Interest of Early Erectile Rehabilitation With Sildenafil After Radiotherapy and Proctectomy for Rectal Cancer (RECTIL)

Intérêt de la rééducation érectile précoce Par Sildénafil après radiothérapie et Proctectomie Pour Cancer du Rectum : Essai contrôlé randomisé

This study aims to evaluate the efficacy of erectile rehabilitation with Sildenafil, in men treated with neoadjuvant proctectomy and radiotherapy for rectal cancer, in preventing long-term erectile dysfunction at 12 months post-operatively.

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Sildenafil; Other: Placebo

Detailed Description

Colorectal cancer is the third most common cancer in men in France, after lung and prostate cancer. Proctectomy (possibly preceded by radiotherapy) is the most effective treatment for this cancer, but erectile dysfunction (ED) is a frequent complication, even when the nerves are preserved during dissection, and has a major impact on the quality of life of operated men.

The cause of erectile dysfunction after rectal cancer surgery is usually neurological, due to intraoperative trauma to the autonomic nerves, while erectile dysfunction after radiotherapy is mainly vascular in origin, with damage to erectile tissue.

Several risk factors for sexual dysfunction after rectal cancer surgery have been reported (age, neoadjuvant radiotherapy, type of resection, operative difficulties and complications, body image affected by protective stoma). On the other hand, surgical expertise may be a protective factor.

In the physiological condition, the nitric oxide released by the pelvic nerves causes an increase in cyclic guanosine monophosphate, which in turn causes smooth muscle cells relaxation and an influx of blood into the cavernous body, triggering and maintaining the erection.

Similar to prostatectomy, nerve damage can occur during proctectomy through stretching, heat, ischemia or inflammation; this nerve damage results in reduced nitric oxide production.

Even in the absence of nerve damage, it has been demonstrated (in an animal model) that post-operative neurapraxia is responsible for the at least temporary disappearance of spontaneous and nocturnal erections, leading to cavernous hypoxia. This is followed by tissue changes (reduction in smooth and elastic muscle fibers in the corpora cavernosa, increase in collagen and endothelial dysfunction), which modify the hemodynamics of the carvernum body and ultimately lead to fibrosis of the erectile tissue.

These changes can become permanent despite subsequent nerve recovery, and are exacerbated by neoadjuvant radiotherapy. It is therefore important not to wait passively for erectile function to be restored, as lack of oxygenation to the corpora cavernosa can lead to permanent fibrosis and dysfunction.

This physiopathology is at the origin of the concept of erectile rehabilitation after prostatectomy, with the aim of maintain erections post-operatively and thus limiting fibrosis.

The benefits of erectile re-education after prostatectomy were first reported in 1997, with the early use of intracavernous injections of alprostadil. Following this study, various rehabilitation strategies have been recommended. Early treatment, i.e. within the first month, is recommended to promote cavernous oxygenation and prevent fibrosis.

The aims of rehabilitation are as follows :

• limit fibrosis;
• limit penis retraction and loss of height;
• oxygenate the cavernum body;
• preserve endothelial structure;
• preserve smooth muscle cell structure.

Various types of rehabilitation have been proposed: oral PDE-5 inhibitors, intra-cavernosal injections, urethral suppositories or vaccum.

PDE-5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thus compensating for the reduction in nitric oxide and enabling a better erection.

Erectile rehabilitation using PDE-5 inhibitors could protect cavernous smooth muscle from irreversible pathophysiological changes. The basic concept is to administer a PDE-5 inhibitor at bedtime to facilitate nocturnal erections, which are thought to have a natural protective effect on the function of the cavernous bodies.

Padma-Nathan et al. reported the prospective administration of sildenafil 50 and 100 mg vs. placebo, daily and at bedtime, in patients undergoing nerve-sparing radical prostatectomy. After 36 weeks, erectile function was significantly better in the sildenafil group, with 27% responders, vs. 4% in the placebo group.

The mechanisms involved in erectile dysfunction after proctectomy for rectal cancer are similar to those of radical prostatectomy for prostate cancer.

The efficacy of PDE-5 inhibitors in the treatment of erectile dysfunction after proctectomy has already been demonstrated. However, its use as a preventive measure has rarely been reported.

Three studies have evaluated PDE-5 inhibitors in patients with erectile dysfunction after rectal resection, two of which used sildenafil (Viagra, Pfizer, New York, NY)

To our knowledge, only one study has evaluated the role of PDE-5 inhibitors (PDE-5i) in a preventive strategy.

Originality and innovation Despite the fact that sexual dysfunction is recognized as a frequent complication of rectal cancer treatment, there are currently no recommendations for its prevention and management.

In contrast to prostate cancer patients, information and treatment concerning erectile dysfunction (ED) are not systematically offered to men with colorectal cancer. The ability of sildenafil to facilitate the return of erections after radical prostatectomy has been demonstrated in several studies, and this treatment could benefit patients treated for rectal cancer.

To date, no randomized study has examined the usefulness of this early rehabilitation in patients managed for rectal cancer. This study proposes, for the first time, to evaluate the use of sildenafil after neo-adjuvant radiotherapy and surgery for rectal cancer.

• Study Type: Interventional
• Enrollment (Estimated): 188
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Valérie Bridoux; Phone Number: +33 0232881347; Email: valerie.bridoux@chu-rouen.fr
• Study Contact Backup: Name: Julie Rondeaux, PhD; Phone Number: +33 0232885427; Email: julie.rondeaux@chu-rouen.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men aged 18 to 70
• Patients undergoing surgery for cancer of the lower or middle rectum by total removal of the mesorectum with colorectal or coloanal anastomosis after neoadjuvant radiotherapy, with normal preoperative erectile function (defined by a combined IIEF erectile function domain score of at least 22).
• Nerve-conserving surgery
• Sexually active patient without treatment for erectile function prior to surgery
• Presence of a regular sexual partner (male or female)
• Adult having read and understood the information letter and signed the consent form
• Membership of a social security scheme

Exclusion Criteria:

• T4 tumor or tumor requiring extended surgery
• Patients with abnormal erectile function defined by a combined IIEF erectile function domain score of less than 22.
• History of prostate cancer
• Sleep disorders, patients taking sedatives/hypnotics
• Contraindication to SILDENAFIL EG 50 mg, film-coated tablet
• Contraindication to placebo
• Patients already treated with PDE5 inhibitors
• Patients suffering from SARS COV 2*
• Person deprived of liberty by an administrative or judicial decision or person placed under court protection / sub-guardianship or guardianship.
• Any history of illness or psychological or sensory abnormality likely to prevent the subject from fully understanding the conditions required for participation in the protocol, or to prevent the subject from giving informed consent.
• Person participating in another drug trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (Sildénafil); Sildénafil during 10 months (50mg daily), start 30 days after surgery	Drug: Sildenafil; Sildénafil during 10 months (50mg daily), start 30 days after surgery; Other Names: Arm I
Placebo Comparator: Arm II (Placebo); Patients receive placebo during 10 month (1 platelet per day)	Other: Placebo; 1 platelet during 10 months (daily), start 30 days after surgery; Other Names: Arm II

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the patient's response	A patient is defined as a responder by a score of at least 22 for the erectile function domain of the International Index of Erectile Function (IIEF), comprising the six IIEF questions relating to erection (Q1-Q5 and Q15).	12 months postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IIEF erectile function domain score	Mesure of IIEF erectile function domain score, comprising the six IIEF erectile function questions (Q1-Q5 andQ15) at D0, M1, M3, M6, M9 and M12	Day 0, Month 1, Month 3, Month 6, Month 9, Month12
International Index of Erectile Function (IIEF) global score	International Index of Erectile Function (IIEF) global score measured at D0, M1, M3, M6, M9 and M12	Day 0, Month 1, Month 3, Month 6, Month 9, Month 12
Quality of life score	Mesure of quality of life score (EORTC QLQ - C30 and QLQ - CR29) at D0, M1, M3, M6, M9 and M12	Day 0, Month 1, Month 3, Month 6, Month 9, Month 12
LARS score	LARS score measured at D0, M1, M3, M6, M9 and M12	Day 0, Month 1, Month 3, Month 6, Month 9, Month 12
Fecal Continence Score	Fecal Continence Score (Wexner score) measured at D0, M1, M3, M6, M9 and M12	Day 0, Month 1, Month 3, Month 6, Month 9, Month 12
Spontaneous erection evaluation	Number of patients with spontaneous erections on treatment at M3, M6, M9 and without treatment at M1, and M12	Month 1, Month 3, Month 6, Month 9, Month 12
Benefits of psychological follow-up	The number of patients with or without regular psychological follow-up. A patient is defined as having regular follow-up if he/she visits a psychologist and/or psychiatrist once or twice a month.	after 10 months of treatment
Compliance with treatment	Number of unused tablets during the study. The patient will be considered as non-compliant if pill-taking over the entire 10-month treatment period is <80%.	after 10 months of treatment
Adverse and suspected adverse events	Number of AEs and SAEs in each group at M1, M3, M6, M9 and M12	Month 1, Month 3, Month 6, Month 9, Month 12

Collaborators and Investigators

• Sponsor: University Hospital, Rouen

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: October 26, 2023
• First Submitted That Met QC Criteria: November 3, 2023
• First Posted (Actual): November 8, 2023

Study Record Updates

• Last Update Posted (Actual): November 8, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 2019/0398/HP; 2020-002682-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No