Are Supplemental Branched-Chain Amino Acids Beneficial During the Oncological Peri-Operative Period: A Systematic Review and Meta-Analysis

Abstract

Background: Branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) are essential amino acids involved in immune responses, and may have roles in protein malnutrition and sarcopenia. Furthermore, certain liver diseases have been associated with a decreased Fischer’s ratio (BCAAs to aromatic amino acids; phenylalanine, tyrosine, and tryptophan). We aimed to evaluate the safety and efficacy of BCAAs use in patients with cancer undergoing surgery. Methods: MEDLINE, Embase, and CENTRAL were searched (inception to July 24, 2020) for randomized controlled trials (RCTs) and comparative observational studies in English evaluating BCAAs (alone or in combinations) during the oncological peri-operative period. Study selection, data extraction, and quality appraisal were done in duplicate. RCT risk-of-bias was appraised using Cochrane Risk-of-Bias tool, and observational studies’ quality assessment was conducted with Newcastle-Ottawa Scale. Meta-analyses were conducted when appropriate. Results: 20 articles were included comprising 13 RCTs and 6 observational cohort studies in 7 reports and 2019 total participants overall. Among 13 RCTs, 77% involved liver cancer. Methodological study quality scored substantial risk-of-bias across most RCTs. Meta-analysis of RCTs found a 38% decreased risk of post-operative infections in BCAAs group compared to controls (RR\u2009=\u20090.62; 95% CI\u2009=\u20090.44 to 0.87; P\u2009=\u2009.006; number of RCTs, k\u2009=\u20096; total sample size, N\u2009=\u2009389; I2\u2009=\u20090%). BCAAs were also found to be beneficial for ascites (RR\u2009=\u20090.55; 95% CI\u2009=\u20090.35 to 0.86; P\u2009=\u2009.008; k\u2009=\u20094; N\u2009=\u2009296; I2\u2009=\u20090%), body weight (MD\u2009=\u20093.24\u2009kg; 95% CI\u2009=\u20090.44 to 6.04; P\u2009=\u2009.02; k\u2009=\u20093; N\u2009=\u2009196; I2\u2009=\u200924%), and hospitalization length (MD\u2009=\u2009−2.07\u2009days; 95% CI\u2009=\u2009−3.97 to −0.17; P\u2009=\u2009.03; k\u2009=\u20095; N\u2009=\u2009362; I2\u2009=\u200959%). No differences were found between BCAAs and controls for mortality, recurrence, other post-operative complications (liver failure, edema, pleural effusion), blood loss, quality of life, ammonia level, and prothrombin time. No serious adverse events were related to BCAAs; however, serious adverse events were reported due to intravenous catheters. No safety concerns from observational studies were identified. Conclusions: Branched-chain amino acids during the oncological surgical period demonstrated promise in reducing important post-operative morbidity from infections and ascites compared to controls. Blinded, placebo-controlled confirmatory trials of higher methodological quality are warranted, especially using oral, short-term BCAAs-enriched supplements within the context of recent ERAS programs. PROSPERO registration: CRD42018086168.