Chemo-radiotherapy as Main Treatment Strategy for Rectal Cancer. Can we Provide a More Precise and Effective Treatment
Conditions: Rectal Cancer, Rectal Adenocarcinoma, Locally Advanced Malignant Neoplasm
Sponsor: Aalborg University Hospital

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Aalborg 15-05-2018,  
Study protocol ver. 4.0 
 
Assessment of organ motion during 
preoperative chemoradiotherapy for 
patients with adenocarcinoma of the 
rectum 
(AMPERE) 
 
 
 
Project group: 
Dennis Tideman Arp, Medical Physcist1 
Martin Skovmos Nielsen, Ph.D., Medical Physicist1 
Mette Nytoft Yilmaz, Chief Physician2 
Rune Vincent Fisker, Radiologist3  
Laurids Østergaard, MD2 
Ane Appelt, Ph.D., Medical Physicist4 
 
1 Department of Medical Physics, Oncology, Aalborg University Hospital, Aalborg, Denmark 
2 Department of Oncology, Aalborg University Hospital, Aalborg, Denmark 
3 Department of Radiology, Aalborg University Hospital, Aalborg, Denmark 
4 Leeds Institute of Cancer And Pathology, University of Leeds, and Leeds Cancer Centre, St James’s University Hospital, 
Leeds, UK 
 
 

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Place of project implementation: 
Oncology Department 
Aalborg University Hospital 
Hobrovej 18-22 
9100 Aalborg 
Tlf: 97 66 00 00 
 
Sponsor-investigator: 
Dennis Tideman Arp 
Department of Medical Physics, Oncology Department 
Klinik Kirugi-Kræft 
Tlf: 97 66 15 93 
E-mail: deta@rn.dk 
 
 
 

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Table of contents 
 
 
 
Background .................................................................................................................................................... 4 
Hypothesis ..................................................................................................................................................... 6 
Method .......................................................................................................................................................... 6 
Endpoints ....................................................................................................................................................... 7 
Inclusion and exclusion criteria ..................................................................................................................... 8 
Benefits and Risks .......................................................................................................................................... 8 
Statistics ......................................................................................................................................................... 9 
Personal privacy ............................................................................................................................................ 9 
Finances ....................................................................................................................................................... 10 
Remunerations and other benefits ............................................................................................................. 10 
Recruitment of participants ........................................................................................................................ 10 
Publication of trial results ............................................................................................................................ 10 
Ethics ........................................................................................................................................................... 11 
References ................................................................................................................................................... 11 
 
 
 

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Background 
 
Patients diagnosed with locally advanced adenocarcinoma of the rectum are treated with concomitant 
chemoradiotherapy (CRT) according to national Danish guidelines1, with the aim of reducing local 
recurrences2,3. Depending on tumor location, this is a pre-operative procedure prior to total mesorectal 
excision (TME) or partial mesorectal excision (PME). Although the introduction of TME has significantly 
reduced the frequency of local recurrences4, the procedure is associated with a high risk of postoperative 
morbidity especially when combined with CRT. The morbidities most often reported include Low Anterior 
Resection Syndrome (LARS), sexual dysfunction and pain5,6. Consequently, recent years have seen an 
increasing focus on other therapeutic approaches, such as “watch and wait”, where the aim is to treat 
some patients with definitive CRT alone. The success of these new approaches directly relies on the 
effectiveness of the radiotherapy treatment and thereby both on the level and the accuracy of the 
delivered dose to the clinical tumor volume (CTV). High precision treatment will also allow for smaller 
overall treatment volumes for standard treatment strategies, as detailed below. 
 
In the past, treatment planning has exclusively been based on Computed Tomography (CT) scans. In recent 
years, introduction of the superior soft tissue contrast of magnetic resonance imaging (MRI) has supported 
improved visualization and delineation of gross tumour volume (GTV), CTV and organs at risk (OAR). In daily 
practice, delineation of treatment targets (GTV and CTV) and OAR is typically done on the treatment 
planning CT scan, with the supporting MRI co-registered to aid delineation. In radiotherapy, planning target 
volumes (PTV) are constructed by means of adding a population-based margin to the CTV to account for 
the random day-to-day variation in position and shape of the CTV. However, current practice is based on 
planning scans (CT and MR) from single point in time for delineation of both GTV, CTV and OAR (Figure 1c).  
 
Multiple scans would allow for estimates of day-to-day variation of the GTV, CTV and OAR (Figure 1a+b). 
This would provide more correct margins for construction of populations based PTV and the possibility for 
individual patient based margins to account for the day-to-day variation of the specific GTV, CTV and OAR 
(Figure 1d). This may be even more important with the introduction of intensity modulated radiation 
therapy (IMRT) and advanced image guided radiation therapy (IGRT), as the administered dose is highly 
conformal and precisely delivered. Incorrect margins increase the risk of inadequate dose coverage of PTV 
and overdose of OAR – both potentially damaging.  
 
Several studies have shown that anisotropic motion and shape variation of the rectum occurs during a CRT 
course 7-9. These variations depend on the region of the CTV and also on the gender of the patient. In 
addition to the random day-to-day variation, systematic change in position and shape of both CTV and OAR 
may occur. Studies have shown an average reduction of the rectal volume of 57 % during radiotherapy 
treatment (RT), with almost all reduction occurring within the first 9 fractions10.  
 
These studies support that a more detailed knowledge of organ motions and changes during treatment 
would allow for more correct PTV margins and an adaptive CRT approach. This could result in an improved 
dose coverage of the PTV or potentially sparing OARs. A sparing of OARs could facilitate a potential dose 
escalation to the GTV or CTV with a reduction in treatment toxicity. 
 

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Figure 1: Construction of CTV-PTV margin. Yellow=OAR, Red=GTV, Green=CTV and Blue=PTV margin. Figure 1a and 1b 
illustrate the difference in motion of GTV/CTV for two different patients. Figure 1c shows a population based PTV 
margin taking into account target motion for both patients. Figure 1d shows the reduced margin using an individual 
margin construction.    
 
The aim of this feasibility study is to address the impact on radiotherapy planning from systematic and 
random day-to-day variation in position and shape of the GTV and CTV in patients with rectum cancer using 
additional MRI scans before and during radiotherapy. 
 
Previous studies of this problem have mainly been based on repeat kVCT or MVCT scans, i.e. without the 
superior soft tissue contrast from the MRI. Furthermore, the ability to introduce functional imaging, 
including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), could provide 

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additional information regarding the OARs as well as GTV and CTV, including imaging-based assessment of 
treatment response and toxicity11. This information along with morphological data could allow for 
comparative analysis of radiation dose distribution relative to e.g. local toxicity providing voxel- or area-
based dose-response relationships12-14. By correlating the dose-response relationship with side effect 
registration it might be possible to predict the risk of local toxicity to OARs. 
 
In this explorative study, patients will be MRI scanned at different time points (days) in the week prior to 
start of radiotherapy, in order to understand the day-to-day random variation in anatomy. Systematic 
changes in position and shape of the GTV and CTV during radiotherapy will be estimated using three 
additional MR-scans over the full course of treatment. Furthermore, annual follow-up scans will be 
performed with side effect assessments based on image analysis and side effect registration during and 
after completion of the RT course. The MRI scans will additionally be used to develop a MRI-based anatomy 
atlas for rectal cancer patient treatment volume delineation. All information provided by the scans will be 
analyzed retrospectively only. The information obtained will therefore not influence any patient treatment. 
However, the second-year follow-up scan will be evaluated on the same terms as a standard follow-up 
scan. Therefore, this can be seen as an additional check of the patient's condition. If there is a relapse of 
the disease, there may be changes in the patient's treatment course earlier than in standard follow-up 
scheme. 
 
Hypothesis 
Current standard treatment for rectal cancer in the department is based on a single planning CT and MRI-
scan one week prior to treatment start. Follow-up scans are performed at one year and three years after 
completions of the RT course. The overall hypothesis is thus that the information from multiple additional 
MRI scans will allow for more precise, less toxic and more individualized treatment for rectal cancer. 
Specifically, performing additional MRI scans prior to, during and after treatment, and defining the GTV, 
CTV and OAR on each scan, will confirm or deny that: 
- 
Systematic and random changes in position and shape of the GTV, CTV and OAR can be 
characterized using additional MRI scans before and during radiotherapy.  
- 
CTV-to-PTV margins for the patient group can be adapted, by characterizing systematic changes in 
position and shape of CTV during radiotherapy. 
- 
An adaptive CRT strategy will facilitate dose escalation to the GTV without an increase in expected 
treatment toxicity. 
- 
MRI scans providing morphological and functional data before, during and after CRT will provide 
information about treatment response and local toxicity. 
- 
It is possible to correlate local toxicity information with registered side effects. 
 
Method 
Patients will be scanned six times in addition to the standard MRI-scan appointments and follow-up: as part 
of the RT therapy scan, three-four days after therapy scan, on the first treatment day before the first 
radiotherapy treatment, after one, two and four weeks of RT, and an additional follow-up scan at two years 
after RT. DCE-MRI and DWI is not a part of the standard routine MRI-scans of rectal cancer patients in our 

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clinic. However, these are widely used modalities in other patient-groups e.g. prostate cancer. DCE-MRI will 
be performed in four of the nine appointments - two of the standard appointments and two of the 
additional. See overview below. The scans will be performed following the standard clinical setting; on a 
flat tabletop and with an empty bladder. Consistent with standard clinical routine the patients will receive 
an anti-peristaltic agent (Buscopan) prior to scanning, and receive a laxative if the rectal filling is too large. 
The MRI-scans consist of T2-weighted and diffusion-weighted sequences for anatomical analysis. The DCE-
MRI will consist of a dynamically acquired T1-weighted sequence. Furthermore, sequences for creation of 
pseudo CT images for dose calculation will be implemented. The scan protocol will have an expected total 
scan time of 35 minutes, with total extra time needed in the clinic of 1 hour. Kidney function will be 
assessed prior to each contrast scan. The scans during radiotherapy treatment will be scheduled as an 
extension of the patients planned treatment course. Only two additional visits to the department is 
therefore needed (MRI scan 2 and 8).  
 
Pre-treatment and during treatment: 
 
 
              +DCE-MRI                +DCE-MRI 
 
            +DCE-MRI 
 
Follow-up: 
 
                     +DCE-MRI 
Green indicate scans which are part of standard management; blue indicate MRI scans which are specific to 
this study. DCE-MRI: dynamic contrast-enhanced MRI. 
 
The GTV, CTV and OAR will be delineated separately on CT and all MRI-scans. Using a rigid bony anatomy 
based method, the MRI-scans will be registered to CT scan, to allow a comparison of the position and shape 
variations of the volumes. Side effect registration will be performed at MRI scans 1, 6, 7 and 9 and consist 
of CTCAE (ver.4), LARS score and EORTC quality of life questionnaires (QLQ-C30 and QLQ-CR29).  
Endpoints 
 
Endpoints relevant to this study are: 
- 
Characterization of the systematic and random changes in position and shape of GTV, CTV and 
OAR. 
- 
Estimation of change in CTV-to-PTV margins, as found by characterizing systematic changes in 
position and shape of CTV during radiotherapy. 
- 
Estimation of the dose escalation to the GTV and/or a reduction in treatment toxicity facilitated by 
an adaptive CRT. 
MRI scan 1
•Therapy 
CT-/MRI 
scan
MRI scan 2
•Pretreat
-ment 
scan
MRI scan 3
•First 
day of 
RT
MRI scan 4
•After 1  
week  
of RT
MRI scan 5
•After 2 
weeks 
of RT
MRI scan 6
• After 4 
weeks 
of RT
MRI scan 7
•Follow-up first year 
(standard)
MRI scan 8
•Follow-up second 
year (additional)
MRI scan 9
•Follow-up third year 
(standard)

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- 
Image-based assessment of treatment response and local toxicity using morphological and 
functional data, based on MRI scans from before, during and after CRT. 
- 
A correlation is found between local toxicity assessment and side effect registrations.  
 
Inclusion and exclusion criteria 
Approximately 25 patients are annually referred to the department of oncology for standard preoperative 
chemoradiotherapy for rectal cancer. Inclusion period is expected to be from June 2018 to June 2020; all 
patients referred in this time period fulfilling the criteria below will be offered participation in the study. 
 
Inclusion criteria: Patients >18 years referred to standard chemoradiotherapy for locally advanced rectal 
cancer.  
 
Exclusion criteria: 
- 
Prior surgery in pelvic minor region 
- 
Pacemaker 
- 
Neurostimulator 
- 
Other non MR-compatible implants 
- 
Pregnancy 
- 
Incapable of undergoing MRI 
- 
Incapable of understanding the patient information 
- 
Allergic to contrast agent 
- 
Contraindication for Buscopan 
- 
Reduced renal function (GFR < 50 ml/min) 
Patients who cannot tolerate the contrast used for DCE-MRI (due to allergies, contraindications for 
Buscopan or reduced renal function (GFR < 50 ml/min)) will still be offered inclusion in the study, but 
without the contrast-based MRI scans. 
 
Benefits and Risks 
The MRI examination is not associated with any exposure to ionizing radiation and there are no additional 
risks involved in comparison to a standard clinical MRI scan with contrast administration. The patient is 
equipped with earplugs for noise reduction and a manual alarm, which always can be activated during the 
scans. The total MR examination consists of multiple scans cf. the methods section. The patient will have to 
spend additional time in the clinic to undergo the MRI scans. All scans will be placed as conveniently as 
possible to accommodate the patient clinical schedule.  
 
DCE-MRI is not a part of the standard routine MRI-scans of rectal cancer patients in our clinic, and 
therefore introduce an added inconvenience and small risk. However, these are widely used modalities in 
other patient-groups e.g. prostate cancer. The DCE-MRI sequence requires the use of intra-venous 
administered contrast agents using a cannula (venflon). The cannula is placed by the radiographer prior to 
the MRI scan, using standard sterile technique. This can be associated with mild discomfort and there is a 

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low risk of infection around the injection-area. Mild to modest side effects occur in about 2% of the 
patients. Possible side effects include skin itch, heating sensation, nausea and very rarely vomiting. In about 
1 of 1 million patients severe hypersensitivity have fatal consequences, as a result of a collapse of the 
circulatory system. The department has an established procedure in case of anaphylactic events during use 
of contrast. This procedure includes an on-call clinician, who will respond promptly to any severe side 
effects. In less than 1% of the patients renal function may be affected, but this risk will be minimized by 
performing a blood test of renal function prior to the use of contrast agent.  
By participating in the trial, the patients will not necessarily have any clinical benefits. All image analysis will 
be performed retrospectively, however the additional follow-up scan at second year will be reviewed by a 
radiologist and therefore a relapse could be detected sooner. The study will foremost contribute to clinical 
development and research of the use of modern radiological imaging techniques for image-guided 
radiation therapy.  
Statistics 
 
This is an exploratory study. There will be a feasibility check after 14 patients: If the results at this point 
suggest that the imaging schedule can be adhered to and that a reasonably proportion of eligible patients 
are willing to participate, the study will continue and is expected to include 25 patients during the inclusion 
period. If the study has included more than 25 patients before the inclusion period has ended, the study 
will be closed. If fewer than 25 patients have been included within the inclusion period, the study will be 
reevaluated. The patients will, in addition to the main analysis, be divided into two sets of subgroups for 
secondary analysis: 
- 
Gender: women vs. men  
- 
Tumor location (height): High/mid vs. low  
Assuming that 50 % of all eligible patients accept participation in the protocol, 25 patients can realistically 
be enrolled in the proposed time frame and will provide enough information that each subgroup can be 
analyzed separately as well as together.  
 
Personal privacy 
Personal information regarding the subjects are protected under the “Personal Data and Health Law”. The 
project will be reported to the “Data Protection Agency”, through the Regions’ framework notification 
system. Individual patient records are reviewed to assess whether the patient is a possible candidate to be 
included in the project. If the health professional who has treated the patient gives permission (see Health 
Law § 46 paragraph. 1 and 3) the patient will be informed about the project. Patients will be asked for 
consent for their data, in completely anonymized form, to be used for follow-up studies, which may include 
sharing the data with collaborators in Denmark and abroad. 
 
From patient records, information will be obtained regarding: 
- 
Patient age  
- 
Gender 
- 
Tumor height 
- 
Clinical TNM stage 
- 
ypTNM 

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- 
Type of surgery 
- 
R0-resection 
- 
Tumor regression grade 
- 
Prior relevant disease 
- 
Prior or current medication 
- 
Status at baseline scan 
- 
Pathological description of biopsy and surgical specimen 
- 
Diagnostic images 
- 
Treatment history 
- 
Radiotherapy doseplans 
- 
Acute and late toxicity 
- 
Follow-up information regarding tumour control and survival 
 
Finances  
Members of the project group are financed via their employment at their departments at Aalborg 
University Hospital. The MRI-scans are provided by The Department of Medical Physics. No external 
financial support to the project members are given for the purpose of conducting this study.  
Remunerations and other benefits  
Participants will not receive any remunerations. 
Recruitment of participants 
All subjects need to be referred to standard chemoradiotherapy for locally advanced rectal cancer. The 
patients are informed about the project by the attending physician in the oncology department. During the 
preliminary consultation in the oncology department, it is clearly stated that the project is a health science 
research project aimed at improving the knowledge about internal movement of the rectum and 
surrounding organs, with the aim of improving the accuracy of delivering radiation therapy.  
Patients are enrolled on trial on the basis of verbal and written information. At the first appointment in the 
department, the doctor informs about the study and the patient receives the written information. At the 
second appointment, any questions can be answered and the patient may subsequently give written 
consent for study participation. The information provided must include the purpose of the study, the risks, 
benefits and disadvantages. Patients are allowed at least 24 hours to consider their decision and must be 
informed that that they may withdraw their consent at any time. Time will also be allowed for asking 
questions. The patient has the right to an assessor or observer. Informed consent must be obtained before 
any study-related procedure. The signed, dated consent form will be stored in a locked room and is 
available for audit and inspection at any time. 
Publication of trial results 
All data will be pseudo-anonymized when used for publications. The final data is expected to be published 
in international journals and presented at scientific conferences in accordance with the Vancouver rules. 
The results will be disseminated through public lectures and popular science post. The results from this 
protocol will be published, whether they are positive, negative or inconclusive. First author on articles 
directly related to the hypotheses of the protocol is the investigator. First authors of derivative works of the 

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protocol are allocated to the persons devising the idea for the work and manages the task (concept, 
protocol application, database manager, data processing, analysis and manuscript). Co-authorship is 
assigned according to the Vancouver rules, but these rules may be waived if the persons are not active, 
and/or the project is handed over to another person at a later date.  
Ethics 
The project is conducted in accordance with the approved protocol and applicable legislation, and complies 
with the principles of the fifth version of the Helsinki Declaration. The information concerning subjects is 
protected by the "Law concerning the processing of personal data" and Health Act, Section 3 concerning 
patients' rights. The project requires approval by the local research ethics committee (north / middle) and 
the Data Protection Agency. Data from the trial is kept for 15 years after completion. The trial is initiated 
when approved by the Ethics Committee for the Northern Region. 
This study is an explorative step into making CRT the definitive treatment modality and sparing the patient 
for the morbidities associated with surgery. The subjects will not have any immediate benefits of 
participation in this study, unless the extra second-year follow-up scan shows relapse of the decease 
leading to an change in treatment course. The results have the potential to make future radiotherapy 
treatments of rectal cancer patient more precise with less side effects and will provide important 
information regarding the organ motion during preoperative CRT. The risk for the patient is described in the 
“Benefits and Risks”-section. The patient is not exposed to any ionizing radiation, but the use of contrast 
agents in the DCE-MRI does add a small risk and inconvenience to the patient. The main inconvenience to 
patients is the time commitment, but this has been sought minimized by scheduling scans in relation to 
standard appointments. The overall risks, discomforts and side-effects are assessed to be acceptable 
compared to the potential benefits of the project (and future secondary research projects). 
 
References 
 
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3. Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective 
postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A 
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