Updated analysis of a prospective, randomized, controlled trial on the impact on clinical outcomes of fish oil supplementation during neoadjuvant chemoradiation for rectal cancer.
Authors: Souza E Silva Virgilio , Silva Mariane Messias Reis Lima , Silva Juliana De Aguiar Pastore , Brito Angelo Borsarelli Carvalho , Silva Maria Leticia GOBO , Mello Celso Lopes , Aguiar Samuel 
Published: June 2022

e15594

Background: The intake of nutritional supplements, such as fish oil, can modulate the inflammatory response and thus interfere with therapeutic results. Methods: Patients clinically staged as T3,4 and / or N + rectal adenocarcinoma were randomized 1:1 to receive oral ingestion four capsules, totaling 4g of concentrated fish oil (each gram of fish oil concentrate contained 1448 mg of Eicosapentaenoic acid (EPA) + 964 mg of docosahexaenoic acid (DHA)) throughout neoadjuvant conventional chemoradiation (intervention group – IG) or chemoradiation without supplement (control group – CG). All patients were operated about 8 weeks after chemoradiation. Correlation of inflammatory response - Glasgow Prognostic Score (GPS) with disease-free survival (DFS) was the primary outcome; measurements were collected at 4 moments: M1: at diagnosis; M2: at the end of chemoradiation; M3: at 4 weeks after end of chemoradiotherapy; and M4: preoperatively. Results: From January, 2015 and July, 2017, a total of 111 patients with cT3, 4 and / or N (+) rectal adenocarcinoma were accrued and randomized; 105 were randomized (IG: 51 and CG: 54). Mean age were 60 years, ranging from 30-86 years. There was no difference between groups in M1. In M2 and M3 there were differences between the IG and the CG in systemic inflammatory response measured by GPS (M2: p = 0.001; M3: p = 0.027). After neoadjuvant therapy, 49 patients in the CG and 46 patients in the IG were submitted to surgery; complete pathological response (pCR) was present in 15 patients in the CG and in 10 patients in the IG; there was no association of pCR and fish oil supplementation (P = 0.34). Median follow-up time was 45 months (range: 2-72). With a median follow up time of 24 months, DFS was shorter in patients with KPS < 90% (47.0% vs 80.1%, P = 0.01), high risk (T4 or N+) rectal cancer (67.4% vs 89.7%, P = 0.01) and patients who did not achieve pCR after neoadjuvant CRT (65.5% vs 95.8%, P = 0.003). Also, shorter DFS was observed in patients with GPS 1 or 2 in M2 (69.1% vs 76.7%, p = 0.01) and M4 (38.9% vs 75.3%, p = 0.04) compared to patients with GPS 0 (reduced inflammatory response). In multivariate analysis, patients with high risk rectal cancer and GPS 1 or 2 in M2 had 3.07 and 2.11-fold greater risk of disease relapse; patients who achieved pCR had 84% reduction risk of DFS. KPS and GPS in M4 were not independent prognostic biomarkers for DFS. Conclusions: The oil fish supplementation during neoadjuvant chemoradiotherapy for rectal cancer was able to reduce the systemic inflammation syndrome (GPS = 0) associated with cancer. This reduction during treatment, especially in the preoperative moment was associated with better DFS. Thus, this intervention proposed in our study, as it is easily accessible and low cost, may be a viable strategy in this population and this finding should be better evaluate in future trials. Clinical trial information: NCT02534389.