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Cover page Title:
Individual Follow-up afee eetal Caneee - Foeus on the Needs of the Patent (FU CA)
[NCT-number not assigned yet] Date: 07 February 2016 1
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content

| 1 Introduction                                                                                                                               |
|----------------------------------------------------------------------------------------------------------------------------------------------|
| 1.1 Objectives                                                                                                                               |
| 2 Hypotheses                                                                                                                                 |
| 3 Material and methods                                                                                                                       |
| 3.1 Patients                                                                                                                                 |
| 3.2 Inclusion                                                                                                                                |
| 3 Randomisation                                                                                                                              |
| 3.4 Data                                                                                                                                     |
| 3.5 Patient reported outcome measures PROM's                                                                                                 |
| 4 Organisation and time schedule...........................................................................................................6 |
| 5 Funding.                                                                                                                                   |
| 6 Ethics                                                                                                                                     |
| 7 Publishing strategy                                                                                                                        |
| 8 Perspectives                                                                                                                               |
| 9 Literature list                                                                                                                            |
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1 inteodueton

Colorectal cancer is the third most common cancer worldwide. Rectal cancer amounts for about one third of colorectal cancers, with a small male predominance (1,2). A total of 1674 new rectal cancer patents (62 ,1 % males) were diagnosed in Denmark in 2014 (3). The oierall 5-year suriiial rate is 62 %, although mortality is decreasing due to improiement in treatment (3). Among the patents undergoing treatment with a curatie intent, the standard treatment is surgery. The two predominant resectonal techniques in Europe are abdomino-perineal resecton (APR) and low anterior resecton (LAR). APR leaies the patent with a permanent stoma, while LAR is a sphincter-sparing procedure that restores bowel contnuity. Surgery is in some cases combined with pre- and/or postoperatie chemo-radiotherapy (4,5). The risk of local recurrence afer rectal cancer has been estmated to 7-9 % and possibly lowers with the additon of preoperatie radiotherapy and improied surgery techniques. Local recurrence is a seiere conditon, and markedly increases mortality (6,7). It is therefore crucial to identfy these indiiiduals at a iery early stage. Most local recurrenses occur within the frst three years past diagnosis, and 65-70 % of the cases will present clinical symptoms (rectal bleeding, pain, sudden change in bowel functon, weight loss). In other cases, the recurrence is asymptomatc (8-10). A large proporton of rectal cancer patents sufer from seiere physical and psychological adierse efects from treatment . Recent studies haie shown that almost half of the LAR patents sufer from seiere bowel dysfuncton one year afer their operaton (11,12). The symptoms consist of fecal/gas incontnence, fecal urgency, frequent bowel moiements and fragmentaton/clustering of stools, which collectiely is referred to as "the low anterior resecton syndrome" - or LARS . Other physical adierse efects from the treatment can be urinary dysfuncton, sexual dysfuncton, pain and fatgue (13-15). Psychological distress and fear of recurrence are known psychological adierse efects following treatment for rectal cancer (8,16). All of which, can infuence negatiely on the patents' symptom burden, eieryday functoning and quality of life (17,18). The follow-up regimen currently ofered to Danish rectal cancer patents is rigidly constructed with standardised controls in the outpatent clinic, has a low leiel of patent inioliement and is based on a poor leiel of eiidence. The primary focus is detecton of local recurrence and methastases. The follow-up regimen consists of rectoscopy and clinical control 6,12,18,24 and 36 months afer surgery (APRpatents receiie less clinical controls and no rectoscopies). Furthermore, a CT-scan of the thorax and abdomen is performed one and three years postoperatiely and a colonoscopy is ofered eiery ffh year untl the age of 75 (19). There is some eiidence that frequent follow-up to detect distant methastases reduces mortality, but eiidence on the efect from frequent routne controls and endoscopies on detectng local recurrences, and the general methodology of follow up programmes is scarce (20,21). Thus, a large number of Danish patents are each year enrolled in comprehensiie follow up programs based on dubious leiels of eiidence. Based on seieral years of clinical experience we know that the specifc needs afer rectal cancer surgery difer substantally from patent to patent. Patents and clinicians request more patent-centred follow up, also focusing on physiological and psychological aspects - in combinaton with monitoring potental recurrence of the cancer (20,22).  
The Danish Health Authorites recommend a more indiiidualised follow-up, in order to detect both recurring cancers and to treat the adierse efects of rectal cancer surgery (20). As a new alternatie we propose a patent-led follow-up program with a higher degree of patent inioliement. The patent-led follow-up programme is based on a standardized educaton program in order to enforce the patents' ability to assess and respond sufciently to symptoms and health problems, by consultng a health professional for adequate assistance and interienton.  
Patent educaton, supportng the patents' self-efcacy and health literacy, together with standardised and eiidence based response algorithms to self-referrals form the basis for patent-led follow-up program.
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1.1 objeetves

This project aims at improiing the follow-up program afer rectal cancer by: 1. Deieloping and implementng a new patent led follow-up program, based on patent educaton and inioliement, and self-referral by direct access to project nurse 2. Examining the efect of the new follow-up program on symptom burden and health related quality of life 3. Examining the efect of the new follow-up program on specifc physiological and psychological symptoms and late adierse efects from treatment, eient-free suriiial, patent experienced satsfacton, informaton and inioliement 4. Eialuatng cost-efectieness of the new follow-up program
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2 hypotheses

We hypothesize, that early identfcaton and treatment of late adierse efects afer rectal cancer surgery, and earlier detecton of local recurrence is possible if the patents are empowered to actiely play a role in their own care pathway. This, by means of the new patent-led follow-up programme, based on standardised educaton and thorough patent informaton regarding releiant symptoms, patents' access to direct self-referral to an afliated nurse, and standardised response algorithms to patent reported data. We belieie that this will reduce the symptom burden from physical and psychological symptoms and greatly improie the quality of life of each indiiidual patent. And that this new follow-up program will improie other patent-reported outcomes such as patent satsfacton, patent inioliement and informaton. Furthermore, we hypothesise that the patent led follow-up program will lead to earlier detecton and treatment of local recurrences, although no efect on oierall suriiial is expected. We expect that the new program will optmise the use of economic resources.
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3 mateeial and methods

The study will be designed as a multcentre randomized controlled trial, with follow-up in three years (see Figure 1)
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3.1 patents

Colorectal surgical departments in Aarhus, Randers, Herning and Aalborg will be iniited to partcipate. These centres coier one third of all Danish rectal cancer patents (556 out of 1675 rectal cancers in 2014= 33 %) (3). Inclusion criteria: Adult patents operated for a primary adenocarcinoma in the rectum (0-15 cm from the anal ierge), with pathology results showing R0/R1 resecton - thus treatment with curatie intent. The patents must be able to read, speak and understand the Danish language and must not sufer from mental dementa or other mental disorders afectng cognitie functons. Moreoier, writen informed consent is required from all partcipants. Patents treated with local excision of the tumour (without resecton of the rectum) are excluded, and likewise if the pathology shows non-radical resecton (R2) or known malignant methastases. Residual life expectancy less than two years and synchronous cancer will lead to exclusion, as will concurrent partcipaton in other research studies with contacts in the follow up periode. Loss to follow-up will be registered as ierifed recurrence, death, emigraton from the partcipatng regions or if a patent requests to interrupt partcipaton. The three partcipatng centres operate about 550 rectal cancer patents each year and taking the in- and exclusion in regard, this leaies about 330 eligible patents each year. An estmaton of samplesize shows, that a total of 334 partcipants are needed in order to obtain statstcally signifcant results (p0.0.05).
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3.2 inelusion

Patents will be approached at the postoperatie iisit in the outpatent clinic where they are presented for the pathology results from the surgery, approximately 2 weeks afer the operaton. The doctor will proiide short oral informaton about the study and hand out writen informaton. A research nurse will contact the patent by telephone a few days later, to help the patent deciding whether or not to partcipate. If the patent agrees to partcipate, the research nurse will collect informed writen consent and baseline informaton from the partcipants before randomisaton. Patents, receiiing postoperatie chemotherapy, will be contacted by the research nurse afer ended treatment.
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3.3 andomisaton

Partcipants are randomised into A) an interienton group, where patents will receiie standardised educaton, and are encouraged to contact the assigned project nurse if they experience symptoms of adierse efects or cancer recurrence a control group, and B) following the current FU-programme with routne check-ups. Follow-up tme in both groups is 3 years. Non-partcipants are asked to complete a baseline questonnaire similar to the one partcipants fll in. The block-randomizaton is set op to stratfy by centre, sex and treatment type (+/- postoperatie oncological treatment and +/- temporary illeal stoma)
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geoup a

The interienton groups, following the patent-led follow-up programme will not atend regular iisits in the outpatent clinic. They will receiie structured educaton by a nurse regarding early signs of recurrence of the cancer and symptoms of adierse efects, and how to respond adequately. The educaton will be performed by the afliated research nurse, and based on a protocolled manual. The educaton is supported by a website proiiding more detailed informaton on the symptoms and adierse efects. The website is exclusiie for the patents in the interienton group. Methods and content for the patent educaton is deieloped by the group of afliated research nurses. Patents are iniolied in the process, by means of two focus group interiiews. Partcipants will be instructed to approach the research nurse in case of symptoms and are informed of the necessity of contactng the research nurse immediately in case of pre-defned alarm symptoms (self-referral). The research nurse will respond to patent's self-referral according to a pre-defned, standardised response-algorithm. The algorithm is deieloped in close cooperaton between partcipatng health professionals, and representaties from other specialites and the primary sector. Patents can contact the research nurse by telephone and e-mail on a daily basis. The patents will haie a CT scan afer 12 and 36 months, and a colonoscopy with fie years interial untl the age of 75.
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geoup b

The control group will follow regular iisits with a doctor in the outpatent clinic (+ rectoscopy) at 6, 12, 18, 24 and 36 months postoperatiely, haie a CEA-test and a CT scan afer 12 and 36 months, and a colonoscopy with fie years interial untl the age of 75.
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3.4 data outcomes

A Symptom burden and health related quality of life, together with late adierse efects from rectal cancer surgery: bowel dysfuncton, urinary and sexual dysfuncton, pain, fatgue, fear of recurrence, anxiety and depression B Self-efcacy and patent actiaton, patentnioliement, and patent's experience of informaton and sense of security. C QALY's D Time to recurrence, 3- year suriiial Most data will be collected using patent reported outcome measures (PROM's). Patents are asked to complete a questonnaire at baseline (tme of inclusion), 12 and 36 months postoperatiely. The questonnaire will focus on symptom burden and quality of life, specifc symptoms, patent actiaton and self-efcacy, patent inioliement and informaton, needs in the follow-up period and how they haie been handled. Data regarding recurrence of cancer, mortality and socioeconomic factors will be extracted from natonal registers. While data on comorbidity is extracted from the natonal clinical database for colorectal cancer surgery. Data on health care utlisaton in the follow-up period will be collected from natonal registers, in combinaton with informaton from patent records (limited access).  
3.5 Patent eepoeted outeome measuees P OM's 1. **Symptom bueden:** 'Functonal Assessment of Cancer Treatment - Colorectal' (FACT-C).  
36 items 2. **Bowel funeton**: Patents without a stoma: 'Low Anterior Resecton Syndrome Score'
(LARS) and Bristol Stool Scale (together 7 items). Patents with a stoma: The Colostomy bother score. 8 items 3. **Ueinaey funeton**: 'Male/Female Lower Urinary Tract Symptoms' (ICIQ-MFLUTS/ICIQFLUTS). 12 and 13 items respectiely 4. **Sexual funeton, female**: 'The sexual functon - Vaginal Changes Questonnaire' (SVQ). 27 items/17 items (shortorm) Sexual funeton, male: 'Internatonal Index for Erectle Functon' (IIEF). 15 items/5 items (shortorm)
5. **Pain**: 'Brief Pain Inientory Short Form' (BPI). 15 items 6. **Fatgue**: The Multdimensional Fatgue Inientory (MFI). 20 items 7. **Feae of eeueeenee**: 'Fear of Cancer Recurrence Inientory' (FCRI). 43 items 8. **Psyehologieal disteess: '**Hospital Anxiety and Depression Scale' (HADS). 14 items. 9. **Quality of Life**: 'EuroQol 5-dimensional health state measure' (EQ-5D). 5 items (+ VAS) 10. **Self-effieaey:** 'Patent Actiaton Measure' (PAM). 13 items 11. **Patent involvement, infoematon and sense of seeueity:** Combinaton of two Danish questonnaires. 11 items 12. **Peesonality:** 'Life orientaton test-reiised' (LOT-R). 10 items 4 Oeganisaton and tme sehedule The head doctors in four surgical departments in two Danish regions haie agreed to partcipate in the study:
Mogens Rørbæk Madsen, Head of Surgical Department, Hospitalsenheden Vest, Regionshospitalet Herning.  
Inge Bernstein, Head of Surgical Department, FBE Kirurgi Syd, Aalborg Uniiersitetshospital.  
Knud Thygesen, Head of Surgical Department P, Aarhus Uniiersity Hospital.  
Lars Maagaard Andersen, Head of Surgical Department, Regionshospitalet Randers.  
The partcipatng centres haie outstanding research eniironments and a long research traditon. The collaboraton between the centres has in preiious studies and projects proien to be irreproachable. The research group in Aarhus will coordinate the project, and the Ph.D.-student will act as daily project-manager and fll the role as research nurse in the centres Aarhus and Randers. All iniestgators are responsible for inclusion and the executon of the research project locally.  
| Time sehedule                                                                                                                                                                                         | Yeae 1   | Yeae 2   | Yeae 3   | Yeae 4   | Yeae 5   |      |        |      |        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|----------|----------|----------|----------|------|--------|------|--------|
| Fall                                                                                                                                                                                                  | Spring   | Fall     | Spring   | Fall     | Spring   | Fall | Spring | Fall | Spring |
| 2015                                                                                                                                                                                                  | 2016     | 2016     | 2017     | 2017     | 2018     | 2018 | 2019   | 2019 | 2020   |
| Deielopment and pilot-testng of  the interienton Systematc literature reiiew Instructon of research nurses Inclusion RCT Follow-up RCT Data analysis, publicatons and  completon of Ph.D.-dissertaton |          |          |          |          |          |      |        |      |        |
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5 funding

The study is initated by researchers and clinicians from the partcipatng centres, and thus partally funded from the centres. Most funding, though, comes from the Danish Cancer Society (3 mio. Dkr). Funding coiers salary for Ph.D.-student, research nurses and consultng statstcian, required electronic equipment and other material and resources. None of the partcipatng iniestgators haie concurrent fnancial interests in the research study.
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6 ethies

The risks and ethical concerns related to the project are limited. The risk of missing a locally recurrent cancer is minimal, as most recurrences are symptomatc. A local quality report from one of the partcipatng centres showed that out of 33 ierifed local recurrences oier a tme period of six years, only two were detected in connecton with a clinical control. The remaining were detected either by patents' self-referral due to symptoms or by CT or MRscans (unpublished data).  
Answering the questonnaire may remind the partcipant of their disease and therefore to some persons be unpleasant and a stress factor. The study will empower the partcipants in the interienton group to be more iniolied in own health care, desirable to some and the opposite to others. Patents acceptng to partcipate should feel secure whateier group they are randomised to follow. We aim to ensure patents of this by thorough and explicit informaton by the tme of inclusion. All partcipants will be asked to proiide writen informed consent. Data will be handled and stored according to natonal law and only anonymised results will be published. The study is reported and approied by the Danish Data Protecton Agency and The Natonal Commitee on Health Research Ethics as required.
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7 publishing steategy

Negatie as well as positie results will be published in internatonal peer-reiiewed scientfc journals. The project will result in at least fie scientfc publicatons, and all sources of funding will be acknowledged in the manuscript. The Ph.d.-student afliated to the project will draf the manuscripts in collaboraton with the superiisors. The iniestgators from the four centres will besides deliiering partcipants to the study also partcipate in data management and preparaton of manuscripts as co-authors. First author will be the one drafing the inital manuscript, last author will be prof. Søren Laurberg. Other authors will be listed alphabetcally.
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8 peespeetves

Results from the study will contribute to strengthen the eiidence base for RC follow-up, and may impact the future follow-up of RC patents in Denmark and internatonally. If the new follow-up program proies successful, it will be readily implementable in daily clinical practce at a natonal leiel. Also, it may atract internatonal atenton due to the huge number of afected patents and the high leiel of costs all oier the Western world.
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9 efeeenee list

(1) Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, suriiial, and risk factors. Clin Colon Rectal Surg 2009 Noi;22(4):191-197. (2) Brethauer M, Kalager M. Colonoscopy as a Triage Screening Test. N Engl J Med 2012 02/23; 2015/02;366(8):759-760. (3) DCCG. Landsdækkende database for kræf i tyk- og endetarm (DCCG). Natonal rsrapport for 2014. 2015. (4) Roikjær O. Anatomi og mesorektal ekscision - DCCG's natonale retningslinjer for diagnostk og behandling af kolorektal cancer. 2014. (5) Sundhedsstyrelsen. Pakkeforløb for Kræf i Tyk- og Endetarm. 2012. (6) M. B. Nielsen. Outcome following intended curatie treatment of locally recurrent rectal cancer Health Aarhus Uniiersity, Department of Colorectal Surgery, Aarhus Uniiersity Hospital; 2012. (7) Wiig N, Søreide O. Locoregional recurrence of rectal cancer. In: Holzheimer RG, Mannick JA, editors. Surgical Treatment: Eiidence-Based and Problem-Oriented Munich: Zuckschwerdt-Verlag; 2001. (8) Engel J, Kerr J, Schlesinger-Raab A, Eckel R, Sauer H, Holzel D. Quality of life in rectal cancer patents: a four-year prospectie study. Ann Surg 2003 Aug;238(2):203-213. (9) Emmertsen K. Funktonelle forstyrrelser efer rectumresekton - DCCG's natonale retningslinjer for diagnostk og behandling af kolorektal cancer. (10) Nielsen MB, Laurberg S, Holm T. Current management of locally recurrent rectal cancer. Colorectal Dis 2011 Jul;13(7):732-742. (11) Emmertsen KJ, Laurberg S. Bowel dysfuncton afer treatment for rectal cancer. Acta Oncol 2008;47(6):994-1003. (12) Chen TY, Emmertsen KJ, Laurberg S. Bowel dysfuncton afer rectal cancer treatment: a study comparing the specialist's iersus patent's perspectie. BMJ Open 2014 Jan 21;4(1):e003374-2013-003374.  
(13) Bregendahl S, Emmertsen KJ, Lindegaard JC, Laurberg S. Urinary and sexual dysfuncton in women afer resecton with and without preoperatie radiotherapy for rectal cancer: a populaton-based cross-sectonal study. Colorectal Dis 2015 Jan;17(1):26-37. (14) Lange MM, ian de Velde CJ. Urinary and sexual dysfuncton afer rectal cancer treatment. Nat Rei Urol 2011 Jan;8(1):51-57. (15) Johansen C. Kræf - Senfølger og Rehabilitering. 1st ed. Københain: Hans Reitzels Forlag; 2013. (16) Simard S, Thewes B, Humphris G, Dixon M, Hayden C, Mireskandari S, et al. Fear of cancer recurrence in adult cancer suriiiors: a systematc reiiew of quanttatie studies. J Cancer Suriii 2013 Sep;7(3):300-322. (17) Denlinger CS, Barseiick AM. The challenges of colorectal cancer suriiiorship. J Natl Compr Canc Netw 2009 Sep;7(8):883-93; quiz 894. (18) Marientano S, Forjaz M, Grosso G, Mistreta A, Giorgianni G, Platania A, et al. Health related quality of life in colorectal cancer patents: state of the art. BMC Surg 2013;13 Suppl 2:S15-2482-13-S2-S15. Epub 2013 Oct 8. (19) Postoperati kontrol - DCCG's natonale retningslinjer for diagnostk og behandling af kolorektal cancer. 2012. (20) Sundhedsstyrelsen. Opfølgningsprogram for tyk- og endetarmskræf. 2015. (21) Jefery M, Hickey BE, Hider PN. Follow-up strategies for patents treated for nonmetastatc colorectal cancer. Cochrane Database Syst Rei 2007 Jan 24;(1)(1):CD002200. (22) Williamson S, Chalmers K, Beaier K. Patent experiences of nurse-led telephone followup following treatment for colorectal cancer. Eur J Oncol Nurs 2014 Dec 16.
addendum foe the sample size
date june 06 2018

An inital estmaton of sample size showed, that a total of 334 partcipants were needed in order to obtain statstcally signifcant results (alpha 0.05, beta 0.20, SD 13, minimally important diference 4 points on the TOI-score). As the end of inclusion draws nearer, a confrmatie updated sample size analysis has been performed. The reason for this was mainly that the assumed standard deiiaton (SD) used for the inital estmaton was subject to considerable uncertainty, as it was based on studies where setng and populatons difered substantally from ours.  
Therefore, an interim analysis of the main-outcome (Trial Outcome Index - TOI) has been performed in order to determine a more precise SD. In the updated sample size estmaton, the following preconditons are listed: 10.4 SD, 0.05 alpha-ialue, 0.20 beta-ialue, an expected diference of 4 points on the TOI-scale and an expected total drop-out of 30%. Furthermore, additonally 15% are added to the sample size, due to the assumpton that the outcome data will be non-parametric. Thus the conclusion from the updated sample size estmaton is that a total of 324 partcipants are needed in order to obtain statstcally signifcant results.