Abstract Background Dietary peptides are believed to contribute to persistent weight loss following gastrectomy or esophagectomy due to cancer. Previous studies have suggested that this effect might be partially mitigated by octreotide. This study aims to investigate the safety and tolerability of intramuscular Sandostatin® LAR depot 10mg, including the frequency and nature of adverse events. It serves as a pilot study for future research aiming to comprehensively assess its effects. Methods A prospective open-label phase-2 study was conducted from November 2021 to June 2023. Twenty patients (10 undergoing gastrectomy, 10 undergoing esophagectomy) were enrolled. Patients received three doses of intramuscular Sandostatin® LAR depot 10mg at 7 days, 1 month, and 2 months post-surgery. All patients were evaluated at 7 days, 1, 2, 3, and 6 months post-surgery. The primary endpoint was safety, determined by the incidence and nature of adverse events, with no occurrence of serious or severe events defined as successful. Tolerability was defined as at the completion of the treatment protocol by at least 90% of patients. Secondary endpoints included weight loss (percent from baseline), Health-Related Quality of Life (assessed via EORTC-QLQ-C30 and OG25 at baseline, 1, 2, 3, and 6 months post-surgery), and the proportion of subjects requiring enteral nutrition via jejunostomy. Results The study protocol was completed by 95% of participants. No serious or severe adverse events were reported. Median weight loss at 6 months was 11% (3 months: 7%, 2 months: 4%, 1 month: 5%). Mean and median Global Quality of Life (part of EORTC-QLQ-C30) remained unchanged at 6 months compared to baseline (mean: 67.6 vs. 67.2; median 66.7 [25-100] vs 70.8 [16.7-100]). The percentage of subjects requiring enteral nutrition was 40%, 30%, and 15% at 1, 2, and 3 months respectively. Conclusion This pilot study suggests that Sandostatin® LAR depot was well tolerated and safe, with no serious or severe adverse events observed. Weight loss, Health Related Quality of Life, and the proportion of subjects requiring enteral nutrition were consistent with expectations. Future studies should consider a double-blinded randomized controlled design preferably with dose-response assessment for more robust investigation.