Short summary

This project addresses a major concern for prostate cancer patients and partners; changes in sexuality, intimacy, male identity, and marital relationship. The study will deliver and test the effect of a multidisciplinary combined prehabilitation and early rehabilitation intervention in elderly prostate cancer patients treated with radiotherapy concomitant with androgen deprivation therapy. The primary focus of the intervention is sexual functioning and secondary to reduce irritative urinary problems. Additionally general health related aspects will be addressed as explorative parameters. 

Rationale

Prostate cancer is the most common cancer among men in Europe. In Denmark 4,534 men were di-agnosed with prostate cancer in 2015. The mortality is stable with 1,200 death annually, and due to increased incidence and improvements in treatment 36,018 Danish men are living with prostate cancer. Most of them are elderly men over 60 years. 

Sexuality and Sexual adverse effects

Sexuality is an important part of people´s physical and mental health. The etiology of sexual dysfunction in men with prostate cancer is multi-factorial and therefore complex. Prostate cancer patients treated with radiotherapy and concomitantly androgen deprivation therapy have often several adverse effects including problems with sexuality. Some sexual problems may be irreversible as radiotherapy has an impact on vascular structures in the penis and may cause arterial insufficiency. Furthermore, androgen deprivation therapy blocks testosterone levels and leads to loss of sexual interest and erectile dysfunction in up to 90% of the patients. Also the partner is affected as sexual adverse effects influence intimacy, sexuality and marital relations. 

Urinary adverse effects

The most frequent urinary adverse effects related to radiotherapy are irritative urinary symptoms causing pain, hematuria, weak urine stream, high frequency, nocturia, urgency, or urge incontinence in 25%; and incontinence in 5-10%. Rehabilitation including homebased pelvic floor exercises has in a Danish study (n=161) significantly reduced these problems, and pelvic floor exercises are known to reduce urinary incontinence, post-micturition dribble, and improve erectile function in prostatecto-mised prostate cancer patients. 

Other adverse effects

Radiated prostate cancer patients also suffer from bowel, hormonal and general physical and mental quality of life problems. Androgen deprivation therapy may cause secondary female characteristics with increased body fat around waists, hips, and thighs affecting bodyimage and male identity, and the occurrence of hot flushes in up to 70%. Furthermore, muscle decay in large muscle groups, oste-oporosis, increased risk of myocardial infarction, stroke, and metabolic syndrome are reported. Some adverse effects turn into chronic adverse effects, as measured in a Danish study (n=317) 1-4 years after radiotherapy, where smokers, obese and single men were most exposed. 

Prehabilitation and early Rehabilitation may help

Rehabilitation for prostate cancer patients treated with radiotherapy and androgen deprivation therapy is a new research area, and evidence of effective interventions for irritative urinary problems is sparse, and almost absent regarding sexual impairment. The key focus in most intervention studies regarding penile rehabilitation is oral phosphodiesterase type 5 (PDE5) inhibitor or different medical devises, and often with positive results. However, most studies include prostate cancer patients with a prostatectomy, and do not target the often complex multi-factorial etiology of sexual impairment. Trials have documented a broad range of physiological effects, but few studies have included other aspects of androgen deprivation therapy on sexuality, physical changes, intimacy, and even less studies have addressed how these treatments affect a couple's relationship. Furthermore, interventions have not been tested systematically in prostate cancer patients treated with radiotherapy and androgen deprivation therapy. Although recommendations underline that rehabilitation should start at the time of diagnosis, most studies have been executed after completion of the main treatment. In this project the prehabilitation period is three month before radiotherapy. 

In summary, the sexual and urinary adverse effects in relation to radiotherapy and androgen depriva-tion therapy have been documented in the literature, but limited evidence exits on how to counteract these problems. We hypothesize that a multimodal approach and a multidisciplinary and partly supervised, early intervention may reduce the sexual decline and result in better physical and mental status after radiotherapy and prevent impairments to become chronical. 

Aims 

The primary aim is to examine if prehabilitation and early rehabilitation can:

• reduce sexual adverse effects in prostate cancer patients treated with radiotherapy and androgen deprivation therapy 

The secondary aims are to examine if prehabilitation and early rehabilitation can:

• reduce irritative urinary problems 
• improve several aspects of quality of life including physical and mental functioning 
• ensure sampling of data needed for a health economic evaluation

Description of the cohort

This is a prospective study with a two-arm randomized non-blinded design. Patients are recruited at Odense University Hospital, Department of Urology, in collaboration with the Department of Oncology.

The inclusion criteria are a) Danish speaking men over 18 years old, b) biopsy documented T1-T3 adenocarcinoma of the prostate, c) referred to curatively intended radiotherapy, d) treated with neo-adjuvant and concomitant androgen deprivation therapy, e) self-reported sexual active in a partnership or as single. 

Data and biological material

At baseline, information about Gleason score and TNM-staging is obtained from the patients´ records. At the same time patient reported information about smoking, alcohol, co-morbidity and civil status is obtained. Generic and disease specific quality of life at baseline will be collected using validated Patients Reported Outcomes measures (PRO). PRO in collected as the patient prefer: with internet links, though the app "Mit Forløb", or with paper questionnaires. Patients willing to participate will be randomised in the Odense Patient data Explorative Network (OPEN) system RedCap in blocks of 4:6 to either an intervention group or a usual care group. Reasons for declining participation will be accounted for to better understand selection bias and enhance recruitment in the future. If the patients reports by paper the data entry will be controlled by the procedure recommended by King et al.

PROs:

All self-reported outcomes will be assessed at baseline, 3 months after radiotherapy (Evaluation), and after 6 months and 9 month after radiotherapy respectively. The primary outcome, sexual functioning, is evaluated 3 month after radiotherapy and measured by the International Index of Erectile Function score (IIEF-5). Secondary disease specific outcomes include urinary incontinence, urinary irritative problems, bowel, sexual and hormonal sum-scores all from the Expanded Prostate Cancer Index EPIC-26, and general quality of life from the Medical Outcome Study Short-form-12 (SF-12), physical activity are obtained from  the International Physical Activity Questionnaire (IPAQ), and the relationship between patient and partner is measured with the Relationship ladder. Data for a health economic evaluation will be measured by EQ-5D.

To understand what is changing with the patient's condition during the rehabilitation process all measures are important, and the data collection will be followed carefully. 

Collaborating researchers and departments

National Collaborators:

Department of Urology, Odense University Hospital

• PhD student Mike Allan Mortensen, MD

Knowledgecenter for Rehabilitation and Palliative care REHPA, Odense University Hospital, Nyborg

• Professor Ann-Dorthe Olsen Zwisler, MD, PhD, 

Department of Oncology, Odense University Hospital

• Professor Jørn Herrstedt, MD

Department of Urology, Odense University Hospital

• Professor Lars Lund, MD

National Research Center for Cancer Rehabilitation, Research Unit of General Practice, University of Southern Denmark

• Associate professor Dorte Gilså Hansen, MD, PhD

International Collaborator:

Institute of Nursing and Health Research, Ulster University, Coleraine, Ireland

• Professor Eilís McCaughan, RN