracted from the national quality registry, the 
392 
Swedish ColoRectal Cancer Registry (SCRCR) 
 
393 
For possible organ preservation long course concurrent chemoradiation will be 
394 
performed (CRT): 
395 
Capecitabine: 825 mg/m² orally, b.d., on radiotherapy days 
396 
Radiotherapy: A dose of 50 Gy applied to the primary tumour and surrounding mesorectum in 
397 
25 fractions of 2 Gy, 5 days a week. 
398 
399 
The first assessment after treatment is at 6-8 weeks (from end of chemoradiotherapy) using 
400 
composite clinical, endoscopic and MRI based assessment will identify the minority of non- 
401 
responders who should convert to TME surgery. Patients demonstrating a clinical complete 
402 
response (cCR) after chemoradiotherapy 6-8 weeks will be offered to enter the national watch 
403 
and wait program and followed accordingly in the WoW study NCT03125343 with 
404 
endoscopy and MRI and clinical follow-up accordingly (at present 3, 6, 9, 12, 15, 18, 21 and 
405 
24 months and then every 6 months for another 3 years and then yearly for five more years). 
 
406 
If near complete response there will be a re-evaluation after 12 weeks after 
407 
chemoradiotherapy to determine if the criteria for clinical complete response (cCR) are met. 
 
408 
Patients who achieve cCR may progress directly to active surveillance and included in the 
409 
Swedish Watch and Wait study (WoW, NCT03125343). Clinical and radiological follow-up 
410 
at 3, 6, 9, 12, 15, 18, 21 and 24 months. First year registered in CRF in this study too, after 
411 
that follow-up at 1, 2 and 3 years. 
412 
Those who do not fulfil the criteria for cCR will progress to TME-surgery. Follow-up at 1, 2 
413 
and 3 years. 

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Time points for follow up and collection of data into CRF 
415 
1.  Inclusion 
416 
2.  Start of neoadjuvant treatment 
417 
3.  Evaluation after neoadjuvant treatment 
418 
4.  Second follow-up after neoadjuvant treatment if applicable 
419 
5.  Third follow-up after neoadjuvant treatment if applicable 
420 
6.  Surgery if applicable 
421 
7.  Postoperative hospitalization if applicable 
422 
8.  1 month follow-up after surgery 
423 
9.  1 year after diagnosis 
424 
10. 2 years after diagnosis 
425 
11. 3 years after diagnosis 
426 
12. 5 years only through SCRCR and Swedish Cause of Death Registry 
427 
5.2 Procedures and flow-chart 
428 
See table 1 for details on each visit. 
429 
Each follow-up visit may vary 2-3 weeks depending on availability to radiology, endoscopy 
430 
and clinical visit. 
431 

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433 
434 
435 
436 
437 
438 
439 
440 
442 
443 
445 
446 
447 
450 
451 
452 
453 
456 
458 
 
432 
 
 
Screening 
Neoadjuvant 
treatment 
 
 
Surgery if 
applicable4 
 
 
Follow-up 
 
At/before first 
visit in 
surgical clinic 
First 
visit in 
oncolo 
gy 
clinic 
End of 
CRT 
treatment 
6-8 weeks 
after end 
of 
neoadjuva 
nt 
treatment 
if not cCR 
10-12 
weeks 
after end 
of 
neoadjuva 
nt 
treatment 
if not cCR 
Surgery 
Hospital 
stay after 
surgery, 
follow-
up 1 
month 
after 
discharg 
e 
3 months 
after 
cCR 
6 months 
after cCR 
9 months 
after cCR 
12 months 
after cCR 
or surgery 
Every 3 
months 
12-24 
monts 
after cCR 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
441 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
X 
 
 
 
 
 
 
 
 
Digital rectal examination 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
444 
Colonoscopy2 
X 
 
 
 
 
 
 
 
 
 
 
Confirmed diagnosis of adenocarcinoma3 
X 
X 
 
 
 
 
 
 
 
 
 
Computerized Tomography (CT) scan 
thorax, and CT or MRI abdomen 
X 
 
 
 
 
 
 
 
 
 
X 
 
High resolution MRI pelvis 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
4X48 
MDT review 
X 
 
 
 
 
 
 
 
 
 
 
Blood sample 
X 
 
 
 
 
X 
 
 
 
 
4X49 
Preparation of FFPE tissue blocks and 
biopsies 3 
X 
 
 
 
 
X 
 
 
 
 
 
QoL questionnaire 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Toxicity related to (chemo)radiotherapy 
registered in CRF 
 
 
X 
 
 
 
 
X 
 
 
 
Complications related to surgical 
procedure according to Clavien-Dindo 
 
 
 
 
 
 
 
 
 
 
454 
455 
Sigmoidoscopy 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Survival status 
 
X 
X 
 
 
 
X 
X 
 
 
457 
459 
460 
461 
462 
  1Medical 
history includes details of current colorectal cancer, previous and current medical conditions and previous treatments received. 2 Colonoscopy should be performed either prior surgery or within 
three months after surgery. At least one colonoscopy to be performed within the first 3 years of follow-up and according to national guidelines. 3 Biopsies taken and sent to routine pathology 
department (note name of pathology department in CRF). 4Surgery can be performed either immediately or when a cCR cannot be achieved or if there is suspicion of regrowth. 

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463 
464 
 
Follow-up 
Not 
registered 
in eCRF 
but 
according 
to clinical 
routine 
Not 
registered 
in eCRF 
but 
according 
to clinical 
routine 
Not 
registered 
in eCRF 
but 
according 
to clinical 
routine 
Not 
registered 
in eCRF 
but 
according 
to clinical 
routine 
 
 
15 
months 
after 
cCR 
18 months 
after cCR 
24 months 
after cCR 
or surgery 
30 months 
after cCR 
36 months 
after cCR 
or surgery 
42 months 
after cCR 
48 months 
after cCR 
54 months 
after cCR 
60 months 
after cCR 
Written informed consent 
 
 
 
 
 
 
 
Medical history1 
 
 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
 
 
Digital rectal examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
 
 
 
 
 
 
Colonoscopy2 
 
 
 
 
 
 
 
Confirmed diagnosis of adenocarcinoma3 
 
 
 
 
 
 
 
Computerized Tomography (CT) scan 
thorax, and CT or MRI abdomen 
 
X 
 
X 
X 
 
X 
High resolution MRI pelvis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDT review 
 
 
 
 
 
 
 
Blood samples 
 
X 
 
X 
 
 
 
Preparation of FFPE tissue blocks and 
biopsies 3 
 
 
 
 
 
 
 
QoL questionnaire 
 
X 
X 
X 
 
 
 
Toxicity related to (chemo)radiotherapy 
registered in CRF 
 
X 
 
X 
 
 
 
Complications related to surgical 
procedure according to Clavien-Dindo 
 
 
 
 
 
 
 
Sigmoidoscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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465 
5.3 Biological sampling procedures 
466 
Pre-therapeutic biopsies will be taken during endoscopy/rectoscopy during examination of the 
467 
tumour in the outpatient clinic. Biopsies will be sent according to local routines to the 
468 
pathology department. The name of the pathology department will be registered in the CRF. 
469 
At end of inclusion in the trial blocks will be collected from the different pathology 
470 
departments for analysis at Sahlgrenska University Hospital. 
471 
Biopsies will be taken from the resected specimen at surgery and sent to the pathology 
472 
department. Blocks will be collected at the end of the study and sent in batches to the study 
473 
centre at Sahlgrenska University Hospital and University of Gothenburg. Patients that are 
474 
considered complete responders after treatment will not be subject to further biopsies. 
475 
Blood samples will be collected at baseline, surgery and at each follow-up and stored 
476 
according to a separate standard operating procedure. They will be sent for analysis to the 
477 
study centre at Sahlgrenska University Hospital and University of Gothenburg. 
478 
5.3.1 Handling, storage and destruction of biological samples 
479 
All biopsies are sent to the routine pathology department. Blocks will be collected from the 
480 
diagnostic procedure as well as when applicable from the surgical specimen. 
481 
Formalin fixed paraffin embedded biopsies will be stained according to our previously 
482 
published multicolour panel (42). They may also be subject to assembly of tissue micro array 
483 
prior to staining. 
484 
5.3.2. Total volume of blood per subject 
485 
The total volume of blood taken from each subject during the trial is a maximum of 50 ml per 
486 
sampling and a total 200-250 ml/patient during the study. 
487 
5.3.3 Biobank 
488 
All samples taken in this trial, covered by the Biobank Act are registered in a biobank and 
489 
handled according to the current national laws and regulations. The samples are coded to 
490 
protect the subject’s identity. All samples and the identification/code lists are stored securely 
491 
and separately to prevent access by unauthorized persons. 
492 
5.4.1 Start of the clinical trial 
493 
The start of the clinical study is defined as the first visit of the first subject at the surgical 
494 
department at any of the recruiting sites. 
495 
5.4.2 Temporary halt or early termination 
496 
The start of the study is defined as the first visit of the first subject at the surgical department 
497 
at any of the recruiting sites. Sponsor will report the start of the trial through notification in 
498 
the Clinical Trial Information System (CTIS) within 15 days. 
499 
The study may be prematurely terminated for safety reasons affecting the risk-benefit balance 
500 
or if the recruitment of subjects cannot be completed within reasonable time. Decisions on 
501 
premature termination are taken by the sponsor. The Competent Authorities should be 
502 
informed as soon as possible via CTIS, but no later than 15 days after trial suspension. 

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If the study is prematurely terminated or suspended, the investigator should immediately 
504 
inform the subjects and ensure appropriate treatment and follow-up. 
505 
5.4.3 End of clinical trial 
506 
The trial ends when the last subject has completed the last follow-up of three years. 
507 
6.0 SUBJECT SELECTION 
508 
6.1 Inclusion criteria 
509 
To be included in the trial, subjects must meet all of the following criteria: 
510 
• 
The subject has given their written consent to participate in the trial 
511 
• 
Be 18 years or older 
512 
• 
Have an adenocarcinoma verified tumour within the rectum below 12 cm from anal 
513 
verge 
514 
• 
Have a tumour stage of TX/T1-3b (regardless of tumour size) 
515 
• 
Have no nodal metastases (NX/N0) 
516 
• 
Have no distant metastases (MX/M0) 
517 
• 
Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 
518 
• 
For female subjects of childbearing potential: 
519 
o Have a negative pregnancy test within 7 days prior to study entry 
520 
o Agree to use adequate, medically approved, contraceptive precautions from 
521 
trial entry until 6 months after the end of study treatment 
522 
• 
If non-sterilised male with a partner of childbearing potential, must: 
523 
o Agree to use adequate, medically approved, contraceptive precautions from 
524 
trial entry until 6 months after the end of study treatment 
525 
6.2 Exclusion criteria 
526 
Subjects must not be included in this trial if any of the following criteria are met: 
527 
• 
Give no informed consent 
528 
• 
No biopsy confirmed rectal cancer (adenocarcinoma) 
529 
• 
Have a recurrent rectal cancer 
530 
• 
An age below 18 
531 
• 
Have concomitant or previous malignancies within 3 years prior to trial entry, except 
532 
those that in the opinion of the MDT are unlikely to relapse within 3 years or lead to 
533 
death within 5 years 
534 
• 
Have unequivocal evidence of metastatic disease (includes respectable metastases) 
535 
(Patients with equivocal radiological lesions (e.g. retroperitoneal, liver, lung) that are 
536 
not classified as M1 are eligible if agreed by MDT) 
537 
• 
Have an MRI node positive tumour (≥N1, defined by protocol guidelines) (Patients 
538 
with equivocal radiological findings that are either classified as NX or N0 are eligible) 
539 
• 
Have MRI extramural vascular invasion (mriEMVI) positive (defined by protocol 
540 
guidelines) 
541 
• 
Have a threatened mesorectal fascia (≤1 mm on MRI or ERUS) 
542 
• 
Have no residual luminal tumour following endoscopic resection prior to first visit at 
543 
surgical department 

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544 
• 
Have contraindications to radiotherapy including previous pelvic radiotherapy 
545 
• 
Have uncontrolled cardiorespiratory comorbidity (includes patients with inadequately 
546 
controlled angina or myocardial infarction or arrhythmia within 6 months prior to trial 
547 
entry) 
548 
• 
Have known complete dihydropyrimidine dehydrogenase (DPYD) deficiency 
549 
• 
Have known Gilbert’s disease (hyperbilirubinemia) 
550 
• 
Have been taking coumarin-derivative anticoagulants (e.g. warfarin) that cannot be 
551 
discontinued at least 7 days prior to starting treatment or substituted by low molecular 
552 
weight heparin 
553 
• 
Are taking metronidazole, phenytoin or sorivudine or its chemically related analogues, 
554 
such as brivudine, within 4 weeks of trial entry (see Section 8.3.5 for further details) 
555 
• 
Are Pregnant or lactating woman 
556 
• 
Have history of severe and unexpected reactions to fluoropyrimidine therapy 
557 
6.3 Screening and inclusion 
558 
Subject eligibility is established at the multidisciplinary meeting that often precedes the first 
559 
outpatient meeting after a diagnosis has been established. If the subject comes to the 
560 
outpatient clinic prior the multidisciplinary meeting, there is a possibility to screen for 
561 
inclusion and give oral and written information. This procedure is decentralized and can be 
562 
performed at any hospital that refers patient to any of the hospitals including in the clinical 
563 
trial. A member of the direct clinical care team will always make the first approach to the 
564 
patient. 
565 
The subject will then be given adequate time to consider the study and agree to participate 
566 
before being referred to the hospital including in the clinical trial. A treatment plan will be set, 
567 
and the patient will sign informed consent and can then either receive the treatment according 
568 
to the study protocol at the hospital participating in the clinical trial or in a decentralized 
569 
manner. 
570 
All clinical information entered into CRFs will be entered by the hospitals participating in the 
571 
clinical trial regardless of decentralized process or not. 
572 
Individuals who do not wish to enter the study will be offered standard treatment according to 
573 
the Swedish National Treatment Guidelines for Colorectal Cancer, i.e. TME surgery. The 
574 
experimental organ saving treatment is not offered outside a study setting unless unfit for 
575 
primary TME surgery. 
576 
Details of all participants approached about the trial will be recorded on the Participant 
577 
Screening Log. The following data will be recorded: 
578 
1.  Sex 
579 
2.  Age 
580 
3.  Clinical TNM according to TNM v8 
581 
4.  Planned oncologic and surgical treatment 
582 
In addition – all patients treated at the participating hospitals are registered in the Swedish 
583 
ColoRectal Cancer Registry (SCRCR). If necessary, missing information will be retrieved 
584 
(sex, age and clinical TNM stage, type of surgery performed and recurrence data) on non- 
585 
included patients using the SCRCR 

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586 
6.4 Withdrawal criteria 
587 
Subjects can discontinue their participation in the study at any time without any consequence 
588 
to his/her continued treatment. The investigator/sponsor can at any time terminate the study 
589 
for a subject due to, e.g., unacceptable adverse events/adverse reactions or because the subject 
590 
does not follow procedures in the clinical trial protocol. If the subject discontinues the trial, 
591 
follow-up of this subject will be performed according to the clinic’s routine. 
592 
7.0 TRIAL TREATMENTS 
593 
7.1 Description of investigational medicinal product(s) 
594 
The only Investigational Medicinal Product (IMP) used in the Next Generation ST study is 
595 
capecitabine. This is a low intervention clinical study and the IMP used is standard for 
596 
patients with rectal cancer. 
597 
7.1.1. Dose and administration 
598 
There is no international standard dosing for the combination of capecitabine with long course 
599 
radiotherapy. The dose chosen in Next Generation ST is based on the STAR TREC study 
600 
where patients received 825mg/m2 bd five days per week. 
601 
A phenotypic or genotypic DPYD deficiency test is recommended prior to starting treatment 
602 
to identify patients likely to develop severe capecitabine-related toxicities due to reduced 
603 
catabolism/increased exposure. The reported DPYD result should be recorded in the CRF and 
604 
will define subsequent patient management: 
605 
• 
Complete DPYD deficiency: Patient cannot be included in the study. 
606 
• 
Partial DPYD deficiency: Capecitabine starting dose to be reduced as per local 
607 
guidelines 
608 
The following criteria must be met prior commencing treatment with capecitabine: 
609 
o Estimated creatinine clearance ≥50 ml/min 
610 
o Absolute neutrophil count ≥1.5x109/L 
611 
o Platelets ≥100 x 109/L 
612 
o Serum transaminase ≤3 x Upper Limit Normal/L (ULN) 
613 
o Bilirubin ≤1.5 x ULN 
614 
Capecitabine should be taken on the days of radiotherapy only (normally Monday-Friday). If 
615 
radiotherapy is not given (e.g. due to bank holiday or machine breakdown, etc.) then 
616 
capecitabine should not be taken. Capecitabine treatment can begin on any day of the week; 
617 
however, there is normally no capecitabine treatment on Saturday or Sunday, unless 
618 
radiotherapy is given on one of these days. 
619 
Patients are asked to swallow whole capecitabine tablets with a glass of water twice daily 
620 
within 30 minutes after the ingestion of food, commencing the morning of the first dose of 
621 
radiotherapy treatment. Tablets should not be crushed or cut. 
622 
It is recommended that patients keep a diary of the number of capecitabine tablets taken to 
623 
assist site research staff in recording dose delivered. 

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624 
7.1.2 Packaging, labelling, and handling of investigational medicinal products 
625 
Trial supplies of capecitabine for the entire treatment period will be prescribed and collected 
626 
at the pharmacy during the study period. The costs for the drugs will be covered through the 
627 
national drug insurance, and no drug costs will be reimbursed. 
628 
The full 5-week course of capecitabine can be dispensed at the start of treatment. 
629 
If a dose reduction is required before the end of the 5 weeks course due to toxicities, all 
630 
remaining capecitabine tablets should be returned, patient weight re-measured and amended 
631 
dose details in the dispensing label. 
632 
Capecitabine will be in commercial stock in standard packaging. 
633 
7.1.3 Drug accountability and treatment compliance 
634 
As this is a low- intervention clinical study we will not perform an extensive traceability 
635 
rather, the responsible physician and nurse that have prescribed the chemotherapy will keep 
636 
track of compliance and document if patients miss/skip a dose. 
637 
7.2 Auxiliary medicinal products 
638 
No auxiliary medicinal products are planned within the study. 
639 
7.3 Concomitant treatment of radiotherapy 
640 
7.3.1 Purpose and scope of radiotherapy guideline 
641 
This document is based on the previous radiotherapy guidelines from the STAR-TREC trial 
642 
(EudraCT no 2016-000862-49)(35). The STAR-TREC study introduced the concept of 
643 
mesorectal treatment planning in early rectal cancer with reduced target volumes compared to 
644 
previous standard in rectal cancer irradiation. The aim of this document is to ensure uniform 
645 
delivery of radiotherapy and the collection of high-quality data for study analysis. 
646 
7.3.2 Radiotherapy treatment planning 
647 
The use of Computed Tomography (CT) scan for treatment planning is considered standard 
648 
practice and is a mandatory requirement. The scan limits are the superior aspect of L5 to 4 cm 
649 
below the anal verge. The recommended slice thickness is 2-3 mm, but a slice thickness of up 
650 
to 5 mm is accepted. The use of intravenous contrast is optional and should align with local 
651 
centre policy. Magnetic Resonance Imaging (MRI) is strongly recommended for guidance in 
652 
target definition. 
653 
7.3.3 Patient position and immobilisation 
654 
Patient set-up follows local routines. The supine position is recommended. If the prone 
655 
position is used; belly board may be used but is not mandatory. This manual comprises no 
656 
bladder or bowel protocol. Local routines should be followed, but a general recommendation 
657 
is that the bladder should be comfortably filled and the rectum as empty as possible. 
658 
7.3.4 Definition of treatment volumes 
659 
All treatment volumes should be named according to current guidelines from the Radiation 
660 
Safety Authority(43). 

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661 
7.3.5 Gross tumour volume (GTV) 
662 
Gross tumour volume (GTV) is named GTVT_50. All macroscopic tumour is delineated on 
663 
each slice. Only involved areas of the rectal wall are included. Rectal faecal contents are not 
664 
to be include in the GTV. 
665 
7.3.6 Clinical target volume (CTV) 
666 
Clinical target volume (CTV) is named CTVT_50. 
667 
7.3.6.1 Superior limit 
668 
Is defined as the S2/S3 interspace. A minimum of 2 cm is required from the superior limit of 
669 
the GTV to the CTV. If the tumour is localized in the upper rectum, CTV may be extended 
670 
above S2/S3 interspace to achieve the 2 cm margin. 
671 
7.3.6.2 Inferior limit 
672 
Is defined as 2 cm inferior of the GTV. An exception is if the tumour is localized in the lower 
673 
rectum and the CTV margin extends into the anal canal. A maximum of 1 cm of the anal canal 
674 
should be included in CTV. 
675 
7.3.6.3 Anterior limit 
676 
The mesorectal fascia is contoured. If the mesorectal fascia disappears anteriorly, the anterior 
677 
border is the anterior rectal wall. For cranial slices with no visible rectum, the anterior border 
678 
is the defined by the contour used for the last carinal slice with visible rectum. 
679 
7.3.6.4 Posterior limit 
680 
Is defined as the anterior margin of the sacrum or coccyx, or the inner border of the 
681 
puborectalis muscle in caudal slices. 
682 
7.3.6.5 Lateral limits 
683 
The mesorectal fascia is contoured. In the most cranial (high pelvis) and caudal slices (low 
684 
pelvis) mesorectal fascia is not present. In high pelvis, the lateral border comprises the inner 
685 
border of the piriformis muscle. In low pelvis, the lateral border comprises the inner border of 
686 
7.3.7 Planning target volume (PTV) 
687 
Planning target volume (PTV) is named PTVT_50. PTV margins will depend on local 
688 
technique, image guidance schedule, and treatment setup procedure and uncertainties. If Cone 
689 
Beam Computed Tomography (CBCT) is used for on-line imaging, the PTV margins may be 
690 
reduced to 6-8 mm. If 2D kV (two-dimensional kilo voltage) imaging is used an anisotropic 
691 
PTV margin is recommended: 10 mm margin in all directions except anteriorly where a 15 
692 
mm margin is recommended. 
693 
7.3.8 Organs at risk (OAR) 
694 
The following organs at risk (OAR) must always be delineated: 
695 
• 
Urinary bladder (Bladder)outer contour of the bladder as it appears on planning CT. 
696 
The structure should be named Bladder according to established nomenclature. 
697 
• 
Bowel bag (BowelBag): The bowel bag is contoured superiorly from 1.5 cm above the 
698 
most superior part of the PTV. Anteriorly to the inside of the abdominal wall. 

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699 
Laterally, it is delineated from bowel edge to bowel edge. The posterior limit is the 
700 
most posterior bowel edge. The most inferior limit includes the most inferior bowel 
701 
that is not rectum or rectosigmoid junction. 
702 
• 
Bowel (Bowel): Individual bowel loops, excluding the rectum, is delineated within the 
703 
bowel bag as defined above. 
704 
• 
Left and right femoral heads (FemoralHead_L; FemoralHead_R): Contoured to the 
705 
most inferior extent including the lesser trochanter. 
706 
7.3.9 Dose and volume guidelines 
707 
Radiation therapy should be delivered with photon energies ≥6 MV using a linear accelerator. 
708 
Volumetric modulated arc therapy (VMAT) is strongly. All fields must be treated during each 
709 
treatment sessions. 
710 
A total dose of 50 Gy in 25 daily fractions over a total time of 5 weeks should be delivered, 
711 
treating 5 days per week, 1 fraction per day using 2.0 Gy per fraction. This is combined with 
712 
Capecitabine 825 mg/m2 twice daily on radiotherapy treatment days. 
713 
7.3.10 Dose-volume objectives and constraints 
714 
The isocentric treatment plan is usually specified to receive 100% with the 95% isodose line 
715 
encompassing the PTV and no more than +5 % and -5% inhomogeneity within the target 
716 
volume. If OAR doses can be limited even further for the individual patient, without 
717 
compromising target coverage, this should be attempted. 
 
Priority 
Structure 
Dose-volume objectives 
1 
GTVT_50 
D99%≥99% 
1 
CTVT_50 
D99% ≥ 98 % 
Dmean ≥100 % 
1 
PTVT_50 
D2% ≤ 105 % 
D98% ≥ 95 % 
2 
Body 
D2% ≤ 105 % 
 
 
 
3 
BowelBag 
V20Gy < 180 cm3 
V30Gy < 130 cm3 
V45Gy < 90 cm3 
3 
Bowel 
V20Gy < 120 cm3 
V30Gy < 90 cm3 
V45Gy < 60 cm3 
3 
Bladder 
V35Gy < 22% 
V50Gy < 7% 
R* 
FemoralHead_L 
FemoralHead_R 
V25Gy <15% 
718 
*Report value 
719 
7.3.11 Treatment verification 
720 
Generally, on-treatment imaging frequency should align with local policy. However, daily on- 
721 
line imaging is highly recommended since reduced margins are used in mesorectal irradiation. 
722 
If daily on-line imaging with CBCT is used, smaller PTV (6-8 mm) margins may be used. 

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723 
7.3.12 Radiotherapy Quality Assurance (RTQA) 
724 
7.3.12.1 Pre-trial QA 
725 
Facility Questionnaire (FQ): general and trial specific questions on equipment, software and 
726 
techniques to be used for the trial. 
727 
Benchmark Outlining and Planning Cases: Each study centre will need to submit a benchmark 
728 
delineation case outlined by clinical oncologist involved in the study. Additionally, a 
729 
benchmark planning case will need to be planned and submitted with a plan assessment form 
730 
(PAF). 
731 
7.3.12.2 On-trial QA 
732 
Radiotherapy related data should be collected and reported by each centre for every patient 
733 
and transferred to the QA centre at Sahlgrenska University Hospital within 2 months after 
734 
finalizing radiotherapy. The data transfer is handled through the Skandionkliniken Sharefile 
735 
service (https://skandionibasa.sharefile.eu/home/shared) 
736 
A folder named NGST_XX_YYYY, where XX is the number of the study site and YYY is 
737 
the patient study number, should be created and include anonymized DICOM files for 
738 
planning CT images, structure set (RS), registered images, treatment plan (RP) and dose 
739 
(RD). Notify the RT-QA office that patient data has been uploaded by sending an e-mail to 
740 
the study specific e-mail address: su.onk.next-generation@vgregion.se 
741 
A safety assessment will be performed after the first 10 RT plans to confirm adherence to the 
742 
protocol regarding target delineation and dose planning. 
743 
7.4 Surgery 
744 
If the patient does not achieve complete response after the second evaluation after 
745 
neoadjuvant treatment surgery will be recommended. Any deviation from this will be 
746 
considered a protocol violation and must be registered. It is important that the patient 
747 
understand that there is an increased risk of tumour progression if surgery is not performed at 
748 
this stage. 
749 
The preoperative and perioperative treatment regarding anaesthesia and antibiotics and all 
750 
other details must follow local guidelines. 
751 
All patients should be given pre-operative prophylactic antibiotics and antithrombotic 
752 
medication such as low molecular heparin before the start of the operation. The type of 
753 
antithrombotic medication should be registered in the eCRF. Any bowel preparation 
754 
performed is according to local/regional/national routine. 
755 
For the purpose of this study TME surgery is defined as previously published (44). No 
756 
distinction is made between different surgical approaches. Laparoscopic, robot assisted 
757 
laparoscopy, or open surgery can all be used and the choice is at the discretion of the surgeon. 
758 
7.5 Treatment after trial end 
759 
No specific treatment will be administered after the study. 

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760 
8 METHODS FOR MEASUREMENT OF ENDPOINTS FOR CLINICAL 
761 
EFFICACY AND SAFETY 
762 
8.1 Methods for measurement of endpoints for clinical efficiency 
763 
8.1.1 Primary endpoint 
764 
Primary variable: clinical complete response rate. Measured as the ratio of patients with a 
765 
non-operative approach at onset that after evaluation by a combination of MRI, clinical and 
766 
endoscopic examination have a clinical complete response at 1 year. 
767 
Definition of clinical complete response (cCR) 
768 
1.  No suspicious metastatic lymph nodes or evidence of remaining tumour on MRI. In a 
769 
majority a complete response on MRI will be seen as areas of homogeneous fibrosis. 
770 
Absence of any remaining pathological tissue is seen in a minority of cases. 
771 
2.  Endoscopic examination with white light. Presence of light/white mucosa or scar, 
772 
telangiectasia. Presence of fibrosis and oedema. 
773 
3.  No palpable tumour on clinical examination if the tumour was palpable initially. 
774 
Definition of near clinical complete response – possible to re-examine again after four 
775 
weeks 
The majority of the tumour is converted to fibrosis with homogeneous low signal 
intensity on T2-weighted images with minor areas of impeded diffusion on high b-
value DWI. 
Using white light endoscopy with phosphate enema (or comparable) bowel 
preparation any one of the following are encountered: 
a. Residual mucosal irregularity 
b. Residual flat ulcer 
c. Submucosal irregularity or swelling 
784 
8.1.2 Secondary endpoints 
Secondary outcome 
Variable 
Summary measure 
Time point° 
Local recurrence 
Registration in CRF 
Proportion 
3 years 
Local regrowth 
Registration in CRF 
Proportion of 
patients that have 
achieved clinical 
complete response 
1, 2 and 3 years 
Surgical morbidity 
measured as 
Comprehensive 
Complications index° 
All complications registered 
according to Clavien-Dindo 
Median value 
90 days postoperatively in 
cases where surgery is 
necessary 
Organ preservation 
rate at 3 years 
Registration in CRF 
Proportion 
Patients with remaining 
rectum without deviating 
stoma at three years. 
Regardless of function. 
776 
1. 
777 
 
778 
 
779 
2. 
780 
 
781 
 
782 
 
783 
 

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Clinical complete 
response rate 
Registration in CRF 
Proportion 
1 and 2- and 3-years follow-up 
after inclusion 
R0 rate among 
operated patients 
Registration in CRF 
Proportion among 
operated patients 
1 and 3 years after inclusion, 
both patients with initial organ 
preservation and TME 
resection surgery 
Metastases 
Registration in CRF 
Proportion as well 
as subgroup 
specification of 
location 
1 and 3 years after inclusion 
Total length of hospital 
stay 
Total number of days 
including readmissions 
Median and range 
Within 365 days after 
diagnosis 
Quality of life 
Measured in QoL 
questionnaire 
Value baseline vs 
follow-up. Likert 
scale with 
dichotomization 
Baseline, post treatment, at 
surgery if applicable and at 
one, two and three years 
Urinary function 
Measured in QoL 
questionnaire focus on 
incontinence, emptying 
difficulties and urgency 
Value baseline vs 
follow-up and 
comparing groups 
Baseline, post treatment, at 
surgery if applicable and at 
one, two and three years 
Sexual function 
Measured in QoL 
questionnaire, focus on both 
function and quality 
Value baseline vs 
follow-up and 
comparing groups 
Baseline, post treatment, at 
surgery if applicable and at 
one, two and three years 
Bowel and stoma 
function 
Measured in QoL 
questionnaire, major LARS 
Value follow-up 
comparing groups 
Baseline, post treatment, at 
surgery if applicable and at 
one, two and three years 
Patients with a stoma 
Measured as number of 
patients with a stoma/total 
number of patients 
Proportion 
One, two, three years 
Health economic 
analysis 
EQ5D as well as cost 
evaluation from both 
societal and health care 
sector perspective. Will 
include number of days on 
sick leave. 
 
3 years after diagnosis 
Mortality 
Registration in CRF 
Proportion 
3 and 5 years after diagnosis 
Patient satisfaction 
Decision regret form 
 
3 years after inclusion 
5- year overall survival 
Registration in CRF 
Proportion 
5 years after inclusion 
785 
° Comprehensive Complications index (45) 
786 
8.1.3 Quality of life assessment 
787 
All patients will be asked to fill in a questionnaire with QoL questions including the LARS- 
788 
score, Decision Regret form, EORTC QLQ C30 and CR29 as well as additional questions 
789 
derived from previous studies within rectal cancer (46). The time points for QoL 
790 
questionnaire collection are the same as for the radiological follow-up: 
791 
1.  Baseline 
792 
2.  End of CRT treatment (at 2-3 months) 
793 
3.  1 year 
794 
4.  2 years 
795 
5.  3 years 

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796 
8.2 Methods for measurement of endpoints for clinical safety 
797 
See point 8.1. If there is any ambiguity in the evaluation the patient will be recommended to 
798 
go to surgery to reduce the risk for insufficiently treated cancer. 
799 
9.0 HANDLING OF ADVERSE EVENTS 
800 
NOTE! In this study the following events are not reported as an AE or SAE: 
801 
• 
Planned surgery (e.g. TME surgery or stoma reversal) 
802 
• 
Planned hospitalization 
803 
• 
Recurrence 
804 
• 
Death due to progression of the disease 
805 
Any adverse events (AE) and serious adverse events (SAE) will be reported during the trial 
806 
during the first year. 
807 
9.1 Definitions 
808 
9.1.1 Adverse Event (AE) 
809 
Adverse events are defined as any undesirable experience occurring to a subject during the 
810 
study, whether or not considered related to the investigational product/the experimental 
811 
treatment. Only adverse events reported spontaneously by the subject or observed by the 
812 
investigator or his staff of grade 3 or 4 will be recorded. 
813 
9.1.2 Serious Adverse Event (SAE) 
814 
A serious adverse event is any untoward medical occurrence or effect that at any dose: 
815 
- results in death 
816 
- is life threatening (at the time of the event) 
817 
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation 
818 
- results in persistent or significant disability or incapacity 
819 
- is a congenital anomaly or birth defect 
820 
- is a new event of the trial likely to affect the safety of the subjects, such as an unexpected 
821 
outcome of an adverse reaction, lack of efficacy of an IMP used for the treatment of a life- 
822 
threatening disease, major safety finding from a newly completed animal study, etc. 
823 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
824 
reporting will occur not later than 7 days after the responsible investigator has first knowledge 
825 
of the adverse reaction. This is for a preliminary report with another 8 days for completion of 
826 
the report. 
827 
828 
All SAEs, irrespective of relationship to the study treatment must be reported to the 
829 
Datacentre. 
830 
The SAE report should include the investigator’s assessment of causality. If follow-up 
831 
information changes the investigator’s assessment of causality, this should be noted on the 
832 
SAEs occurring within 30 days after discontinuation of the study treatment should be 
833 
reported. 
834 
9.1.3 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
835 
Adverse reactions are all untoward and unintended responses to an investigational product 

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836 
related to any dose administered. 
837 
Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not 
838 
consistent with the applicable product information (e.g. Investigator’s Brochure for an 
839 
unapproved IMP or Summary of Product Characteristics (SPC) for an authorised medicinal 
840 
9.2 Assessment of Adverse Events (AE) 
841 
9.2.1 Assessment of causal relationship 
842 
The investigator is responsible for determining whether there is a causal relationship between 
843 
the AE/SAE and use of the investigational medicinal product. 
844 
Consideration should be given to whether there is a reasonable possibility of establishing a 
845 
causal relationship between the adverse event and the investigational medicinal product based 
846 
on the analysis of the available evidence. 
847 
All AE can be categorized as either likely related, possibly related, unlikely related or not 
848 
related, in accordance with the definitions below: 
849 
Likely related: Clinical event, including abnormal results from laboratory analyses, occurring 
850 
within a reasonable time after administration of the intervention/investigational medicinal 
851 
product. It is unlikely that the event can be attributed to underlying disease or other 
852 
medications but is most likely caused by the investigational medicinal product and its 
853 
emergence is reasonable in relationship with use of the investigational medicinal product. 
854 
Possibly related: Clinical event, including abnormal results from laboratory analyses, 
855 
occurring within a reasonable time after administration of the intervention/investigational 
856 
medicinal product. The event could be explained by the investigational medicinal product, 
857 
and its emergence is reasonable in relationship with use of the investigational medicinal 
858 
product, but there is insufficient information to determine the relationship. The event could be 
859 
explained by an underlying disease or other medications. 
860 
Unlikely related: Clinical event, including abnormal responses from laboratory tests, unlikely 
861 
to be related to the intervention/investigational medicinal product and can be reasonably 
862 
explained by other medication or underlying disease. 
863 
Not related: Clinical event, including abnormal results from laboratory analyses, that is not 
864 
reasonably related to the use of the intervention/investigational medicinal product. 
865 
Those AEs which are suspected of having a causal relationship to the investigational 
866 
medicinal product will be followed up until the subject has recovered or is well taken care of 
867 
and on the way to good recovery (see also section Error! Reference source not found., 
868 
Error! Reference source not found.). 
869 
If the reporting investigator does not provide any information on causality, the sponsor should 
870 
consult with the reporting investigator and encourage the expression of a position on this 
871 
issue. The sponsor must take into account the assessment of causality provided by the 
872 
investigator. If the sponsor disagrees with the investigator's assessment of causality, both the 
873 
investigator's and the sponsor's views should be included in the report. 

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874 
9.2.2 Assessment of intensity 
875 
Patients should be reviewed at least weekly during CRT to perform an assessment of acute 
876 
toxicity. Remote toxicity assessments (e.g. over the telephone) are allowed as per local 
877 
practice 4. The local team should have a structure in place that ensures that patients 
878 
experiencing side effects can be seen and undergo review. 
879 
The following guidance should be followed for the management of acute toxicity and dose 
880 
modifications: 
881 
§ 
Adverse Events (AEs) should be graded according to the NCI Common Terminology 
882 
Criteria for Adverse Events version 4.03 (CTCAE v4.03) 
883 
§ 
In the event of overlapping toxicities, dose modification should be based on the worst 
884 
toxicity grade observed. 
885 
§ 
All dose modifications should be documented with clear reasoning and documentation of 
886 
the approach taken in the CRF and in the medical notes. 
887 
§ 
If a patient experiences a toxicity, then dose modifications should be applied as specified 
888 
in the protocol section 8.3.7. 
889 
§ 
In the event of a second episode of the same grade ≥3 toxicity, capecitabine should be 
890 
permanently discontinued. 
891 
Dose modification and toxicity should be managed according to local routines. Details on 
892 
toxicity is registered in CRF. 
893 
9.3 Reporting and registration of Adverse Events 
894 
NOTE! In this study the following events are not reported as an AE or SAE: 
895 
• 
Planned surgery (e.g. TME surgery or stoma reversal) 
896 
• 
Planned hospitalization 
897 
• 
Recurrence 
898 
• 
Death due to progression of the disease 
899 
At each trial visit, adverse events (AE) are registered, starting after study start, up to and 
900 
including one year after the subject has entered the study. All AE that occurs during the trial 
901 
and which are observed by the investigator/trial nurse or reported by the subject will be 
902 
registered in the CRF regardless of whether they are assessed as related to the investigational 
903 
medicinal product or not. Assessment of causal relationship, severity, and whether the AE is 
904 
considered to be an SAE will be made by the investigator directly in the CRF. At minimum 
905 
for each AE/SAE, a description of the event is recorded (diagnosis/symptom if diagnosis is 
906 
missing), start and stop dates, causal relationship, severity, if the AE is considered to be an 
907 
SAE, measures and outcome. 
908 
9.3.1 Reporting of Adverse Events (AE) 
909 
All AE shall be registered in the CRF within 72 hours. 

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910 
9.3.2. Reporting of Serious Adverse evets (SAE) 
911 
Serious Adverse Events (SAE) are reported to the sponsor on a special SAE form within 24 
912 
hours of the investigator being informed of the SAE. 
913 
Follow-up information describing the outcome and handling of the SAE is reported as soon as 
914 
this information is available. The original SAE form should be kept in the Investigator Site 
915 
File. 
916 
9.3.2. Reporting of Suspected Unexpected Serious Adverse Reactions (SUSAR) 
917 
Those SAE which are assessed by sponsor to be SUSAR are to be reported to the 
918 
EudraVigilance database. The completed CIOMS form will be the basis for the reporting, by 
919 
Swedish Medical Products Agency in the EudraVigilance database according to the specified 
920 
time frames. 
921 
SUSAR that are fatal or life-threatening are reported as soon as possible and no later than 7 
922 
days after the SAE has become known to the sponsor. Relevant follow-up information is sent 
923 
thereafter within an additional 8 days. Other SUSAR are reported as soon as possible and no 
924 
later than 15 days after they have come to the sponsor’s knowledge. 
925 
Information about SUSAR occurring during the trial is compiled by the sponsor and sent to 
926 
the principal investigators at all participating sites. 
927 
9.4 Follow-up of Adverse Events 
928 
All adverse events will be followed until they have abated, or until a stable situation has been 
929 
reached. Depending on the event, follow up may require additional tests or medical 
930 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
931 
9.5 Independent Data Monitoring Committee 
932 
As the study is not randomized low intervention study a formal safety committee will not be 
933 
appointed. 
934 
9.6 Annual Safety Report (ASR) 
935 
Since the sponsor is non-commercial and the marketing authorization holder of the 
936 
investigational medicinal product is within the EU/EEA the SPC is used as RSI. The 
937 
simplified template of Annual Safety Report will be used for the ASR reporting. 
938 
9.7 Procedures in case of emergencies, overdose or pregnancy 
939 
Medication errors, pregnancy and use of other medicinal products than those specified in the 
940 
protocol, including misuse and abuse of the investigational medicinal product, shall be subject 
941 
to the same reporting obligations as adverse reactions. 
942 
If an unforeseen event is likely to have a serious impact on the benefit/risk relationship of the 
943 
trial, the sponsor and investigator should take appropriate Urgent Safety Measures (USM) 
944 
necessary to protect the subjects. Examples of such measures are to temporarily halt the 
945 
clinical trial or to introduce supplementary monitoring measures. The sponsor should, via 
946 
CTIS, inform the concerned Member States about the event and the measures taken. 
947 
Notification must be made as soon as possible, but no later than seven days after the measures 
948 
have been taken. 

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949 
If a subject or partner to a subject who participates in a clinical trial, becomes pregnant, this 
950 
person will be followed up until the birth has taken place. If the foetus/child has any 
951 
congenital malformation, this must be reported as a serious adverse event (SAE). 
952 
10 STATISTICS 
953 
10.1 Analysis population and statistical analyses including sample size 
954 
calculations 
955 
A statistical analysis plan will be developed for the primary endpoint before start of inclusion and 
for all secondary endpoints before analysis. Descriptive statistical methods will be used to present 
data, and assuming a non-normally distributed data non-parametric statistics will be used. 
956 
Using a sample size of 82, the critical number of successes is 49. If 49 or more patients achieving 
complete response at one year, the null hypothesis will be rejected at alpha 0.05. Conversely, if 34 
or more patients have negative response, then the null hypothesis cannot be rejected. If at any time 
49 complete responses or 34 negative responses are observed, rejection/failure to reject is known 
with 100% certainty. However, we plan to include patients until the randomized controlled trial 
STAR-TREC continues follow-up. 
957 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
958 
11.1 Quality Assurance and Sponsor oversight 
959 
The sponsor's quality-related work is based on a risk analysis of the trial as a whole: design, 
960 
conduct, data collection, evaluation, reporting and archiving. The sponsor will perform quality 
961 
assurance and quality control activities for the trial; however, responsibility for the accuracy, 
962 
completeness, and reliability of the trial data presented to the sponsor lies with the PI (and 
963 
delegate(s)) generating the data. 
964 
11.2 Monitoring 
965 
The trial will be monitored by an independent monitor before the trial begins, during the 
966 
conduct of the trial, and after the trial has been completed. This is to ensure that the trial is 
967 
carried out according to the protocol and that data is reliably and robust and are collected, 
968 
documented, and reported according to ICH-GCP and applicable ethical and regulatory 
969 
requirements. Monitoring will be risk-based, which means that the extent of the monitoring is 
970 
based on the sponsor`s risk-assessment and is performed as per the trial’s monitoring plan, 
971 
The monitoring is intended to ensure that the subject’s rights, safety, and well-being are met 
972 
and that data in the CRF are complete, correct, and consistent with the source data. 
973 
11.3 Source data 
974 
The investigator must keep source documents for each subject in the trial. A document 
975 
describing what has been classified as source data in the trial (source data reference 
976 
document) should be included in the Investigator Site File (ISF). The investigator must ensure 
977 
that all source documents are accessible for monitoring and other quality control activities. 
978 
Source data is defined before trial start at each individual site and can, in cases where source 
979 
data is not registered in another document, consist of the CRF. This should be decided in 
980 
consultation with the monitor and clearly stated in the source data reference document. 

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987 
Access to trial-related documentation, such as subjects' medical records, data acquisition tools 
988 
(DATs) (including CRFs), other source data and other trial documentation will be provided 
989 
for monitoring and auditing purposes. Access to subjects' medical records will require a 
990 
confidentiality agreement to be signed by the person in charge of the medical records at the 
991 
trial site and by the monitor and auditor, if applicable. Access will also be granted in the 
992 
context of regulatory inspections. 
993 
11.4 Deviations, serious breaches and other reporting obligations 
994 
The responsible investigator and/or any involved service provider shall, without delay, report 
995 
to the sponsor any suspected serious breaches from the trial protocol, the CTR, ICH-GCP and 
996 
other regulations that are likely to affect the safety, rights of the subjects and/or the data 
997 
reliability and robustness to a significant degree. The sponsor should assess the suspected 
998 
serious breach, the consequences of the deviations and without undue delay, but no later than 
999 
7 days (from knowledge), report these to the Competent Authorities via CTIS. 
1000 
Other unexpected events that may affect the benefit/risk relationship for the clinical trial must 
1001 
be reported via CTIS without undue delay, but no later than 15 days after the sponsor 
1002 
becomes aware of the event. 
1003 
Minor deviations that do not affect subjects’ integrity or safety, nor significantly affect the 
1004 
trial’s scientific value, are documented in the trial documentation of the principal investigator 
1005 
and the sponsor and appropriate measures shall be taken. The deviations, including minor 
1006 
deviations, must be recorded in the clinical trial report. 
1007 
11.5 Audits and inspections 
1008 
The purpose of an audit or inspection is to review trial-related activities and documents 
1009 
systematically and independently, to determine whether these activities were performed, 
1010 
registered, analysed and reported correctly according to the protocol, ICH-GCP and 
1011 
applicable regulations. 
1012 
Authorized representatives for the sponsor and Competent Authorities (CA) may carry out 
1013 
audits or inspections at the trial site, including source data verification. The investigator must 
1014 
ensure that all source documents are available for audits and inspections. 
1015 
12 ETHICS 
1016 
12.1 Compliance to the protocol, ICH-GCP and regulations 
1017 
The trial will be performed in compliance with this clinical trial protocol, the EU regulation 
1018 
on clinical trials on medicinal products for human use (536/2014), the Declaration of 
1019 
Helsinki, ICH-GCP (Good Clinical Practice), and current national regulations governing this 
1020 
clinical trial. This is to ensure the safety and integrity of the trial subjects as well as the 
1021 
quality of the data collected 
1022 
12.2 Ethical review of the trial 
1023 
The final protocol for clinical trials on medicinal products must be approved, as a part of the 
1024 
application for a permit for clinical trials via CTIS, by the Competent Authorities, before the 
1025 
trial can be conducted. The authorities must be informed via CTIS of any changes in the trial 
1026 
protocol in accordance with current requirements. 

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1027 
12.3 Procedure for obtaining informed consent 
1028 
The principal investigator at each site shall ensure that the subject is given full and adequate 
1029 
oral and written information about the trial, its purpose, any risks and benefits as well as 
1030 
inclusion and exclusion criteria. Subjects must also be informed that they are free to 
1031 
discontinue their participation in the trial at any time without having to provide a reason. 
1032 
Subjects should be given the opportunity to ask questions and be allowed time to consider the 
1033 
provided information. If the subject chooses to participate, both the subject and the 
1034 
investigator shall sign the informed consent form. A copy of the subject information as well 
1035 
as the informed consent form shall be provided to the subject. The subject’s signed and dated 
1036 
informed consent must be obtained before any trial-specific activity is performed. Each 
1037 
subject who participates in the trial will be identified by a subject number on a subject 
1038 
identification list. The subject agrees that monitors, auditors, and inspectors may have access 
1039 
to the subject’s medical records and other source data. If new information is added to the trial, 
1040 
the subject has the right to reconsider whether he/she will continue their participation. 
1041 
12.4 Data protection 
1042 
In the information provided to subjects, subjects will be fully informed about how their trial 
1043 
data will be collected, used and disclosed. The content of the informed consent form complies 
1044 
with relevant integrity and data protection legislation. The subject information and the 
1045 
informed consent form will explain how trial data are stored to maintain confidentiality in 
1046 
accordance with national data legislation. All information processed by the sponsor will be 
1047 
pseudonymized only identifiable with the study id. 
1048 
The informed consent form will also explain that for verification of the data, representatives 
1049 
delegated by the sponsor, as well as relevant authorities, may require access to parts of 
1050 
medical records or trial records that are relevant to the trial, including the subject’s medical 
1051 
history. 
1052 
12.5 Insurances 
1053 
All subjects participating in the trial are covered by the Swedish Patient Insurance 
1054 
(patientförsäkringen) through Regionernas Ömsesidiga Försäkringsbolag, LÖF. 
1055 
13 SUBSTANTIAL CHANGES TO THE STUDY 
1056 
Substantial changes to the signed clinical trial protocol are only possible through approved 
1057 
protocol amendments. 
1058 
In the event that substantial changes to the protocol which may affect the safety, rights of 
1059 
subjects or the reliability and robustness of data generated need to be implemented during the 
1060 
course of the trial, permission from the relevant authority via application in CTIS should be 
1061 
obtained before implementing the change. This includes the addition of a new trial site or a 
1062 
change of the principal investigator at the trial site. 
1063 
Non-substantial amendments are entered into the CTIS in the next substantial amendment 
1064 
application concerning the same part. If the non-substantial change is relevant to the 
1065 
Authority's oversight (e.g. contact details), the CTIS should be updated on an ongoing basis. 

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1066 
14 COLLECTION, HANDLING AND ARCHIVING OF DATA 
1067 
14.1 Case Report Form - eCRF 
1068 
The REDCap system will be used as electronic clinical record form (CRF) 
1069 
(https://www.project-redcap.org/). All data is kept within Region Västra Götalands firewall. 
1070 
Two-factor authentication is used, and data is securely stored according to rules and 
1071 
regulations for class III data. Data will be entered prospectively unless the patient is included 
1072 
after completed neoadjuvant treatment, when data up to that visit will be entered 
1073 
retrospectively. Data will be entered at the following time points and details on required 
1074 
information is presented in Table 1. Details on data entered in the CRF is presented in 
1075 
appendix. 
1076 
14.2 Data collection 
1077 
All clinical data at inclusion, during and after neoadjuvant treatment, during surgery, during 
1078 
postoperative hospital stay and at yearly follow-ups will be entered into the REDCap CRF. At 
1079 
inclusion the study centre at SSORG, Sahlgrenska University Hospital will receive a phone 
1080 
call and register the patient to ascertain that all patients are registered properly. 
1081 
After this all registration will be performed using a study number, not the personal 
1082 
identification number. The personal identification number and the study number will be kept 
1083 
either in a locked storage or at in a password protected and secure SharePoint document. 
1084 
The postoperative questionnaires will be administered by the study secretariat at SSORG. 
1085 
All data will be kept within University of Gothenburg and Sahlgrenska University Hospital IT 
1086 
systems using inherent security systems. 
1087 
A logistic database with complete patient ID will be used, kept within a separate IT-system 
1088 
from the result database with all study information. Security measures will include one to 
1089 
maximum two users of this database, with unique usernames and personal login, as well as 
1090 
automatic throw-out. 
1091 
The result database, based on trial number and without patient ID, will be kept within another 
1092 
IT system than the logistic database. The database will be kept on a server with automatic 
1093 
backup and will be registered with “integritetsskyddsombudet” for Sahlgrenska University 
1094 
Hospital. 
1095 
14.3 Data management plan 
1096 
A data management plan (DMP) based on the Swedish National Data Service (SND) checklist 
1097 
has been drawn up and will be continuously revised during the project. The plan covers all 
1098 
handling of data from project planning, through collection, analysis, and archiving. 
1099 
The project has a designated data manager who work with storing and validating of data in the 
1100 
project. To uphold data security and integrity of study participants the routines of Västra 
1101 
Götaland Region and University of Gothenburg guidelines for handling sensitive data are 
1102 
followed. 
1103 
Data in this project will contain information concerning health and is thereby classified as 
1104 
sensitive personal data by General Data Protection Regulation (GDPR). The processing of the 

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1105 
sensitive data for scientific research purposes in this project will be according to GDPR article 
1106 
9 with lawful basis of public interest article 6e. The organisations that act as data controller 
1107 
for this project is Sahlgrenska University Hospital and University of Gothenburg. 
1108 
Confidentiality is identified as grade III and will thereby be protected by strong authentication 
1109 
when stored and encryption when transferred. 
1110 
Integrity is identified as grade III and will be protected against unintentional and unauthorised 
1111 
alteration. Routines for data to be regularly backed up as well as logging of alteration will be 
1112 
in place. 
1113 
Availability is identified as grade II and should be accessible at most hours and is established 
1114 
by stable and well tested IT-infrastructure. 
1115 
All data is pseudonymised and the key is stored in a separate secure server system not 
1116 
containing any study data. 
1117 
Clinical data will be entered directly in an electronic clinical record (CRF) by each 
1118 
participating centre through the REDCap web interface (https://www.project-redcap.org/). 
1119 
Data collected via REDCap will be stored directly on a server within the Västra Götaland 
1120 
Region firewall and is accessed through a two-factor authentication. Data can be accessed and 
1121 
retrieved from the data base only with the authorization by the principal investigator. 
1122 
Patient-reported outcomes will be retrieved by questionnaires. The study secretariate has well 
1123 
built-up infrastructure as well as experiences of handling sensitive and confidential data from 
1124 
randomised clinical trials. The logistics database with contact information on study 
1125 
participants is password protected. Accesses is given only to personnel who work in direct 
1126 
contact with participants for retrieving questionnaire during the study follow up period. 
1127 
Radiological and radiotherapy data will be analysed, stored, and processed according to 
1128 
regulation. The infrastructure used will either be within the Sahlgrenska University Hospital 
1129 
or by an external infrastructure explicitly for research purpose. In the latter case a data 
1130 
processor agreement will be established. 
1131 
Blood samples and biopsies will be marked only with study code and stored in biobank 
1132 
according to regulation. Data for the translation sub study will be analysed, stored, and 
1133 
processed according to the routines and infrastructure at Core Facilities at Sahlgrenska 
1134 
Academy, University of Gothenburg. 
1135 
Access to data will be given only for those who will actively work with data. Access to data 
1136 
for researchers and statisticians will be restricted to the data need for each analysis. Data 
1137 
manger will have access to all data retrieved by the study secretariate, as well as data in each 
1138 
analysis used for publication. Only the principal investigator group will have full access to all 
1139 
collected data in the project. 
1140 
If any data is to be processed outside of the data controller organisations a data processor 
1141 
agreement will be established to ensure that GDPR is followed. 
1142 
Any physical data containing personal information (e.g. paper questionnaires, consent forms) 
1143 
will be stored in locked rooms in buildings accessed only by authorised personal within the 
1144 
Sahlgrenska University Hospital. 

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1145 
All participants will be informed on how data are managed and their rights according to 
1146 
GDPR before entering the study. 
1147 
15 NOTIFICATIONS OF TRIAL COMPLETION, REPORTING AND 
1148 
PUBLICATION 
1149 
End of recruitment of subjects and end of the trial is reported in CTIS, within 15 days. Within 
1150 
one year of trial completion a summary of the clinical trial results must be reported in CTIS, 
1151 
including a summary for lay people. In addition, a full clinical trial report with individual data 
1152 
is to be completed and archived in the trial master file by sponsor and in the investigator-site 
1153 
files at each site. 
1154 
The trial will be published after completion of the inclusion and completion of follow-up of 
1155 
patients with respect to results regarding the primary and secondary endpoints. As this is a 
1156 
prospective cohort study without randomization short term results may be published before 
1157 
the primary endpoint has been reached. 
1158 
The principal investigators will be first author and/or last authors of main papers based on this 
1159 
study. Members of the writing committee qualify for co-authorship and will be determined 
1160 
according to section 1.4. The others qualify for acknowledgements. 
1161 
In case of papers of side results authors have to be appointed by the writing committee based 
1162 
on the topic studied and investigators involved. 
1163 
16 BIBLIOGRAPHY 
1164 
1. 
Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy 
1165 
in resectable rectal cancer. N Engl J Med. 1997;336(14):980-7. 
1166 
2. 
Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, 
1167 
et al. The TME trial after a median follow-up of 6 years: increased local control but no 
1168 
survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 
1169 
2007;246(5):693-701. 
1170 
3. 
MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. 
1171 
Lancet. 1993;341(8843):457-60. 
1172 
4. 
Bosset J-F, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. 
1173 
Chemotherapy with Preoperative Radiotherapy in Rectal Cancer. New England Journal of 
1174 
Medicine. 2006;355(11):1114-23. 
1175 
5. 
Maurer CA, Renzulli P, Kull C, Käser SA, Mazzucchelli L, Ulrich A, et al. The 
1176 
Impact of the Introduction of Total Mesorectal Excision on Local Recurrence Rate and 
1177 
Survival in Rectal Cancer: Long-Term Results. Annals of Surgical Oncology. 
1178 
2011;18(7):1899-906. 
1179 
6. 
Bernardshaw SV, Øvrebø K, Eide GE, Skarstein A, Røkke O. Treatment of 
1180 
rectal cancer: reduction of local recurrence after the introduction of TME - experience from 
1181 
one University Hospital. Dig Surg. 2006;23(1-2):51-9. 
1182 
7. 
den Dulk M, Krijnen P, Marijnen CA, Rutten HJ, van de Poll-Franse LV, Putter 
1183 
H, et al. Improved overall survival for patients with rectal cancer since 1990: the effects of 
1184 
TME surgery and pre-operative radiotherapy. Eur J Cancer. 2008;44(12):1710-6. 
1185 
8. 
Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup WH, Wiggers T, 
1186 
et al. Acute side effects and complications after short-term preoperative radiotherapy 

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1187 
combined with total mesorectal excision in primary rectal cancer: report of a multicenter 
1188 
randomized trial. Journal of Clinical Oncology. 2002;20(3):817-25. 
1189 
9. 
Wallner C, Lange MM, Bonsing BA, Maas CP, Wallace CN, Dabhoiwala NF, et 
1190 
al. Causes of fecal and urinary incontinence after total mesorectal excision for rectal cancer 
1191 
based on cadaveric surgery: a study from the Cooperative Clinical Investigators of the Dutch 
1192 
total mesorectal excision trial. J Clin Oncol. 2008;26(27):4466-72. 
1193 
10. 
Karlsson L, Bock D, Asplund D, Ohlsson B, Rosenberg J, Angenete E. Urinary 
1194 
dysfunction in patients with rectal cancer: a prospective cohort study. Colorectal Dis. 
1195 
2020;22(1):18-28. 
1196 
11. 
Sorensson M, Asplund D, Matthiessen P, Rosenberg J, Hallgren T, Rosander C, 
1197 
et al. Self-reported sexual dysfunction in patients with rectal cancer. Colorectal Dis. 
1198 
2020;22(5):500-12. 
1199 
12. 
Sandberg S, Asplund D, Bisgaard T, Bock D, Gonzalez E, Karlsson L, et al. 
1200 
Low anterior resection syndrome in a Scandinavian population of patients with rectal cancer: 
1201 
a longitudinal follow-up within the QoLiRECT study. Colorectal Dis. 2020;22(10):1367-78. 
1202 
13. 
Pieniowski EHA, Nordenvall C, Palmer G, Johar A, Tumlin Ekelund S, 
1203 
Lagergren P, et al. Prevalence of low anterior resection syndrome and impact on quality of 
1204 
life after rectal cancer surgery: population-based study. BJS Open. 2020. 
1205 
14. 
Bolton WS, Chapman SJ, Corrigan N, Croft J, Collinson F, Brown JM, et al. 
1206 
The Incidence of Low Anterior Resection Syndrome as Assessed in an International 
1207 
Randomized Controlled Trial (MRC/NIHR ROLARR). Ann Surg. 2020. 
1208 
15. 
Bach SP, Hill J, Monson JR, Simson JN, Lane L, Merrie A, et al. A predictive 
1209 
model for local recurrence after transanal endoscopic microsurgery for rectal cancer. Br J 
1210 
Surg. 2009;96(3):280-90. 
1211 
16. 
Endreseth BH, Myrvold HE, Romundstad P, Hestvik UE, Bjerkeset T, Wibe A. 
1212 
Transanal excision vs. major surgery for T1 rectal cancer. Dis Colon Rectum. 
1213 
2005;48(7):1380-8. 
1214 
17. 
Garcia-Aguilar J, Mellgren A, Sirivongs P, Buie D, Madoff RD, Rothenberger 
1215 
DA. Local excision of rectal cancer without adjuvant therapy: a word of caution. Ann Surg. 
1216 
2000;231(3):345-51. 
1217 
18. 
Verseveld M, de Wilt JHW, Elferink MAG, de Graaf EJR, Verhoef C, Pouwels 
1218 
S, et al. Survival after local excision for rectal cancer: a population-based overview of clinical 
1219 
practice and outcome. Acta Oncol. 2019;58(8):1163-6. 
1220 
19. 
Ricciardi R, Madoff RD, Rothenberger DA, Baxter NN. Population-based 
1221 
analyses of lymph node metastases in colorectal cancer. Clinical gastroenterology and 
1222 
hepatology : the official clinical practice journal of the American Gastroenterological 
1223 
Association. 2006;4(12):1522-7. 
1224 
20. 
Wong RK, Tandan V, De Silva S, Figueredo A. Pre-operative radiotherapy and 
1225 
curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst 
1226 
Rev. 2007(2):CD002102. 
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17. APPENDIX 
Appendix A – Frågeformulär 
 
 
Appendix B – Variabellista 
 
 
Appendix C – Flow chart