Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea

Introduction : Chemotherapy-induced diarrhea (CID) is one of the most disturbing side effects of chemotherapy with respect to the patient’s quality of life, often dose-limiting if not calling into question the entire therapeutic strategy. CID prevention could enhance treatment safety and outcome by enabling the administration of optimal therapeutic doses. Diarrhea prevention is a major challenge for future oncological therapies, as CID is a frequent side effect of modern biological agents. In this multicentric, Belgian, prospective non-randomized trial, we tested the secondary prevention of CID with long-acting octreotide (LAO) in patients receiving cytotoxic chemotherapy associated with a high risk of digestive toxicity. Methods : In the study’s observational phase, all patients treated with a high-risk chemotherapy regimen were prospectively screened after having provided written consent. Patients experiencing a CID = 2 were proposed to enter the interventional phase, after having signed a second informed consent. They received a monthly Sandostatin LAR30 IM injection and the next chemotherapy course was administered with a 25% dose decrease. If no grade = 2 CID occurred, subsequent chemotherapy doses were increased to the initial 100% values. The main endpoint of the study was the diarrhea control rate for patients participating in the interventional phase of the study and receiving the optimal dose of chemotherapy for a minimum of 2 cycles. The statistical plan used a 2-step Simon design, with a first step after successful secondary CID prevention in 19 out of 25 patients. LAO would be considered as efficient in secondary prevention of CID if no diarrhea > grade 1 had been observed in at least 62 out of 79 patients treated with full-dose chemotherapy. Results : From March 2007 to March 2009, a total of 57 patients were included in the trial. The study was terminated before reaching its target size population because of poor accrual. 29 patients did not develop any CID and participated only in the observational phase. Of the 28 patients included in the interventional part after the first onset of a = grade 2 CID, 5 patients (17.8%, 95% CI = 6.1% - 36.9%) experienced no improvement after a 25% decrease in chemotherapy dose. 9 patients (32.1%, 95% CI = 15.9% - 52.4%) did not continue for the following reasons : rapid tumor progression (7), local reaction after LAO injection (1) and refusal (1). The screen failure rate is thus 14/28 (50%, 95% CI = 30.6% - 69.4%). Of the 14 patients whose CID was resolved after chemotherapy dose reduction, only 2 experienced a = grade 2 CID recurrence after receiving full dose chemotherapy. The remaining 12 patients were treated at the optimal chemotherapy dose without significant digestive side effects (85.7%, 95% CI = 57.2% - 98.2%). The overall success rate of the tested strategy is 12/28 (42.8%, 95% CI = 24.5% - 62.8%). Conclusions : While this trial did not recruit enough patients to answer the study question, available data suggest that LOA is very effective in allowing the return to optimal doses of chemotherapy in patients whose moderate to severe CID was improved after an initial chemotherapy dose reduction. Moreover, the high rate of screen failures emphasizes the need for more aggressive management of acute CID in addition to secondary prevention