Continuous intraoperative monitoring of pelvic autonomic nerves during TME to prevent urogenital and anorectal dysfunction in rectal cancer patients (NEUROS): a randomized controlled trial

The primary objective of this trial is to assess urinary functional outcome in rectal cancer patients undergoing TME with pIONM, when compared to TME without pIONM, in a 12 months follow-up period per patient. The secondary objectives are to assess sexual and anorectal functional outcome in rectal cancer patients undergoing TME with pIONM, when compared to TME without pIONM, in a 12 months follow-up period per patient and to assess the safety, especially oncologic safety and quality of TME.

The NEUROS study is a prospective two-arm randomized controlled multicenter clinical trial with a follow-up period of 12 months per patient.

Patients undergoing TME for rectal cancer presenting at one of the participating hospitals.

Assessment of urinary function is carried out on the basis of the International Prostate Symptom Score (IPSS, total score range from 0 to 35 points) and the Quality of life index (Qol, Quality of life due to urinary symptoms, total score range from 0 to 6 points) [10]. A higher score indicates diminished urinary function and quality of life. Previous studies reported that the IPSS also applies to females and demonstrated that women have comparable scores to those of age-matched men [11, 12].

Sexual function in females is evaluated with the Female Sexual Function Index (FSFI) and in males with the International Index of Erectile Function (IIEF). The FSFI has been developed and validated as a brief, multidimensional self-report instrument for assessing the key dimensions of sexual function in women. It was designed and validated for assessment of female sexual function and quality of life in clinical trials and has demonstrated ability to discriminate between clinical and non-clinical populations [13]. The FSFI is a 19-item questionnaire with a total score range from 2 to 36 points. A lower score indicates diminished sexual function. The IIEF has been developed and validated as a brief and reliable self-administered scale for assessing erectile function [14]. The IIEF is a 19-item questionnaire with a total score range from 5 to 75 points. The brevity and ease of comprehension of the measure provide practical advantages.

Anorectal function is determined by the Wexner-Vaizey score (WVS) (minimum score = 0 = perfect continence; maximum score = 24 = totally incontinent) [15].

The rate of patients with an IPSS increased by at least 5 points 12 months after surgery compared to the preoperative IPSS is assumed to be 10 % in patients undergoing TME with pIONM. The corresponding rate for patients undergoing TME without pIONM is expected to be 30 %. A total number of 164 study patients is needed to demonstrate a significant difference between the study arms with a power of 90 % using Fisher’s exact test (alpha = 0.05, two-sided). Dropout rates are expected to be 2 % perioperatively and 10 % during the follow-up period in both study arms resulting in an overall dropout rate of 12 %. 188 patients have to be allocated to the trial.

Study participants can leave the study for the following reasons:

The investigator can decide to withdraw a participant from the study for the above mentioned reasons. This will be documented in the case report form (CRF) and the physician is required to notify the Coordinating Investigator. In all cases, the reason for withdrawal must be recorded in the CRF and in the patient’s medical record. All patients who discontinue because of adverse events or clinical laboratory abnormalities should be followed up until they recover or stabilize, and the subsequent outcome should be recorded.

Patients who underwent randomization and were withdrawn will not be replaced.

All patients who meet the inclusion criteria will be randomized. Randomization ratio is 1:1 to TME with pIONM or TME without pIONM (Fig. 1). Randomization is stratified according to neoadjuvant therapy and gender using blocks of variable length. Central randomization via FAX is conducted in this study.

In patients undergoing neoadjuvant therapy a prescreening is scheduled 21 to 1 day before therapy begins. The preoperative screening (baseline) is scheduled 14 to 1 day before TME. Study visits and follow up are summarized in Fig. 2.

The primary analysis population for the efficacy parameters is the intention-to-treat (ITT) population. The ITT population includes all randomized patients for which a preoperative and postoperative measurement of IPSS is available. Patients will be analyzed in the treatment group to which they were randomized. In addition, analyses for the Per-Protocol population will be performed. Only patients with a minimum of compliance to the study protocol will be included into the Per-Protocol population. Relevant violations of the study protocol will be defined in the statistical analysis plan, which is finalized before the database is closed and unblinded. Differences between rates of patients with an IPSS increased by at least 5 points 12 months after surgery compared to the preoperative IPSS will be evaluated using the Wilcoxon signed rank test (two-sided, alpha = 0.05). Patients for which no postoperative IPSS is available will be excluded from the confirmatory analysis of the primary endpoint due to missing information about postoperative urinary function. Missing IPSS scores 12 months after surgery will be imputed according to the Last Observation Carried Forward (LOCF) method if a postoperative IPSS is available. Postoperative IPSS measured under the influence of additional therapies against urinary dysfunction must not be used. Therefore, the last observed IPSS before urologic treatment will be analyzed. As dropout rates and imputed missing values are expected to be equal in both study arms no selection bias is expected by the application of these procedures. The secondary outcome parameters will be analyzed only descriptively. Preoperative IPSS, IPSS 12 months after surgery and intra-individual changes of IPSS within 12 months after surgery will be analyzed by distributional parameters such as mean, median, range and standard deviation separately for each study arm. An analogous analysis will be performed for the IIEF in male patients, the FSFI in female patients and the WVS. For male patients the rates of patients with an IIEF reduced by at least 15 points 12 months after surgery compared to the preoperative IIEF score will be displayed separately for each study arm. For female patients these rates will be calculated for the FSFI analogously. The threshold for discretizing the change in FSFI within 12 months after surgery is set to 8 points.

For the safety population summaries and listings of safety data will be performed. Frequencies of subjects experiencing at least one adverse event will be displayed by body system and preferred term according to MedDRA terminology. Detailed information collected for each adverse event will include: A description of the event, duration, whether the adverse event was serious, intensity, relationship to trial treatment, action taken and clinical outcome. Summary tables will present the number of subjects observed with adverse events and corresponding percentages. Additional subcategories will be based on event intensity and relationship to trial treatment. A subject listing of all adverse events will be prepared.

For the assessment of oncologic safety the rates of pCRM-positive specimen and the quality of mesorectum will be displayed by means of absolute and relative frequencies separately for each study arm.

The access to the confident patient information may be granted only to the governmental bodies and authorized representatives of the trial sponsor (clinical monitors). Only patients who explicit consented to these provisions will be enrolled in the clinical trial. The name of the subjects and other confidential information are subject to medical professional secrecy and the regulations of the applicable local data protection regulations. During the clinical trial, subjects will be identified by means of a unique individual identification code (pseudonym). The final trial report, public trial registers as well as scientific publications will solely contain anonymized statistical data.

The study will be continuously monitored by the clinical research associates of the IZKS. Monitoring will be done by personal visits, telephone and mail contacts by a clinical monitor according to standard operating procedures. All participating centers will be visited by the monitor to ensure compliance with study protocol, good clinical practice and legal aspects.

In this trial a DSMB will monitor and supervise the progress of the trial (including the safety data and the critical efficacy endpoints at intervals), review relevant information from other sources, ensure adherence to protocol, advise whether to continue, modify, or stop this trial. Furthermore it will provide the funding organization with information and advice. DSMB will meet annually and on special request. The trial management will organize these meetings and provide all necessary information for the work of the data monitoring board.

The trial is ongoing and in the recruiting phase at the time of manuscript.