Proton Versus Photon Therapy in Anal Squamous Cell Carcinoma - Swedish Anal Carcinoma Study
Phase: NA
Conditions: Anal Cancer Squamous Cell
Sponsor: Umeå University

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Proton versus photon therapy in anal 
squamous cell carcinoma 
 
 
 
 
 
Swedish anal carcinoma study 
(SWANCA) 
 
 
 
 
 
Sponsor 
 
The anal carcinoma study group 
 
 
Umeå University Hospital 
 
 
SE 901 85 Umeå 
 
 
Sweden 
 
Protocol Version:  
1.3 (Non-substantial amendment) 
Protocol Date:  
2021-01-26 
 
Previous Protocol Versions: 
- 
Version 1.2, 2020-11-10 (Non-substantial amendment) 
- 
Version 1.1, 2020-09-30 (Non-substantial amendment) 
- 
Version 1.0, 2020-06-23 (Initial Protocol) 
 

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Contacts 
Principal investigator 
 
Björn Zackrisson, oncologist 
 
 
 
Cancercentrum 
 
 
 
Norrlands universitetssjukhus 
 
 
 
903 37 Umeå 
 
 
 
bjorn.zackrisson@umu.se 
 
Study steering committee 
Björn Zackrisson, oncologist  
 
 
 
Norrlands universitetssjukhus, Umeå 
 
 
 
bjorn.zackrisson@umu.se 
 
Martin Nilsson, oncologist 
Skånes universitetssjukhus, Lund 
martin.nilsson@med.lu.se 
 
Anders Johnsson, oncologist 
Skånes universitetssjukhus, Lund 
anders.johnsson@skane.se 
 
Calin Radu, oncologist 
Akademiska sjukhuset, Uppsala 
calin.radu@akademiska.se 
 
Nina Cavalli-Björkman, oncologist 
Akademiska sjukhuset, Uppsala 
nina.cavalli-bjorkman@igp.uu.se 
 
Per Albertsson, oncologist 
Sahlgrenska universitetssjukhuset, Göteborg 
per.albertsson@oncology.gu.se 
 
Michael Blomquist, radiation physicist 
Norrlands universitetssjukhus, Umeå 
michael.blomquist@regionvasterbotten.se 
 
Johanna Färlin, oncologist 
Skandionkliniken, Uppsala 
johanna.farlin@skandion.se 
 
Erik Fura, radiation physicist 
Skandionkliniken, Uppsala 
erik.fura@skandion.se 
 
Ulrica Langegård, registered nurse 
Göteborgs universitet, Göteborg 
Ulrica.langegard@gu.se 
 
 
 

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Study Group 
Nationell vårdprogramgrupp, analcancer.  
This group are responsible for producing and 
maintaining the national care program and comprises 
specialist in oncology, surgery, diagnostic radiology 
and cancer nursing. The representatives are 
appointed by the Regional Cancer Centres. 
 
Data Center and monitoring 
Cancercentrum, Norrlands universitetssjukhus,  
SE-90185 Umeå 
 
Quality of Life  
Proton Care Study Group 
Sahlgrenska Akademin vid Göteborgs Universitet  
Institutionen för vårdvetenskap och hälsa  
SE-405 30 Göteborg 
 
Statistician  
 
Björn Tavelin and Ove Björ 
 
 
 
RCC Norr, Umeå 
bjorn.tavelin@umu.se, 
ove.bjor@regionvasterbotten.se 
 
 
 
 
 
 
 
 

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Protocol Amendment and Version History 
Protocol Version 
Date 
Reason for change 
Change type 
1.0 
2020-06-23 
Initial version 
N/A 
1.1 
2020-09-30 
Administrative changes and changes to visits 
in sections 11 and 22 
Non-
substantial 
1.2 
2020-10-10 
Administrative changes and clarifications to 
sections 10, 11, 16, 18 and 22 
Non-
substantial 
1.3 
2021-01-26 
Correction to section 12.11 
Non-
substantial 
 
List of Changes from previous version 1.2 
Section  
Change 
Change Type 
Section 12.11 
Removed item 6 due to being irrelevant. Listing corrected. 
Non-
substantial 
 
 

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1 Synopsis 
Protocol title 
Proton versus photon therapy in anal squamous cell carcinoma – 
Swedish anal cancer study 
 
NCT number 
NCT04462042 
 
Development phase 
Phase II 
 
Study population 
Patients with squamous cell anal carcinoma aimed for radical 
radiotherapy with concomitant chemotherapy. 
 
Endpoints 
Primary endpoint 
• Grade >3 acute GI and haematological side-effects during 
therapy and up to three months after the end of treatment. 
Secondary endpoints 
• Other acute side-effects than GI and hematologic assessed 
during and up to three months after the treatment. 
• Late side effects 1, 2 and 5 years after completion of treatment 
• Patient reported quality of life during and after treatment up to 
5 years 
• Tumour response rate at 3-6 months after completion of 
treatment 
• Locoregional failure  
• Disease free survival  
• Overall survival  
• Health economic analysis 
• Feasibility 
 
Study design 
 The study is an open label, multi-centre, randomised phase II 
study. 100 evaluable patients with anal squamous cell carcinoma 
as defined above will be randomised in a 1:1 ratio to treatment 
consisting of  
• Arm 1: Radiotherapy delivered with protons 
• Arm 2: Radiotherapy delivered with photons 
 
Eligibility criteria 
Inclusion criteria 
1. The patient must be at least 18 years old. 
2. Histologically confirmed squamous cell carcinoma of anal 
canal or distal rectum with known p16/HPV status.  
3. The patients may have TNM-stage T2(>4 cm)-4, N0-1c,M0 
(UICC 8th edition).  
4. WHO/ECOG performance status 0-1.  
5. Hb >100 g/L 
6. ANC >1.5 x 109/L 
7. Platelets >100 x 109/L 
8. Creatinine <1.5 x ULN 
9. Bilirubin <3 x ULN 
10. ALAT <3 x ULN 
11. The patient must be expected to tolerate the treatment 
(radiotherapy with concomitant capecitabine and mitomycin C)  

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12. The patient must be able to understand the information about 
the treatment and give a written informed consent. 
 
Exclusion criteria 
1. Patients with cancer of the perianal skin without 
involvement of the anal canal (ICD-O-3 C44.5) are not 
eligible. 
2. Patient judged to have any other treatment than 
radiotherapy with concomitant chemotherapy as the 
preferred treatment 
3. Concomitant or previous malignancies. Exceptions are, 
adequately treated basal cell carcinoma or squamous cell 
carcinoma of the skin or, other previous malignancy with a 
disease-free interval of at least 5 years. 
4. Two or more synchronous primary cancers in the pelvic 
region at time of diagnosis 
5. Previous radiotherapy, surgery or chemotherapy that may 
interfere with the planned treatment for the present disease, 
as judged by the investigator. 
6. Co-existing disease prejudicing survival (expected survival 
should be >2 years). 
7. Pregnancy or breast feeding 
8. When prosthetic materials (e.g. hip prostheses) are present 
close to the target volume it must be considered if this may 
introduce uncertainties in dose calculations that precludes 
especially, proton therapy.  
9. Patients with pacemaker/ICD are not eligible. 
 
Stratification 
 To avoid imbalance between treatment arms patients the 
minimisation method will be used to achieve balance between sex 
(F/M), p16/HPV status (+/-) and colostomy before treatment. 
 
Duration of treatment 
Approximately six weeks 
 
Radiotherapy 
The prescribed doses to different target volumes will be equivalent 
to those recommended in the Swedish National Care program for 
anal carcinoma. For the patients in this study it means, 57.5 
Gy(RBE) in 27 fractions (2.13 Gy(RBE)/fraction). Any lymph 
node metastases equal to or greater than 2 cm in its largest 
dimension will be treated with the same dose and fractionation as 
the primary tumour. Lymph node metastases with a diameter less 
than 2 cm will be treated with 50.5 Gy(RBE) in 27 fractions (1.87 
Gy(RBE)/fraction). Prophylactic treatment of clinically uninvolved 
lymph nodes consists of 41.6 Gy(RBE) in 27 fractions (1.54 
Gy(RBE)/fraction). Treatment is given once daily, 5 days per 
week.  
 
Chemotherapy 
The Swedish national care program for anal cancer recommend 
concomitant chemotherapy during radiotherapy. In the present 
study, chemotherapy will be administered according to the national 
guidelines irrespective of treatment arm. In this study, the 

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treatment with a combination of mitomycin C and capecitabin 
(CAPMI) will be used. 
 
Efficacy control 
Local and regional failure 
 
Disease free survival 
 
Overall survival 
 
Safety evaluation 
Acute and late side effects; Adverse events and side effects graded 
according to CTCAE v5.0  
 
QL; Patient scored morbidity and QL 
 
Statistical methods 
Efficacy: Stratified Cox regression analysis, Kaplan-Meier and 
Breslow methods. For locoregional failure the Fine-Gray 
regression will be considered. 
 
Shift in distributions of side effects: Mann-Whitney U-test 
 
 
Criteria for evaluation 
Per protocol: Patients that have started the assigned study 
treatment. 
 
Intention to treat:  
All correctly randomised and included patients 
 
Planned sample size 
100 evaluable patients (patients completing primary treatment) 
Analysis plan 
The primary end point will be analysed when all patients have 
finished treatment and when median follow-up is two years. 
Further analyses when all patients have been followed for at least 
two years. 
 
Duration of the study 
Two to four years inclusion, five years follow-up after inclusion of 
the last patient. 
 
 

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2 Abbreviations 
AC 
 
Anal carcinoma 
AE 
 
Adverse event 
AJCC 
 
American Joint Committee on Cancer 
ANC 
 
Absolute neutrophil count 
CRF 
 
Case Report Form 
CT 
 
Computed tomography 
CTCAE 
 
Common terminology criteria for adverse events 
CTV 
 
Clinical tumour volume 
DCE 
 
Dynamic contrast enhanced 
eCRF 
 
electronic Case Report Form 
EORTC 
 
European Organisation for Research and Treatment of Cancer 
GI 
 
Gastro-intestinal 
GTV 
 
Gross tumour volume 
Gy 
 
Gray 
Gy(RBE) 
 
“Biological” or “photon equivalent” dose 
Hb 
 
Haemoglobin concentration 
HPV 
 
Human papilloma virus 
ICH-GCP 
 International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use-
Good Clinical Practice 
ICRU 
 
International Commission on Radiation Units and Measurements 
IMPT 
 
intensity modulated proton therapy 
IMRT 
 
Intensity modulated radiotherapy 
MFO 
 
Multifield optimization 
MRI 
 
Magnetic resonance imaging 
MV 
 
MegaVolt 
NTCP 
 
Normal tissue complication probability 
OS 
 
Overall survival 
PET 
 
Positron Emission Tomography 
PRV 
 
Planning organ at Risk Volume 
PTV 
 
Planning target volume 
QA 
 
Quality assurance 
 
 
QL 
 
Quality of life 
QLQ 
 
Quality of Life Questionnaire 
RBE 
 
Relative biological effectiveness 
RT 
 
Radiotherapy 
RTOG 
 
Radiation Therapy Oncology Group 
SAE 
 
Serious adverse event 
SCC 
 
squamous cell cancer 
SFO 
 
Single field optimization 
SFUD 
 
Single field uniform dose 
SIB 
 
Simultaneously integrated boost 
TLV 
 
Dental and Pharmaceutical Benefits Agency 
TNM 
 
Tumour Node Metastasis classification 
Vd 
 
Volume (of an organ) receiving >d Gy(RBE) 
WBC 
 
White blood cell count 
VMAT 
 
Volumetric modulated arc therapy 
WHO/ECOG 
World Health Organization/Eastern Cooperative Oncology Group 

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3 Table of contents 
Innehållsförteckning 
1 
Synopsis.................................................................................................................................................. 6 
2 
Abbreviations ......................................................................................................................................... 9 
3 
Table of contents .................................................................................................................................. 10 
4 
Background and introduction ............................................................................................................. 13 
4.1 
Study rationale .................................................................................................................................. 13 
4.2 
Background....................................................................................................................................... 13 
4.3 
Organisation ..................................................................................................................................... 14 
4.4 
Radiotherapy .................................................................................................................................... 14 
4.4.1 
Proton therapy .......................................................................................................................... 14 
5 
Objectives of the trial ........................................................................................................................... 15 
5.1 
Primary objective .............................................................................................................................. 15 
5.2 
Secondary objectives ......................................................................................................................... 15 
6 
End points ............................................................................................................................................ 15 
6.1 
Primary end point ............................................................................................................................. 15 
6.2 
Secondary end points ........................................................................................................................ 15 
7 
Study design ......................................................................................................................................... 15 
8 
Study period ......................................................................................................................................... 16 
9 
Overview of study treatment ............................................................................................................... 16 
9.1 
Radiotherapy .................................................................................................................................... 16 
9.2 
Chemotherapy ................................................................................................................................... 16 
10 
Patient selection criteria ...................................................................................................................... 17 
10.1 
Inclusion criteria .......................................................................................................................... 17 
10.2 
Exclusion criteria ......................................................................................................................... 17 
11 
Study procedure ................................................................................................................................... 17 
11.1 
STUDY ENTRY ............................................................................................................................. 17 
11.2 
Baseline evaluations ..................................................................................................................... 17 
11.3 
Evaluation during therapy (weekly) ............................................................................................... 18 
11.4 
Evaluation 1, 2 and 3 weeks after end of treatment ........................................................................ 18 
11.5 
Evaluation 1-2 months after end of treatment ................................................................................ 18 
11.6 
Evaluation 4-6 months after end of treatment ................................................................................ 18 
11.7 
Every 3 months for the first 2 years and then every 6 months until 5 years ..................................... 18 
11.8 
Side effects during radiotherapy .................................................................................................... 19 
11.9 
Evaluation after completion of radiotherapy ................................................................................. 19 

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11.10 
Follow up ..................................................................................................................................... 19 
11.11 
End of treatment or follow up ........................................................................................................ 19 
12 
Radiotherapy ....................................................................................................................................... 20 
12.1 
Patient position and immobilisation .............................................................................................. 20 
12.2 
Patient data acquisition ................................................................................................................ 20 
12.3 
Target volumes ............................................................................................................................. 20 
12.3.1 
Tumour volumes ................................................................................................................. 20 
12.3.2 
Elective lymph node volumes .............................................................................................. 21 
12.4 
Organs at risk ............................................................................................................................... 21 
12.5 
Structure names in the treatment planning system ......................................................................... 21 
12.6 
Treatment technique ..................................................................................................................... 21 
12.7 
Treatment planning....................................................................................................................... 22 
12.7.1 
Photon plans ........................................................................................................................ 22 
12.7.2 
Proton plans ........................................................................................................................ 22 
12.8 
Beam qualities .............................................................................................................................. 22 
12.9 
Photon and proton beam dose calibration ..................................................................................... 22 
12.10 
Dose specification and fractionation ............................................................................................. 23 
12.11 
Dose-volume constraints/objectives............................................................................................... 23 
12.12 
Radiotherapy, quality assurance (RT-QA) ..................................................................................... 24 
12.13 
Dummy run procedure .................................................................................................................. 24 
12.14 
Individual patient checks .............................................................................................................. 25 
13 
Quality of life and patient reported symptoms.................................................................................... 25 
14 
Cost-utility analysis.............................................................................................................................. 26 
15 
Statistical plan...................................................................................................................................... 26 
15.1 
Sample size determination............................................................................................................. 26 
15.2 
Statistical methods ........................................................................................................................ 27 
15.3 
Subject populations(s) for analysis ................................................................................................ 27 
16 
Reporting of adverse events ................................................................................................................. 27 
16.1 
Definition ..................................................................................................................................... 27 
16.2 
Reporting procedure ..................................................................................................................... 28 
17 
Quality assurance ................................................................................................................................ 28 
17.1 
Control of data consistency ........................................................................................................... 28 
17.2 
Site monitoring ............................................................................................................................. 28 
17.3 
Legal aspects ................................................................................................................................ 29 
17.4 
Direct access to data/documents ................................................................................................... 29 
18 
Data management ................................................................................................................................ 29 
18.1 
Patient registration/randomisation procedure ............................................................................... 29 
18.2 
Case report forms ......................................................................................................................... 29 
18.3 
Quality of life forms and Questionnaires ....................................................................................... 29 

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19 
Ethical considerations .......................................................................................................................... 30 
19.1 
Patient protection ......................................................................................................................... 30 
19.2 
Patient integrity ............................................................................................................................ 30 
19.3 
Informed consent .......................................................................................................................... 30 
19.4 
Independent ethical review............................................................................................................ 30 
19.5 
Risk benefit analysis ..................................................................................................................... 30 
20 
Participating centres ............................................................................................................................ 31 
21 
Ownership of data................................................................................................................................ 31 
21.1 
Meetings ....................................................................................................................................... 31 
21.2 
Reporting ..................................................................................................................................... 31 
22 
Flow chart of study procedures ........................................................................................................... 32 
23 
References ............................................................................................................................................ 33 
Addendum 1 - Organs at risk ....................................................................................................................... 34 
Addendum 2 - Radiotherapy QA reporting ................................................................................................. 35 
Addendum 3 - Dosreduktionsschema för radio-kemoterapi av analcancer från Akademiska sjukhuset, 
Uppsala ......................................................................................................................................................... 36 
Addendum 4 – Photography ......................................................................................................................... 37 
Addendum 5 - Flow chart of Patient Reported Data .................................................................................... 38 
Addendum 6 – Skin Care Guidelines ........................................................................................................... 39 
Addendum 7 – Skandion Patient position and immobilisation .................................................................... 41 
 
 
 
 

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4 Background and introduction 
4.1 Study rationale 
Dosimetric studies suggest that radiotherapy with protons has a potential to reduce side 
effects compared to treatment with photons for patients with anal carcinoma (AC). There are 
so far no studies comparing these treatment techniques in a randomised setting. The aim of 
this study is to compare side effects following photon therapy versus proton therapy within 
the framework of a randomised controlled trial. 
 
4.2 Background 
Recent data suggests that close to 200 patients with AC are diagnosed each year in Sweden 
and the trend is increasing. AC is approximately twice as common in women as in men. There 
is a strong association between human papilloma virus (HPV), especially the subtypes HPV 
16 and 18 and AC. The median age for AC patients is about 65. The overall survival after 5 
years is approximately 70%. Radiotherapy is usually the first line treatment and given in 
combination with chemotherapy as recommended in the national care program.  
Virtually all clinical studies have been performed with conventional photon techniques (3-D 
conformal or intensity modulated radiotherapy (IMRT/VMAT)). These techniques have gone 
through a strong development during the last 1-2 decades. Advanced proton radiotherapy with 
intensity modulated proton therapy (IMPT) and spot scanning has been available for a little 
more than a decade. The main difference between proton and photon techniques consists of 
the resulting dose distribution due to the physical properties of protons. Protons often allow 
for lower radiation doses in structures at a distance from the target while the target dose 
remains similar. For treatment of large volumes in the pelvis the absorbed dose in organs such 
as intraperitoneal bowel, urinary bladder and pelvic bone marrow will differ between the two 
techniques. 
The standard treatment of AC T2(>4 cm) - 4,N0-1c,M0, according to the Swedish care 
programme for anal carcinoma, is radical radiotherapy of known tumour tissue and 
prophylactic radiotherapy to pelvic lymph nodes concomitant with chemotherapy (RCC 
2020). A substantial proportion of side effects emanates from structures in proximity to the 
site of the tumour, i.e. rectum/anal canal and perineal skin surfaces. Since these structures are 
part of the tumour volume the doses will be similar regardless of treatment technique. Thus, 
the side effects from these sites may be assumed to be similarly severe after proton or photon 
therapy.  
Haematological toxicity is particularly relevant in the case of combined radio- and 
chemotherapy. Radiotherapy of the pelvic region alone seldom causes major haematological 
complications. Chemotherapy frequently does. The combined haematological toxicity from 
radiotherapy and chemotherapy may lead to dose reduction of chemotherapy with a 
potentially detrimental effect on treatment outcome (Bazan et al.2012). It has been shown that 
a mean dose to the pelvic bone marrow of more than 32 Gy progressively increases the risk of 
grade >3 haematological toxicity in intensity modulated photon radiotherapy with concurrent 
chemotherapy (Franco et al 2016). Septic complications as a consequence of haematological 
toxicity may also cause serious problems for the patients. Furthermore, severe acute side 
effects may lead to treatment interruptions due to patient compliance and/or a compromised 
general condition. The pelvic bones harbour up to 40% of the haematopoietically active bone 
marrow (Ellis, 1961). It is known that grade >3 haematological toxicity is reported to occur in 
well over 50% of patients treated for AC with photons and chemotherapy (Franco et al. 2016). 
In the photon case, virtually all pelvic bone marrow is exposed to radiation, due to the 
treatment technique and the properties of photon radiation. In silico simulations of proton 
therapy shows that, at least, 50% of the pelvic may be completely spared from radiation dose. 
It may thus be assumed that proton therapy only to a limited extent will add to the 

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haematological toxicity of chemotherapy. The incidence of haematological toxicity grade >3 
may then be assumed to decrease substantially to a reported level of 20% (Franco et al. 2016). 
The situation is different regarding dose-volume parameters that determine dose constraints 
for intraperitoneal bowel. Data are comparatively sparse and the proposed normal tissue 
complication probability (NTCP)-models are therefore not validated and not robust enough 
for predictive purpose (Jadon et al 2019). Published studies have used different organ-at-risk 
definitions and different end-points which makes the interpretation of results even more 
difficult (Jackson et al 2010). An unpublished study of 170 patients performed retrospectively 
the frequency of at least grade 3 toxicity was 34% after VMAT (personal communication: 
Martin Nilsson, Skåne University hospital, Lund, Sweden). This is probably a relevant figure 
to use since it is derived from a population receiving similar treatment as the population in the 
present study. Similar frequencies have been reported by others (e.g. Devisetty et al 2009). 
These results reflect the difficulties to reach the optimisation objectives with photon 
techniques. At least in advanced tumour cases.  
In summary, AC is a disease in which modern therapy is reasonably successful in achieving 
tumour control/cure. Both acute and late side effects are substantial. Proton radiotherapy is 
hypothesised to have the potential to decrease the incidence/severity of some acute side 
effects from certain organs at risk e.g. bone marrow and intraperitoneal bowel. By sparing the 
dose to these organs it is also possible that late effects might be less evident. Sparing of the 
bone marrow may lead to fewer septic events and dose reductions of chemotherapy which 
may, as a consequence, improve tumour control. The primary aim of this study is to find ways 
to decrease acute side effects primarily to alleviate some discomfort from the patient during 
and after a usually painful treatment experience. It has also been concluded by others that 
reduction of acute side effects is a relevant aim and end point for the evaluation of new 
treatment techniques and both patient reported and physician reported data are recommended 
for assessment (Glynne-Jones et al 2017). 
 
4.3 Organisation 
Presently, in Sweden all patients aimed for curative intent chemo-radiotherapy are treated in 
one of four university hospitals (in Göteborg, Lund, Umeå and Uppsala) according to an 
agreement on a national level. Before start of therapy, all patients are discussed at a national 
multidisciplinary board. This ensures that all patients that may be eligible for a clinical trial 
are reviewed before treatment.  
 
4.4 Radiotherapy 
Radiotherapy techniques have developed rapidly during the last decades with the introduction 
of intensity modulated therapy and automated computer optimisation of treatment plans. 
These techniques have contributed to the reduction of side effects and increased the tolerance 
to radiotherapy of large volume. These techniques are considered a prerequisite for modern 
radiotherapy and are thus, in this context considered as the conventional treatment. 
 
4.4.1 Proton therapy 
From a clinical point of view the main difference between photon and proton radiation can be 
attributed to the proton Bragg-peak that deposit the main part of the energy in a small 
spot/volume. This leads to a different dose distribution compared with photons and, perhaps 
most important, a very rapid fall at depth. On the other hand, the penumbra of protons at 
depth is usually wider than that of photons. This may be a disadvantage of protons if critical 
organs are situated close to the tumour target. In radiotherapy of anal carcinoma some 
sensitive structures are situated within the volume of high dose and can thus not be spared by 
either photons or protons. Other organs at risk such as small bowel and bone marrow are 

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predominantly quite distant from the target and could therefore be spared to some degree by 
protons. It is therefore justified to investigate if protons will give a clinically detectable 
reduction of the frequency and/or severity of side effects from these organs 
 
5  Objectives of the trial 
5.1 Primary objective 
• To study the acute side effects during, and in the first three months after radiotherapy 
with proton therapy versus photon therapy of localised anal cancer stage T2 (>4cm)-
T4 and/or N0-1c and M0.  
 
5.2 Secondary objectives 
To compare: 
• Other acute side-effects than GI and hematologic 
• The frequency of late side effects up to 5 years after treatment 
• Patient reported quality of life during and after treatment up to 5 years 
• Tumour response rate at 3-6 months 
• Locoregional failure  
• Disease free survival  
• Overall survival  
• Health economic between the treatment groups 
• Feasibility 
 
6 End points 
6.1 Primary end point 
• Grade >3 acute GI and haematological side-effects during therapy and up to three 
months after the end of treatment. 
 
6.2 Secondary end points 
• Other acute side-effects than GI and hematologic assessed during and up to three 
months after the treatment. 
• Late side effects 1, 2 and 5 years after completion of treatment 
• Patient reported quality of life during and after treatment up to 5 years 
• Tumour response rate at 3-6 months after completion of treatment 
• Locoregional failure  
• Disease free survival  
• Overall survival  
• Health economic analysis 
• Feasibility 
 
7 Study design 
The study is an open label, multi-centre, randomised phase II study. 100 patients with anal 
carcinoma (including carcinoma of the perianal skin) will be randomised in 1:1 ratio to 
treatment consisting of 
• Arm 1: Radiotherapy delivered with protons 
• Arm 2: Radiotherapy delivered with photons 

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Randomisation will be stratified by sex, presens of colostomy and p16/HPV-status using the 
minimisation method (Pocock 1983). 
 
8 Study period 
The inclusion is estimated to be 2-4 years. The study ends five years after inclusion of the last 
patient 
 
9 Overview of study treatment 
Radiotherapy with concomitant chemotherapy is the recommended curative treatment for anal 
carcinomas T2(>4cm)-T4/N+M0. The recommended treatment is described in detail in (RCC 
2020). The treatment in this study does in all aspects follow the national recommendations. 
The treatment in both treatment arms will be identical in all aspects except the fact that in the 
experimental arm will consist of proton radiation. The care program suggests a few alternative 
possibilities concerning the choice of radiotherapy dose and fractionation and chemotherapy 
prescription. In practice only one radiotherapy schedule and one alternative for chemotherapy 
are frequently used. In the present study these dominating alternatives should be used.  
 
9.1 Radiotherapy 
This means for radiotherapy that it is delivered in 27 fractions with five fractions per week 
during an overall treatment time of 5.5 weeks. 57.5 Gy(RBE) in 27 fractions is the planned 
dose for the primary tumour and lymph nodes with a greatest diameter of at least 2 cm will 
receive the same dose as the primary tumour (corresponding to PTVT_57.5 and PTVN_57.5). 
Lymph node metastases less than 2 cm are prescribed 50.5 Gy(RBE) in 27 fractions 
(corresponding to PTVN_50.5). Elective treatment of clinically uninvolved nodes will be 
delivered to a total dose of 41.6 Gy(RBE) in 27 fractions (PTVN_41.6). 
It is implied that photon therapy is given with intensity modulated radiotherapy 
(IMRT)/volumetric arc therapy (VMAT)/helical tomotherapy (HTT). Proton plans will be 
produced by single field optimization (SFO)/single field uniform dose (SFUD) or multifield 
optimization (MFO)/intensity modulated proton therapy (IMPT) depending on which 
technique that renders the best result regarding target coverage, radiation doses to organs at 
risk and plan robustness. SIB will be used in all cases to reach the intended dose for each 
target volume in 27 fractions. 
For converting proton dose from physical dose (Gy) to “biological” or “photon equivalent” 
dose Gy(RBE) a factor of 1.1 is used.  
 
9.2 Chemotherapy 
The national care program recommends two similar alternatives as first choice of 
chemotherapy. One is the combination of mitomycin C and 5-flurouracil (FUMI). The other is 
mitomycin C and capecitabin (CAPMI). Presently, in Sweden the latter combination is 
predominant. To avoid possible sources variation, CAPMI will be the combination used in the 
present study. The dosage and administration of drugs shall follow the national care program, 
irrespective of treatment arm. This is also the case regarding instructions for dose reduction 
and/or discontinuation of drug delivery. A schedule for dose-reduction of chemotherapy 
components that is in use at the Uppsala Akademiska hospital is enclosed (in Swedish) as 
Addendum 3 for guidance. 

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10 Patient selection criteria 
10.1 Inclusion criteria 
1. The patient must be at least 18 years old. 
2. Histologically confirmed squamous cell carcinoma of anal canal or distal rectum with 
known p16/HPV status.  
3. The patients may have TNM-stage T2(>4 cm)-4, N0-1c,M0 (UICC 8th edition).  
4. WHO/ECOG performance status 0-1.  
5. Hb >100 g/L 
6. ANC >1.5 x 109/L 
7. Platelets >100 x 109/L 
8. Creatinine <1.5 x ULN 
9. Bilirubin <3 x ULN 
10. ALAT <3 x ULN 
11. The patient must be expected to tolerate the treatment (radiotherapy with concomitant 
capecitabine and mitomycin C)  
12. The patient must be able to understand the information about the treatment and give a 
written informed consent. 
 
10.2 Exclusion criteria 
1. Patients with cancer of the perianal skin without involvement of the anal canal (ICD-O-
3 C44.5) are not eligible. 
2. Patient judged to have any other treatment than radiotherapy with concomitant 
chemotherapy as the preferred treatment 
3. Concomitant or previous malignancies. Exceptions are, adequately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or, other previous malignancy with 
a disease-free interval of at least 5 years. 
4. Two or more synchronous primary cancers in the pelvic region at time of diagnosis 
5. Previous radiotherapy, surgery or chemotherapy that may interfere with the planned 
treatment for the present disease, as judged by the investigator. 
6. Co-existing disease prejudicing survival (expected survival should be >2 years). 
7. Pregnancy or breast feeding 
8. When prosthetic materials (e.g. hip prostheses) are present close to the target volume it 
must be considered if this may introduce uncertainties in dose calculations that 
precludes especially, proton therapy.  
9. Patients with pacemaker/ICD are not eligible. 
 
11 Study procedure 
11.1 STUDY ENTRY 
1. Written informed consent is needed before any study-specific procedures are 
performed.  Treatment should start within 3 weeks after registration. 
 
11.2 Baseline evaluations 
1. Recording of toxicity according to CTCAE v5.0 
2. Adequate clinical assessment with a TNM (UICC 8th edition) classification (MRI 
and CT/MR-PET of the pelvis and thoracic CT/pulmonary X-ray, and histology 
showing squamous cell carcinoma). 
3. Medical history 
4. ECOG perfomance status 

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5. Haematology: Hb,WBC, WBC differential, ANC, platelets 
6. Blood chemistry: Bilirubin, ALP, ALAT, ASAT, creatinine, Na, K, Ca, albumin 
and Mg 
7. p16/HPV analysis of the primary tumour  
8. Digital photo of perianal area (saved into patient’s clinical files) 
9. Body weight and height 
10. Questionnaires (see addendum 5) 
 
11.3 Evaluation during therapy (weekly) 
1. Recording of toxicity according to CTCAE v5.0 
2. Haematology; Hb, WBC, WBC differential, ANC, platelets 
3. Blood chemistry (only week 4 of radiation); Bilirubin, ALP, ALAT, ASAT, 
creatinine, Na, K, Ca, albumin and Mg 
4. Daily Questionnaires (see addendum 5) 
5. Digital photo of perianal area (saved into patient’s clinical files) 
 
11.4 Evaluation 1, 2 and 3 weeks after end of treatment 
1. Hb, WBC differential, ANC, platelets 
2. Questionnaires (see addendum 5) 
 
11.5 Evaluation 1-2 months after end of treatment 
1. Recording of toxicity according to CTCAE v5.0 
2. Digital rectal examination 
3. ECOG performance status and weight 
4. Hb,WBC, WBC differential, ANC, platelets 
5. Bilirubin, ALP, ALAT, ASAT, creatinine, Na, K, Ca, albumin, Mg 
6. Digital photo of perianal area (saved into patient’s clinical files) 
7. Questionnaires (see addendum 5) 
 
11.6 Evaluation 4-6 months after end of treatment 
1. Recording of toxicity according to CTCAE v5.0 
2. Digital rectal examination 
3. CT-PET 
4. Response evaluation 
5. ECOG performance status and weight 
6. Haematology; Hb,WBC, WBC differential, ANC, platelets 
7. Blood chemistry; Bilirubin, ALP, ALAT, ASAT, creatinine, Na, K, Ca,albumin 
and Mg 
8. Questionnaires (see addendum 5) 
 
11.7 Every 3 months for the first 2 years and then every 6 months until 5 years 
1. Recording of late toxicity (Late toxicity according to CTCAE c 5.0, except for late 
skin toxicity which will be graded according to RTOG ) 
2. Digital rectal examination 
3. ECOG performance status and weight 
4. CT thorax and abdomen once yearly for the first 3 years 
5. MRI of the pelvis / CT-PET if clinically indicated 
6. Questionnaires (see addendum 5) 

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11.8 Side effects during radiotherapy 
The most common acute side effects from radiotherapy of anal carcinoma are varying degrees 
of fatigue, diarrhoea, nausea and radiation dermatitis. 
Dermatitis is common in skin of the gluteal cleft, peri-anal area, groins and external genitalia. 
It occurs usually during the third week of treatment and increases during therapy. Normally it 
subsides after therapy (often the improvement starts a couple of weeks after cessation of 
therapy. The restitution process is gradual and may go on for several months. The skin 
reaction is graded into 5 grades (0-4) by the CTCAE 5.0. Recommendations for treatment of 
reactions are listed in the Swedish Care Program (RCC 2020) which should be followed. 
Other side effects are also graded according to CTCAE 5.0 and treated as indicated. 
 
Skin care is a major problem for patients undergoing radiotherapy for anal carcinoma. 
Different routines are used at different centres. It is recommended that the skin care program 
produced by the department of oncology in Skåne university hospital is used as a general 
recommendation for patients in the present study. A copy of the protocol (in Swedish) is 
enclosed as an addendum (Addendum 6) 
 
11.9 Evaluation after completion of radiotherapy 
At two to three months after completion of therapy an assessment of tumour control and 
morbidity must be made. Tumour control is assessed as judged by the responsible physician, 
national and local routines. Side effects are graded according to CTCAE 5.0 using CTC 
terminology. 
 
11.10 
Follow up 
Patients should be seen every three months for two years after completion of radiotherapy and 
a full clinical assessment should be made. During this time, it is recommended that an 
oncologist sees the patient with at least 6 months intervals. Information on locoregional and 
distant tumour control should be recorded. After two years, evaluation of locoregional control 
should be made every 6 months up to 5 years. During this time the follow-up is done 
according to the National Care program.  
Late side effects should be monitored according to the CTCAE 5.0 from three months and up 
to five years after completion of radiotherapy. 
 
Questionnaires as per section 13 should be administered at 1, 3, 6, 9, 12, 24, 36 months and 5 
years after randomisation. 
 
Patients should be monitored for local recurrence and if symptoms arise that are suspicious of 
distant metastases appropriate investigations must be carried out to confirm or exclude their 
presence. Also, if a locoregional recurrence is found, an MRI and a PET-CT for 
documentation is mandatory and screening for distant metastases should be performed. If 
distant metastases develop but there is no evidence of local recurrence within the irradiated 
volume, effort should be made to continue to monitor the primary site. If possible, 
histological confirmation should be performed in all cases. 
 
11.11 
End of treatment or follow up 
Follow-up by the protocol ends when any of the events below occurs: 
• If 5 years of follow-up is reached 
• If residual tumour or a locoregional recurrence is diagnosed. Survival will then be 
followed by the Swedish population registry 

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• In cases of other serious medical conditions, follow-up ends as judged by the 
investigator. Survival will then be followed by the Swedish population registry 
• If the patient dies before 5 years’ follow up 
• Withdrawal of consent 
 
12 Radiotherapy 
Radiotherapy must start within three weeks from the date of study entry (randomisation). 
Prolongation of overall treatment time should be avoided. In cases of unplanned treatment 
breaks or of a Bank Holiday, the overall treatment time may be kept by giving the patient two 
fractions per day with 7 h interval (the interval may be longer, but never shorter than 6 h) for 
maximum four days. The overall treatment time is ideally 37 days and must not exceed 40 
days. 
 
12.1 Patient position and immobilisation 
The patient should preferably be treated in supine position, adequately positioned and 
immobilised according to the Skandion routines. If the patient has not been randomized when 
treatment planning imaging is performed, the preparations must be performed according to 
the Skandion routines described for proton treatment (described in Addendum 7). 
 
The patient should be instructed to void the bladder and drink 3 dl of liquid 30 min before 
treatment planning imaging and each fraction. If applicable and possible, the patient should 
also empty the bowel. 
 
12.2 Patient data acquisition 
Treatment planning CT-imaging (slice thickness < 3mm) should be performed with the 
patient in treatment position and according to proton treatment routines except for patients 
that have already been randomized to photon treatment. If the rectum is distended to a 
diameter of >5 cm by scybala and/or gas, the patient is asked to use a laxative before the 
procedure is repeated. If the rectum still is distended, it is assumed that the state is habitual 
and thus may serve as a base-line for planning. A co-registered MRI- or PET-scan is 
recommended to facilitate tumour delineation. MRI-only procedures are not allowed since the 
method is not verified for protons. 
 
12.3 Target volumes 
12.3.1 Tumour volumes 
Gross Tumour Volume(s) (GTVT_57.5, GTVN_57.5, GTVN_50.5) of the primary tumour 
(GTVT) and metastatic regional lymph nodes (GTVN) are outlined based on available 
information (clinical examination, endoscopy, diagnostic MRI/PET). GTVT and GTVN 
should always be delineated as separate volumes. 
 
Clinical Target Volume(s) (CTVT_57.5, CTVN_57.5, CTVN_50.5) CTVT_57.5 consist of 
GTVT with a 10-15 mm margin, depending on anatomical borders, tumour growth pattern 
etc. Wider margins allowed when indicated. CTVN_57.5/50.5 consist of corresponding 
GTVN with a 5-10 mm margin, depending on size and appearance. CTVT and CTVN should 
always be delineated as separate volumes. 
 
Planning Target Volumes (PTVs) PTVT_57.5 and PTVN_57.5/50.5 are CTVT_57.5 and 
CTVN_57.5/50.5 with a 7 mm margin in all directions. Imaging (CBCT or orthogonal 
images) should be performed daily for set-up verification. PTVT/N should generally not be 

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delineated closer than 4mm to the skin surface. However, if there is tumour closer than 4 mm 
to the skin surface, PTV should extend to (or outside) the skin surface and a bolus should be 
used during photon treatment (see also section 12.6 “Treatment planning”). PTVT and PTVN 
should be delineated as separate volumes. 
 
12.3.2 Elective lymph node volumes 
CTVN_41.6 is an adjuvant lymph node volume and consists of regional lymph nodes at risk 
for subclinical spread of the tumour at a distance. The lymph nodes/sites relevant elective for 
treatment of anal carcinoma are the following (in accordance with the National care program) 
 
• Presacral, mesorectal, obturator and internal iliac lymph nodes (in all cases). 
• External iliac nodes 
• Inguinal nodes, may be omitted only if the tumour is entirely located in the rectum 
• The ischiorectal fossa if the tumour engages the external sphincter or levator muscle 
• The anus with a margin of 20 mm circumferentially and distally. 
 
CTV should not extend more than 10 mm into the urinary bladder and not more than 1 mm 
into bone or muscle if these structures are not engaged by tumour growth. 
 
PTVN_41.6 consists of the CTVN_41.6 with an isotropic margin of 7 mm. The PTV_41.6 
should not be delineated closer than 4 mm to the skin surface (See also 12.7 “Treatment 
planning”) 
 
12.4 Organs at risk 
The following organs at risk (OAR) must be delineated 
• Urinary bladder 
• Intestine (operationalised by the volume named “Bowel bag”) 
• Skin 
• Pelvic bone marrow  
• Femoral heads 
 
12.5 Structure names in the treatment planning system 
All structures should be named according to the Swedish standard nomenclature in 
radiotherapy (Strålsäkerhetsmyndighetens rapport 18:2016). The following structure names 
should be used: 
“GTVT_57.5”, “GTVN_57.5”, “GTVN_50.5”, “CTVT_57.5”, “CTVN_57.5”, 
“CTVN_50.5”, “CTVN_41.6”, “PTVT_57.5”, “PTVN_57.5”, “PTVN_50.5”, “PTVN_41.6”, 
“Bladder”, “BowelBag”, “Skin”, “BoneMarrow”, “FemoralHead_L”, “FemoralHead_R” 
Other OARs should be delineated when relevant according to local routines. For delineation 
guidelines, see Ad 1. For dose limitations, see dose-volume objectives/constraints below. 
 
12.6 Treatment technique 
Radiation treatment with photons should be delivered with external photon beam therapy with 
IMRT/VMAT/HTT. 
Radiation treatment with protons should be delivered with scanned proton beam therapy with 
either SFO/SFUD or MFO/IMPT. 
The position of the patient should be verified with electronic kV or MV portal imaging or x-
ray volumetric imaging (cone beam CT) according to local routines at each treatment centre, 
and included in the quality assurance (QA) report (see below). Patients undergoing proton 
therapy will perform repeated CT-scans according routines at the Skandion clinic, and 

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patients treated with photons will be re-scanned according to local routines at each treatment 
centre. The monitor units (dose) used for verification of position should be considered if MV 
portal imaging is used. 
 
12.7 Treatment planning 
The clinician should assess the imaging and ascertain whether the tumour is adequately 
bolused by the surrounding buttocks ie. 5mm of tissue surrounding GTV. If there is not 5mm 
of tissue around whole GTV, tailored wax or sheet bolus should be considered in patients in 
whom additional bolus is required. 
 
12.7.1 Photon plans 
Treatment planning should be performed using IMRT/VMAT/HTT software. Corrections for 
heterogeneities should be performed. The international Commission on Radiation Units and 
Measurements (ICRU) report number 83 should be considered. 
Maximum allowed voxel size for the dose calculation grid is 3 mm in the transversal plane. A 
size equal to the CT slice thickness is recommended. 
During treatment planning in order to achieve the appropriate radiation dose close to the skin 
surface a “planning bolus” or extended fields outside the skin should be used. In order to 
evaluate dose homogeneity in overlapping target volumes, separate “optimizing planning 
volumes” may be created according to local routines. During treatment planning it must be 
ensured that the different CTVs are delineated as separate, not overlapping, volumes. PTVs 
can be replaced by robust treatment plan evaluation of the corresponding CTVs. If robust 
treatment plan evaluation is employed, this must be included in the QA report. The use of 
bolus in the inguinal region is normally required only if skin is invaded by tumour. 
 
12.7.2 Proton plans 
Proton plans can be produced as SFO/SFUD or MFO/IMPT using proton software of the 
Skandion clinic. The international Commission on Radiation Units and Measurements 
(ICRU) report number 78 should be considered. Maximum allowed voxel size for the dose 
calculation grid is 3 mm in the transversal plane. A size equal to the CT slice thickness is 
recommended. Artifacts in the tissue, such as implants, ports, teeth, clips, shunts etc. must be 
contoured and overridden with appropriate HU, according to the routines at the Skandion 
clinic. This should be done prior to optimization. When necessary, in superficial targets, a 
range shifter should be used. During treatment planning it must be ensured that the different 
CTVs are delineated as separate, not overlapping, volumes. PTVs can be replaced by robust 
treatment plan evaluation of the corresponding CTVs according to routines at the Skandion 
clinic. If robust treatment plan evaluation is employed, this must be included in the QA report. 
Proton plans are to be recalculated to physical dose using the RBE value 1.1. 
 
12.8 Beam qualities 
Photon beam quality is chosen to optimise the individual dose distribution but should be no 
less than 6MV. 
Proton treatment will be delivered with pencil beam spot scanning, with beam energies up to 
240 MeV. 
 
12.9 Photon and proton beam dose calibration 
In order to check the reference dosimetry of the accelerators used in the study, it is 
recommended that participating centres take part in external dosimetry audits. 
 

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12.10 
Dose specification and fractionation 
The prescribed target doses 57.5/50.5 Gy(RBE) to tumour volumes and 41.6 Gy(RBE) to 
adjuvant volumes) shall be given as homogeneously as possible to each target volume (see 
dose-volume constraints/objectives below). 
 
Radiotherapy is given daily, 5 days/week, with 27 fractions of 2.13 Gy(RBE) (PTV_57.5), 
1.87 Gy(RBE) (PTV 50.5) and 1.54 Gy(RBE) (PTV_41.6). Overall treatment time is thus 
optimally 37 days. Maximum allowed treatment time is 40 days. 
Dose recording and reporting shall be performed as described below in the QA section. 
 
12.11 
Dose-volume constraints/objectives 
Since photon plans and proton plans will not have the same dose distributions to OARs, every 
effort should be made to keep radiation doses as low as possible to OARs even if 
constraints/objectives already are met.  
Objectives and constraints in the table below are grouped according to their priority in priority 
group 1. In priority group 2 there is no ranking between the volumes in the priority group. 
Group 3 is for data collection purposes and is thus not used for optimisation. The numbering 
in the list is for data management purposes only. For each patient, the responsible physician 
decides how the priority between the structures within this priority group should be employed 
during treatment plan optimization. 
 
Priority 
Volume 
Objective 
(all doses 
given in 
Gy(RBE)) 
Constraint 
(all doses 
given in 
Gy(RBE)) 
Description 
 
Priority group 1 
 
1* 
PTVT_57.5, 
PTVN_57.5 
D98% ≥54.6 
 
The “near minimum dose” to PTVs_57.5 
should be equal to or higher than 54.6 
Gy(RBE) 
2* 
PTVN_50.5 
D98% ≥48.0 
 
The “near minimum dose” to PTV_50.5 
should be equal to or higher than 48.0 
Gy(RBE) 
3* 
PTVN_41.6 
D98% ≥39.5 
 
The “near minimum dose” to PTV_41.6 
should be equal to or higher than 39.5 
Gy(RBE) 
4* 
PTVT_57.5, 
PTVN_57.5 
D2% <60.4 
 
The “near maximum dose” to PTVs_57.5 
should be equal or lower than 60.4 
Gy(RBE) 
5* 
PTVN_50.5 
D2% <53.0 
 
The “near maximum dose” to PTVN_50.5 
should be equal or lower than 53.0 
Gy(RBE) 
6 
BowelBag 
 
V30 <450 cc 
V45 <195 cc 
The volume of Bowel bag receiving 30 
Gy(RBE) should be smaller than 450 cc and 
the volume receiving 45 Gy(RBE) should 
be smaller than 195 cc 
7 
BoneMarrow Dmean <32 
 
The mean dose to the pelvic bone marrow 
should preferably not exceed 32 Gy(RBE) 

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8 
Femoral 
heads 
D2% <52 
 
The “near maximum dose” in one femoral 
head should be kept below 52 Gy(RBE) 
9 
Bladder 
Dmean <45 
 
The mean dose in the urinary bladder not 
included in the PTV (Bladder-PTV) should 
be less than 45 Gy(RBE) 
 
Priority group 2 
 
10 
Z_Skin 
D0.1 cc 
<50 
 
The dose to 0.1 cc of Z_skin (the skin (1-5 
mm depth) outside of the CTVs volumes 
(including a 9 mm margin) 
should be equal to or less than 50 Gy(RBE) 
11 
Testes 
Dmean <2 
 
The mean dose to the testes should 
preferably not exceed 2 Gy(RBE) 
 
Priority group 3 
(for data collection only) 
 
12 
Genitals 
 
 
Defined for dose monitoring purposes 
 
* Dose objectives and constraints for PTVs can be replaced by robust treatment plan 
evaluation of the corresponding CTVs. The geometric and dosimetric uncertainty parameters 
employed in the robust evaluation must correspond to the margins added when expanding 
from CTV to PTV. 
 
12.12 
Radiotherapy, quality assurance (RT-QA) 
The purpose of the QA protocol is to ensure uniformity of all radiotherapy data for all 
patients. A working group will be assigned in order to collect treatment and verification data 
to ensure compliance to the study protocol. 
 
Radiotherapy related treatment information and other relevant documentation for each patient 
shall be sent to the QA group at completion of radiotherapy (see below). Patient data stored 
digitally in the DICOM format, such as CT-images, dose plans, and dose distributions, should 
be sent to Michael Blomquist, Centrum för medicinsk teknik och strålningsfysik, 
Strålningsfysik, Norrlands Universitetssjukhus, Umeå, according to Ad 2. 
 
Dummy runs, including both delineation of structures and treatment planning will be 
performed and there will be individual patient checks. When ten patients in each treatment 
arm have been included, structure delineation and dose-volume constraints/objectives will be 
evaluated. Quality audits may be performed.  
 
In order to maintain the quality of the treatment, each participating centre should strive to 
include a minimum of 5 patients per year. If a centre includes less than 2 patients per year, 
this centre should be considered for closing. 
 
12.13 
Dummy run procedure 
A dummy run should be performed before the start of the patient trial. CT and MR images of 
an anal cancer patient will be sent to participating centres from the QA group. Delineation of 
target volumes and OARs according to the study protocol will be performed at each centre, as 
well as a proton and photon treatment plan according to the study protocol. Evaluation of 

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target delineation and treatment plans will be performed by the QA group before the centre 
starts to include patients. 
 
12.14 
Individual patient checks 
A detailed description how to prepare and process the data needed for the QA process is 
presented in Addendum 2. Additionally, the treatment plans for the first 5 patients from each 
centre will be reviewed at the weekly national multidisciplinary conference. 
 
13 Quality of life and patient reported symptoms 
The patient reported outcomes (PRO) will be a main source of the assessment of treatment 
related side effects. The patients will be asked for a written consent to take part in both the 
present study and the ongoing “ProtonCare”-study. The reported data will be used for 
evaluation of the questions specific to both studies. The data will thus be shared for dual 
purposes. A common patient information document will be presented for the patients in order 
to make it easier for the patient to understand how their personal data will be used for 
answering study questions.   
 
PROs will be collected during and at the start of RT, after 3 weeks, end of treatment, 1, 3, 6, 9, 
12, 24, 36 and 60 months after the termination of RT. The timing for data collecting is chosen 
to capture the expected maximum increase in symptom burden after treatment. All PROs will 
be collected by paper questionnaires. 
 
 
The forms specific for the present study are the following: 
• HRQoL will be investigated with the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire, the QLQ-C30, version. 
This is a generic cancer-specific questionnaire covering physical, social and 
psychological functioning, as well as cancer-specific symptoms. The instrument 
consists of 30 items covering five functioning scales (physical, role, emotional, 
cognitive and social function), three symptom scales (fatigue, pain and 
nausea/vomiting) and two global health/QoL items. Six single items address 
additional symptoms commonly reported by cancer patients (loss of appetite, 
insomnia, dyspnea, diarrhea and constipation) and financial difficulties are also 
included.  The QLQ-C30 will be supplemented with the disease specific module (anal-
cancer) QLQ-ANL27. 
• Fatigue will be measured with the Multidimensional Fatigue Inventory (MFI-20). This 
questionnaire consists of 20 items that assess five dimensions of fatigue based on 
different modes of expression: (1) general fatigue (2) physical fatigue (3) reduced 
activities; (4) lack of motivation; and (5) mental fatigue. A total score is calculated for 
each scale by summation of the individual item scores, that range from 4 to 20. 
• Anxiety and depression will be measured with the Hospital Anxiety and Depression 
Scale (HAD).The questionnaire is a 14-item screening questionnaire, with seven items 
respectively relating to anxiety (HAD-A) and depression (HAD-D). Ratings are made 
on a four-point scale with scores ranging from 0  to 21 for each item. HAD scores are 
classified as follows: 0-7 = non-cases, 8-10 = doubtful cases and 11-21 = cases 
• Sleep disturbance was measured with the seven-item Insomnia Severity Index (ISI). 
The ISI uses a five-point Likert scale to rate difficulty with sleep onset, sleep 
maintenance and early morning awakening, as well as interference with daytime 
functioning, how noticeable sleep problems are to others, distress caused by 

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problematic sleep and overall sleep satisfaction. Total scores range from 0 to 28, with 
higher scores indicating greater severity. 
• EuroQol (EQ-5D) is a generic QoL instrument designed for self-administration. The 
result could be expressed as a weight with values between zero and one (0-1). 
Together with information about survival the QoL weight can be expressed as quality-
adjusted life-years (QALYs). EQ-5D is a validated instrument available in many 
different languages. The instrument is frequently used in a variety of diagnoses in both 
Swedish and international studies which makes comparisons across studies and patient 
populations possible. 
• During radiotherapy, daily reported symptoms will be investigated by a newly 
developed symptom scale, Radiotherapy related symptom assessment scale (RSAS). 
The questionnaire includes 13 items specific for current diagnose. The RSAS is a 
validated instrument for assessing symptom intensity and distress in patients with 
different cancer disease undergoing radiotherapy, with psychometric properties within 
the expected range. Answering categories ranges from not at all to a great deal (1-4). 
 
14 Cost-utility analysis 
A health-economic evaluation of interventions could provide important information to aid 
decision making in health care. The evaluation is a tool to assess the benefits and 
consequences and costs of different treatment options. 
 
Since quality of life is a central issue in the present study, a cost-utility analysis is most 
appropriate, i.e. costs and quality of life as well as clinical outcome measured as survival time 
will be considered. The results of the health-economic part of the study will be expressed as 
cost per quality adjusted life years (QALYs) saved of one intervention in comparison with the 
other. 
 
According to Swedish guidelines for health-economic studies the analysis should be 
performed from a societal perspective, i.e. all relevant costs irrespectively of where they occur 
should be identified, quantified, and valued. A societal perspective includes indirect costs, i.e. 
costs related to loss of production when patients cannot work due to their disease.  
Specifically, not only the costs of the two interventions will be assessed but all type of 
resources associated with the two treatment arms during the total follow-up time should be 
considered. That includes, e.g. costs for treatment of side-effects, costs for surgery when 
performed, and travelling costs for patients. Costing will be performed at the end of the study. 
For evaluation and analysis of the study results, a relatively simple health-economic model 
will be developed. This model will be used for evaluation of the two treatment arms from 
inclusion into the study until 5 years of follow up or death 
 
15 Statistical plan 
15.1 Sample size determination 
Based on previous reports of acute side effects from photon therapy, (Mauch et al. 1995, Mell 
et al. 2008, Franco et al 2016), in silico planning during study preparation, and current 
knowledge about acute and late side effects after VMAT treatment in this patient group we 
assume that acute bone marrow side effects will decrease with proton therapy. The 
assumption is that we the conventionally treated patients will have at least 50% risk of grade 3 
or higher haematological toxicity. With proton therapy the corresponding toxicity is assumed 
to be reduced to 20%. If these proportions are assumed, based on Fishers exact test with two-

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sided level of significance of 0.05 and an allocation of 1:1 between control and interventions 
groups, 100 randomised and evaluable patients will give the statistical power of 0.85. It is 
assumed that a proportion of patients will be unevaluable due to e.g. withdrawal of consent or 
inability to complete the treatment. For that reason a maximum number of 120 patients will be 
randomised. If 100 evaluable patients complete the treatment before 120 are randomised, the 
randomisation will close. 
 
The statistical power may potentially be increase for several secondary end points when 
combinations of side effects and patient reported outcomes are taken into consideration.  
Other end points (e.g. bowel, skin or urinary side effects) are less studied and the magnitude 
of the effects are less predictable. However, it is planned to investigate possible shifts in the 
distribution of side-effect grades between the two treatments, which may strengthen the 
inference. 
 
15.2 Statistical methods 
Stratification will be made for sex, HPV/p16 positivity and colostomy before treatment start. 
Primary end points will be analysed using the Fishers exact test for inference of proportions. 
Shifts in distributions of side effects will be analysed by using the Mann-Whitney U-test, in 
this test the stratification is not used. For efficacy analysis, survival curves will be computed 
using both the Kaplan-Meier and the Breslow method. Cumulative incidence of failure of 
locoregional control together with mortality will be performed. Cox regression analysis 
adjusted for all eligible covariates will be applied for efficacy analyses. For failure of 
locoregional control, Fine-Gray regression will also be considered. . Baseline data will be 
tabulated and illustrated graphically if appropriate. 
 
The analyses will be based on received treatment and will include eligible patients, but 
analyses will also be performed on the intention-to-treat analysis set (see below). Every effort 
will be made to collect survival data on subjects, including subjects withdrawn from treatment 
for any reason, who are eligible to participate in the study and who have not withdrawn 
consent for survival data collection. OS is defined for each patient as the time between 
randomization date and death. If a patient has not expired, the patient will be censored at the 
time of last contact (last known alive date). Loco-regional failure will also be analysed by 
methods accounting for death as acompeting risk. DFS is defined for each patient as the time 
between randomisation and the time of first recurrence, locoregional, systemic or death. If a 
patient has residual disease after treatment, the time of recurrence will be defined as end of 
radiotherapy. 
 
The analyses will be made according to stratification and/or a combination of stratification 
and other adjustments.  
 
15.3 Subject populations(s) for analysis 
Intention to treat population: All correctly randomised and included patients.  
Protocol-compliant population: Patients that have started the assigned study treatment . 
 
16 Reporting of adverse events 
16.1 Definition 
Safety will be reported as adverse events as per ICH-GCP.  
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product (or receiving a treatment) and 

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which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavourable and unintended sign (such as rash), symptom (such as nausea 
or pain), laboratory finding, or disease temporally associated with the use of a medicinal 
(investigational) product (or a treatment), whether or not related to the medicinal 
(investigational) product. 
A Serious Adverse Event (SAE) is an adverse event that: 
• results in death, 
• is life-threatening, 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
or 
• is a congenital anomaly/birth defect 
 
16.2 Reporting procedure 
Side effects related to given treatment should be reported and graded according to CTCAE 
v5.0 using CTC terminology and noted in the eCRF. Adverse events clearly associated to 
disease progression should not be reported as AE, however, if there is any uncertainty 
regarding the attribution of the malignancy under study to an AE, it should be reported. 
 
Hospitalization due to investigations or planned surgical procedures should not be classified 
as SAEs. Hospitalization due to pain, GI symptoms, need of nutritional support or infections, 
which is regarded as expected and common side effects during chemo and radiotherapy of AC 
patients, should not be classified as SAEs.  
 
• All SAEs during the study must be reported to the sponsor within 24 hours after 
notification by the study personnel using provided SAE-forms 
• SAEs will be reported until 30 days after completion of radiotherapy. 
 
17 Quality assurance 
For quality assurance of radiotherapy, see above. 
 
17.1 Control of data consistency 
All patients included in the study are identified by the patient identification number. 
Identification code lists that links patients’ names to the patients’ identification number must 
be stored in the Investigator File.  
Study data will be recorded via electronic Case Report Forms (eCRF). Study data may be 
recorded directly into the eCRF, i.e. the eCRF may be the source data, or be transcribed by 
the site from the paper source documents onto the eCRF according to the local source-data 
list. Prior to study start, the Investigator and the Monitor must identify and document the 
expected source location of every CRF data. Expected source locations are for example the 
subject’s medical record, laboratory reports and the CRF itself.  
Accurate and reliable data collection will be assured by verification of the eCRF against the 
investigator’s records and medical records by a study monitor, as well as study integrity, 
compliance with the protocol and applicable regulations. 
 
17.2 Site monitoring 
In consistency with the principles of ICH-GCP, the sponsor takes responsibility for 
monitoring of the study. As external monitor for the study each treatment centre will appoint a 
research nurse, or equivalent, not involved in any aspects of the study. The external monitor 

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should be experienced in clinical trials and monitoring. The site monitoring reports will be 
sent to the Data Centre for further evaluation. 
During the study, there will be regular contacts with the study sites, including on-site visits in 
order to ensure that the study is conducted and documented properly in compliance with the 
protocol, ICH-GCP and applicable regulatory requirements. 
The trial will be monitored consistent with the demands of the trial and site activity to verify 
that the: 
• Data are authentic, accurate, and complete 
• Safety and rights of subjects are being protected 
• Trial is conducted in accordance with the currently approved protocol and any other 
trial agreements, ICH-GCP and all applicable regulatory requirements. 
 
17.3 Legal aspects 
Investigators of participating centres agree to co-operate with any quality assurance visit 
undertaken by third parties.  
The study will be performed according to ICH-GCP guidelines and after approval of the 
Swedish Ethical Review Authority. Changes in the protocol must be communicated with the 
Swedish Ethical Review Authority. 
 
17.4 Direct access to data/documents 
The sponsor has the responsibility to maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently verified. 
Investigators files and subjects clinical source documents must be kept for at least 10 years 
after completion or discontinuation of the study. 
 
18 Data management 
18.1 Patient registration/randomisation procedure 
Subject eligibility will be established before treatment randomisation. Subjects will be 
randomised strictly sequentially, as subjects are eligible for enrolment/randomisation.  
If a subject discontinues from the study, the subject number will not be reused, and the subject 
will not be allowed to re-enter the study.  
The randomisation list will be created by an independent statistician at RCC Norr. When a 
patient is found to be eligible and has signed a written informed consent, randomisation will 
be performed electronically.  
 
18.2 Case report forms 
Study data will be recorded via the eCRF. During study treatment the eCRF should be filled 
in weekly, and after completion of treatment the eCRF should be filled in at each time point 
for follow-up.  
The investigator at the enrolling site is responsible for collection of source data if patient 
visits are decentralized to other clinics. 
 
18.3 Quality of life forms and Questionnaires 
Questionnaires will be administered to the subjects as described in sections above. The 
questionnaires will be sent directly to the subjects or to the participating centres by the Proton 
Care Study group in order to be forwarded to the patient. The questionnaires will be enclosed 
with postage-paid, pre-addressed envelopes to be returned by the patient directly to the Proton 

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Care study group. Proton Care are responsible for entering the answers of the questionnaires 
into their specific data base. 
 
19 Ethical considerations 
19.1 Patient protection 
The study is to be performed in accordance with the ethical recommendations of the Helsinki 
declaration and the ICH-GCP guidelines, or the laws and regulations of the country, 
whichever provides the greatest protection of the patient. 
 
19.2 Patient integrity 
The investigator must assure that the patient’s anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents collected in 
this study patients will only be identified by their identification code, year and date of birth. 
 
19.3 Informed consent 
All subjects will receive written and oral information about the aims of the study, possible 
hazards, and the mechanism of treatment allocation. They will be informed about the strict 
confidentiality of their patient data, but that their medical records may be reviewed for trial 
purposes by authorized individuals other than their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to 
decline further participation whenever he/she wants. If the patient wishes to withdraw from 
the study, he or she will be offered the standard treatment at the clinic. 
A signed, informed consent must be obtained from the patient before study entry. In the cases 
were the patient declines to participate in the study the conventional treatment according to 
local practice should be offered. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information, given a copy of the revised 
form and give their consent to continue in the study. 
 
19.4 Independent ethical review  
This protocol and any accompanying material provided to the patient, such as written patient 
information used to obtain informed consent, will be submitted by the investigator to the 
Swedish Ethical Review Authority. Approval from the authority must be obtained before 
starting the study and should be documented in a letter to the investigator specifying the date 
on which the authority granted the approval. 
 
19.5 Risk benefit analysis 
Patients with AC have a good prognosis with standard treatment consisting of radiotherapy 
delivered with photons combined with chemotherapy. Proton therapy has been performed for 
more than 20 years in many countries, and although there are no studies directly comparing 
photon and proton treatment in this patient group, there are no indications that treatment 
results should be inferior with proton therapy. In silico studies suggest that side effects will be 
reduced with proton therapy.  
Benefit for patients included in the study is thorough surveillance during and after treatment 
and guarantee of high-quality radiotherapy. Benefit for the patient group is enhanced 
knowledge about the treatments in the study. 
The Skandion clinic is situated in Uppsala, which means that some patients receiving proton 
therapy will have to travel longer distances and spend more time away from home during 

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their treatment period. However, this is often the case for patients not included in this study 
since AC therapy is centralised to four Swedish hospitals. Travelling expenses for the patients 
will be reimbursed according to the routines at each treatment centre. 
The patients in the study are covered by the Swedish Patient Insurance. 
 
20 Participating centres 
The four Swedish hospitals engaged in the treatment of AC patients will be invited to take 
part in the study.  
Each centre must expect to include a minimum of 5 patients per year. If a centre includes less 
than 2 patients per year, that centre should be considered for closing. Previously included 
patients will then be followed according to the protocol, but no further inclusion is accepted 
from that centre. 
Centres from other European countries may be accepted as participants in the study as 
decided by the study group. 
 
21 Ownership of data 
The data are owned by the Study Group consisting of the investigators at the participating 
centres. The patient material of the individual centre cannot be extracted for publications to 
answer the questions of this study. Future research projects utilising data from the present 
study must be approved by the Study Group. 
Data collected using questionnaires by ProtonCare is regulated per a separate agreement. 
ProtonCare remains responsible for safe keeping the data collected under their supervision. 
The agreement regulates data sharing between the Study Group and ProtonCare during and 
after this study   
 
21.1 Meetings 
Regular meetings with representatives from all participating centres (Study Group) will be 
held once per year or when considered necessary. The Study Steering Committee will also 
have separate regular meetings. In the time between Study Group meetings, the members of 
the Study Steering Committee shall act as contact persons and will have an executive role. 
Decisions taken shall be discussed at the meetings of the Study Group. The Study Steering 
Committee shall prepare and arrange the meetings of the Study Group. 
The Study Group will invite a pre-selected member from the Proton Care study Group at each 
meeting as regulated in a separate agreement.  
 
21.2 Reporting 
All presentations of data from the study should only be made after agreement within the 
Study Group. The results of the study will be submitted to an internationally recognized 
scientific medical journal. Apart from the Study Group, each participating centre with at least 
10 patients included will be guaranteed co-authorship for one person. In addition to this, 
persons with special responsibilities within the study may become co-authors. The Vancouver 
declaration will be followed in all publications based on this study. See also separate 
agreement between the Study Group and Proton Care study group regarding data 
responsibilities and publication rights. 
 

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22 Flow chart of study procedures 
Flow chart for patient reported data is presented in Addendum 5 
 
* Blood samples to be taken once weekly up to 3 weeks. 
** Only week 4 
*** Photography only for local use as reference, to be stored in patient clinical records. 
 
 
Baseline Weekly 
during RT 
and at 
treatment 
completion 
1, 2 and 3 w  
After 
treatment 
1-2 
months 
after 
treatment 
4-6 
months 
after 
treatment 
Every 
3 
months 
for 2 
years 
 
Every 
6 
months 
until 5 
years 
 
End of 
study at 5 
year or 
prematurely 
Physical examination 
(physician/registered nurse) 
X 
X 
 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
Performance status (ECOG) 
X 
 
 
X 
X 
X 
 
X 
Length, weight 
X 
weight 
 
weight 
weight 
weight 
weight 
weight 
Biopsy including p16 analysis 
X 
 
 
 
 
 
 
 
Haematology (Hb, WBC differential, ANC, 
platelets) 
 
X 
X 
X * 
X 
X 
As 
needed 
 
 
Blood Chemistry (Bilirubin, ALP, ALAT, ASAT, 
creatinine, Na, K, Ca, albumin and Mg)  
X 
X** 
 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Side effects and adverse events 
X 
X 
 
X 
X 
X 
X 
X 
*** Photography (optional) 
X 
X 
 
X 
 
 
 
 
Tumour control (including measures if applicable) 
 
 
 
 
X 
X 
X 
X 
Biopsy + MRI+PET/CT if recurrence 
 
 
 
 
X 
X 
X 
X 
Questionnaires  
According to Addendum 5 

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23 References 
 
Jadon R, Higgins E, Hanna L, Evans M, Coles B, Staffurth J. A systematic review of dose-
volume predictors and constraints for late bowel toxicity following pelvic radiotherapy. 
Radiat Oncol. 2019;14:57. 
Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, 
Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on 
dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010;76(3 
Suppl):S155-60.  
Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, Miften M. Radiation 
dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76(3 
Suppl):S101-7. 
Devisetty K, Mell LK, Salama JK, Schomas DA, Miller RC, Jani AB, Roeske JC, Aydogan 
B, Chmura SJ. A multi-institutional acute gastrointestinal toxicity analysis of anal cancer 
patients treated with concurrent intensity-modulated radiation therapy (IMRT) and 
chemotherapy. Radiother Oncol. 2009;93:298-301. 
Franco P, Ragona R, Arcadipane F, Mistrangelo M, Cassoni P, Rondi N, Morino M, Racca P, 
Ricardi U. Lumbar-sacral bone marrow dose modeling for acute hematological toxicity in 
anal cancer patients treated with concurrent chemo-radiation. Med Oncol. 2016;33:137.  
Bazan JG, Luxton G, Mok EC, Koong AC, Chang DT. Normal tissue complication 
probability modeling of acute hematologic toxicity in patients treated with intensity-
modulated radiation therapy for squamous cell carcinoma of the anal canal. Int J Radiat Oncol 
Biol Phys. 2012;84:700-6.  
Mell LK, Schomas DA, Salama JK, Devisetty K, Aydogan B, Miller RC, Jani AB, Kindler 
HL, Mundt AJ, Roeske JC, Chmura SJ. Association between bone marrow dosimetric 
parameters and acute hematologic toxicity in anal cancer patients treated with concurrent 
chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 
2008;70:1431-7. 
Mauch P, Constine L, Greenberger J, Knospe W, Sullivan J,Liesveld JL, et al. Hematopoietic 
stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J 
Radiat Oncol Biol Phys. 1995;31:1319–39. 
Ellis RE. The distribution of active bone marrow in the adult. Phys Med Biol. 1961;5:255–8. 
Glynne-Jones R, Adams R, Lopes A, Meadows H. Clinical endpoints in trials of 
chemoradiation for patients with anal cancer. Lancet Oncol. 2017;18:e218-e227. 
Pocock. Clinical Trials - A Practional Approach: Wiley, New York; 1983 
RCC (Regionala cancercentrum i samverkan). Analcancer – Nationellt vårdprogram. 
https://www.cancercentrum.se/samverkan/cancerdiagnoser/tjocktarm-andtarm-och-
anal/anal/vardprogram: 2017;Version1.0 
 
 

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Addendum 1 - Organs at risk 
 
The following organs at risk must always be delineated: 
• Urinary bladder 
• Intestine (operationalised by the volume named “Bowel bag”) 
• Skin 
• Z_Skin 
• Pelvic bone marrow  
• Femoral heads 
• Genitals 
 
 
Delineation Guidelines 
 
Urinary bladder 
The outer wall of the bladder is contoured as it appears on 
treatment-planning CT 
Bowel bag 
The bowel bag is contoured superiorly from 1.5 above the most 
superior part of the PTV. Anteriorly to the inside of the abdominal 
wall. Laterally, it is delineated from bowel edge to bowel edge. The 
posterior limit is the most posterior bowel edge. The most inferior 
limit includes the most inferior bowel that is not rectum or 
rectosigmoid junction (Devisetty et al. 2009) 
 
Skin 
The skin should be delineated from 1 to 5 mm depth inside the 
patient (structure Body), i.e. have a thickness of 4 mm, and cover 
at least all the irradiated patient surface. 
Z_Skin  
should be based on the Skin structure, but exclude all intersecting 
CTV volumes, including and margin of 9 mm. 
Pelvic bone marrow 
The external contour of the PBM is delineated on the planning CT 
using bone windows. Pelvic BM is divided into three subsites: (1) 
iliac BM (IBM), extending from the iliac crests to the superior 
border of the femoral head, (2) lower pelvis (LP), consisting of the 
pubes, ischia, acetabula, and proximal femora, extending from the 
superior border of the femoral heads to the inferior border of the 
ischial tuberosities, and (3) lumbosacral spine (LS), extending 
from the superior border of the L5 vertebral body to the coccyx but 
not extending below the superior border of the femoral head. (Mell 
et al.2008). 
Femoral heads 
Femoral heads as they appear on CT 
Genitals 
Males: Penis and testes. Penis and testes are defined separately 
(since testes have a dose restriction)  
Females: Clitoris, major and minor labiae defined as a single 
volume. 
 
 

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Addendum 2 - Radiotherapy QA reporting 
Radiotherapy related data should be collected and reported by each centre for every patient 
and transferred to the QA-centre. The data transfer is handled through the Sharefile service 
provided by Skandionkliniken (https://skandionibasa.sharefile.eu/). Each participating centre 
has access to a Sharefile folder named “SWANCA NNN”, where NNN is the name of the 
centre. 
 
Sharefile reporting 
For each patient a subdirectory to “SWANCA XX” should be created and named “XX-YYY”, 
where XX-YYY is the patient number (XX identifies each participating centre and YYY is a 
running patient number). 
• 
From the TPS, DICOM export and save under the directory “XX-YYY”: 
o CT-images 
o Structures 
o Treatment plan 
o Total dose distribution (in Gy) in DICOM-RT format 
o co-registered MR or PET images, when applicable 
• 
Create a document (Word, Excel, Text or pdf) stating the date of the first and the last 
treatment fraction. Name the file “XX-YYY history” and save it under the directory 
“XX-YYY”. 
  
Data to RT-QA office 
  
Notify the RT-QA office that patient data has been uploaded by sending an e-mail to or call: 
Michael Blomquist, Medical physicist 
E-mail: michael.blomquist@regionvasterbotten.se 
  
Phone: +46 (0)90 785 8460 
  
 

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Addendum 3 - Dosreduktionsschema för radio-kemoterapi av 
analcancer från Akademiska sjukhuset, Uppsala 
 
Dosreduktion Mitomycin ej aktuellt inför Dag 1. 
  
Dosreduktion Capecitabin: 
Tox grad 
0 Neutrofila >= 2.0 TPK >= 100 ges Capecitabin 100% 
1 Neutrofila >= 1.5-< 2.0 TPK >= 75-< 100 ges Capecitabin 100% 
2 Neutrofila >= 1.0-< 1.5 TPK >= 50-< 75 ges Capecitabin 75% 
3 Neutrofila >=  0.5-< 1.0 TPK >= 10-< 50 Uppehåll tills återhämtning 
4 Neutrofila < 0.5 TPK <10 Uppehåll tills återhämtning 
Dosreduktion för patienter med sänkt kreaclearence <50 ml/min enl. FASS.  
  
Dosreduktion Diarreér: 
 
Tox grad 0,   
Ingen diarré, och ingen ökning av avf.frekvens, ges Capecitabin 100%, Strålbehandling- 
Fortsätt 
 
Tox grad 1, 
< 4 avföringar per dag, ges Capecitabin 100%, Strålbehandling- Fortsätt 
 
Tox grad 2,  
4-6 avföringar per dag, eller måttliga kramper , Strålbehandling- Fortsätt (1,2,och 3;e gången) 
och administrera Loperamid 
Uppehåll tills grad <= 1, sen 
1 gången: ges Capecitabin 100% 
2 gången: ges Capecitabin 75% 
3 gången: ges Capecitabin 50% 
 
Tox grad 3 
7-9 avföringar per dag eller inkontinens (om pat var kontinent före beh), eller svåra kramper 
Uppehåll tills grad <= 1, sen 
Strålbehandling- Uppehåll tills diarrén är grad <= 2 
1 gången: ges Capecitabin 75% 
2 gången: ges Capecitabin 50% 
 
Tox grad4 
>=10 avföringar per dag, eller melena eller behov av parenteral support.- Avbryt 
Capecitabinbeh. 
Strålbehandling- Avbryt tills diarrén är <= grad 2 (om det tar > 2 veckor ska strålbeh. 
avbrytas permanent) 
 
 

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Addendum 4 – Photography 
 
The perineal area should, if possible, be documented by a digital photo weekly during 
radiotherapy and further at the scheduled physical examinations thereafter. The purpose is 
to document the external tumour component and the skin reaction in short and long terms. 
  
1. The choice of camera is free but it should, if practically possible, be the same 
camera for all patients at the same clinic. 
2. A ruler should be included in the images 
3. The images are stored in the patient’s clinical records. 
 

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Addendum 5 - Flow chart of Patient Reported Data 
 
 
 
RT = Radiation Therapy  
w = weeks 
EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
EORTC QLQ-ANL27= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (diagnos specific) 
MFI-20 = Multidimensional Fatigue Inventory  
ISI = Insomnia Severity Index 
HAD = Hospital Anxeity and Despression Scale 
EQ5D = EuroQol 
RSAS = Radiotherapy Related Symptoms Assessment Scale 
 
 
 
 
Questionnaire Baseline – 
prior RT 
treatment 
start 
Daily 
during RT 
treatment 
3 w - after 
RT 
treatment 
start 
End of 
treatment 
1 
month 
3 
months 
6 
months 
 
9  
months 
12 
months 
 
24 
months 
36 
months 
60 
months 
QLQ-C30 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QLQ – ANL27 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MFI-20 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAD 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISI 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ5D 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RSAS 
 
X 
 
 
 
 
 
 
 
 
 
 

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Addendum 6 – Skin Care Guidelines  
Below information is an excerpt from addendum 5 and 6 from the document “Analcancer – 
Specific Omvårdnad vid strålbehandling” version 1.0 date 1880409 issued by Skånes 
Universitetssjukhus, VO Hematologi, onkologi, och strålningsfysik. 
 
The text below is intended to serve as a guideline in caring for radiated skin in the study. 
 
 
 
 
 
 
 
 
 

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Addendum 7 – Skandion Patient position and immobilisation 
 
 
20140701 
 
 
 
Fixationsmall Bäcken 
UserOrigin i lasermarkering i patienten 
 
Observera att Skandions fixeringsrutiner inte tillåter någon madrass under patienten. 
 
Dessa fixationer kan fästas i bordet med indexeringspinne (Lock-bar) och positionerna anges 
i mallen. 
Indexering Bord: Klicka här för att ange text. 
 
Nackkudde Civco:Välj ett objekt. 
 
Civco Kneefix 3: ☐ 
Civco Elevation Block: ☐ 
Civco Feetfix 3: ☐ 
Scanflex Armstrap: 
Armstrap 60: ☐ 
Armstrap 70: ☐ 
 
Civco Rectangle: ☐ 
Civco Head Support: ☐ 
 
 
Övriga upplysningar: Klicka här för att ange text. 
 
 
 
 
 
 
 
 
OBS Nyhet 2020-02-12 
Information om position av referenspunkt - se nästa sida! 

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Positioner som anges nedan underlättar bedömning av behov av bordsförlängning samt 
gör andra simuleringar av behandlingen möjliga innan patienten kommer till 
Skandionkliniken. 
 
 
 
 
Ange: 
 
Ttref (cm): Klicka här för att ange text. 
 
BI (ovanför Refpunkt (CT)): Klicka här för att ange text. 
 
U (cm): Klicka här för att ange text.