The Stoma Closure Before or After Adjuvant Therapy Trial (STOMAD)

Multicenter Randomized Controlled Phase III Trial Comparing Ileostomy Closure Before or After Adjuvant Therapy in Patients Operated for Rectal Cancer

This is an open-label multicenter controlled trial, including 28 centers from the Rete Oncologica (Oncological Network) of Piemonte and Valle d'Aosta in Italy (http://www.reteoncologica.it). After a curative resection for rectal cancer and temporary ileostomy, 270 patients with indication to adjuvant chemotherapy will be randomized to early (before starting adjuvant treatment) or late (after adjuvant treatment completion) stoma closure. Primary end point will the compliance to adjuvant therapy. Secondary endpoint will include quality of life and bowel function evaluation, postoperative morbidity, chemotherapy toxicity, oncological outcomes and costs comparison.

Diverting ileostomy is effective in reducing severity of anastomotic complications in rectal low anterior resections and it is therefore widely used especially after neoadjuvant chemoradiation treatment. In current clinical practice, in patients with indication to adjuvant chemotherapy, closure of ileostomy is usually performed after the end of the treatment. However, a prolonged presence of the ostomy can induce the onset of ostomy-related complications such as stoma prolapse, parastomal hernia, mechanical ileus, high flow dehydration and damage to renal function. The ostomy-related complications may require unplanned or prolonged hospitalization, thus increasing costs. Furthermore, the presence of the stoma may affect quality of life, causing alteration of the body image and imposing changes in the daily routine and lifestyle. Early closure of the ileostomy in patients without signs of postoperative fistula has therefore been proposed. Outcomes of early closure (within one month from surgery) of diverting ileostomy were demonstrated to be equal to those of late closure (more than 12 weeks from surgery) in 2 randomized trials. Early closure may favor a better quality of life for patients, shortening the life-period with ileostomy, reduces health system economic expenditure and may represent the most desirable and convenient choice. It was also associated with better long term functional results in a randomized trial. In patients with indication to adjuvant therapy, however, timing to closure of the ostomy (before the start, during or at the end of treatment) is still a matter of debate in terms of compliance to systemic treatment, quality of life and overall costs. A recent multicenter retrospective study reported an increase in gastrointestinal toxicity in ostomy patients with a significant reduction in treatment compliance. On the other hand, early closure of the ostomy could unmask anterior resection syndrome (LARS) before chemotherapy, with potential negative impact on the tolerability of the treatment, or reveal postoperative complications thus delaying chemotherapy treatment. The trial will investigate which is the best strategy of dealing with temporary ileostomy in relation to adjuvant therapy.

Composite outcome measure including timeliness and percentage of planned dose received. In each subject, treatment compliance is defined as good if both the following conditions are met: adjuvant therapy starting date within 10 weeks of rectal resection; total cumulative received dose (mg/m2) >=70% of planned. The percentage of participants with good compliance in both arms will be compared.

Immediately after the end of every single cycle (each cycle duration varies from 5 to 14 days according to the chosen scheme)

At baseline, at the end of cycle 3 (regardless of the cycle duration, that varies from 5 to 14 day according to local investigators choice) and at 12 months from randomization

At baseline, at the end of cycle 3 (regardless of the cycle duration, that varies from 5 to 14 day according to local investigators choice) and at 12 months from randomization

At baseline, at the end of cycle 3 (regardless of the cycle duration, that varies from 5 to 14 day according to local investigators choice) and at 12 months from randomization

Mean cumulative costs in euro of the postoperative phase including outpatient visits, hospital stay for stoma closure, hospital re-entry and expenditures for stoma care appliances based on life-days with the stoma. Excluded are costs related to adjuvant treatment.

Inclusion Criteria: Patient treated with a curative resection for rectal cancer Presence of a temporary ileostomy Age >= 18 years Indication to adjuvant treatment Absence of anastomotic dehiscence (as proved by enema and/or endoscopy) Able to give written informed consent Exclusion Criteria: ASA >3 ECOG Performance Status >=2 UICC stage IV Severe and non-controlled systemic, oncologic, or infectious disease

Anonymized IPD will be available for 36 months after the results publication upon request to the principal investigator. Data will be provided in an electronic dataset containing deidentified participant files by the Unit of Epidemiology of the Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Turin (Italy) after evaluation and approval of the request by the trial steering committee.

Address data sharing request to the principal investigator. All requests will be evaluated and must be approved by the trial steering committee.

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Massucco P, Fontana A, Mineccia M, Perotti S, Ciccone G, Galassi C, Giuffrida MC, Marino D, Monsellato I, Paris MK, Perinotti R, Racca P, Monagheddu C, Saccona F, Ponte E, Mistrangelo M, Santarelli M, Tomaselli F, Reddavid R, Birolo S, Calabro M, Pipitone N, Panier Suffat L, Carrera M, Potente F, Brunetti M, Rimonda R, Adamo V, Piscioneri D, Cravero F, Serventi A, Giaminardi E, Mazza L, Bellora P, Colli F, De Rosa C, Battafarano F, Trapani R, Mellano A, Gibin E, Bellomo P. Prospective, randomised, multicentre, open-label trial, designed to evaluate the best timing of closure of the temporary ileostomy (early versus late) in patients who underwent rectal cancer resection and with indication for adjuvant chemotherapy: the STOMAD (STOMa closure before or after ADjuvant therapy) randomised controlled trial. BMJ Open. 2021 Feb 19;11(2):e044692. doi: 10.1136/bmjopen-2020-044692.