Background
Periods of prolonged stress and advanced malignant disease can cause the body to enter into a catabolic state, which puts one at risk for malnutrition and weight loss. In cancer this phenomenon is known as cancer cachexia, but malnutrition is frequently observed in noncancer patients undergoing surgery as well. (7) Certain patients, such as those with liver pathologies, are more often in a hypercatabolic state. For example, liver cirrhosis is often associated with increased basal energy expenditure, increased protein breakdown in the body, as well as malnutrition, which negatively impacts prognosis. (5)(7) Unfortunately, liver cirrhosis is a common underlying condition among patients with hepatocellular carcinoma. Advanced cirrhosis often affects amino acid metabolism and results in low plasma levels of branched-chain amino acids (BCAAs). (11) BCAAs—leucine, isoleucine, and valine—are essential amino acids that are involved in the immune system. Specifically, they have been shown to improve the immune system by facilitating protein synthesis and enhancing lymphocyte function. (3) In cirrhotic patients, BCAAs may improve the function of neutrophils and natural killer (NK) cells. (6)(10) As a nutritional intervention, BCAAs have demonstrated improved clinical outcomes in advanced liver pathologies (7) as well as in cases of liver transplantation. (8) In fact, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends that patients with advanced cirrhosis use oral BCAAs long term. Given the potential of BCAA supplementation to improve clinical outcomes in advanced malignant disease, the authors of this study explored the application of BCAAs during the oncological perioperative period. They completed the first systematic review and meta-analysis evaluating the safety and efficacy of BCAAs used in patients with cancer undergoing surgery.Methods
This systematic review and meta-analysis included 13 randomized controlled trials (RCTs) to evaluate BCAA efficacy and seven observational cohort studies to evaluate safety. Cohort studies were used with the aim of providing a broader safety analysis. The inclusion criteria for the studies included patients undergoing cancer-related surgery; studies evaluating branched-chain amino acids using any route of administration, dose, duration, and formulation (i.e., used alone or in combinations); and the intervention being compared to placebo, active control, or no adjunctive treatment (e.g., usual care, standard nutrition). Primary outcomes included mortality, cancer treatment response, recurrence, remission, metastasis/disease progression, and stable disease. Secondary outcomes of interest included adverse events, postoperative infections and other postoperative complications, bleeding, wound healing, pain, length of hospitalization, quality of life/performance status, weight/body mass index (BMI)/arm and waist circumferences, fatigue, and cancer biomarker, immune cell, and inflammatory marker levels. Studies excluded were those using concomitant chemotherapy, radiation or radiofrequency ablation, and non-English reports. Meta-analyses were conducted on the RCTs using STATA 12. However, meta-analyses were not performed for the cohort studies due to heterogeneity.Results
The literature search yielded 4,171 studies. After abstract and full-text screening, 20 studies were included involving 2,019 participants. Mean ages of the participants ranged from 53 to 67 years old, and participants were mostly male. The majority of the RCTs involved liver cancer, while two were on gastrointestinal cancer and one was on bladder cancer. In terms of administration, nine RCTs evaluated oral intake of BCAAs, while four administered BCAAs intravenously in hospital. The dose of oral BCAAs administered ranged from 3 to 12 g per day. A common dosing regimen across studies with oral BCAA supplementation was 4 to 5.5 g three times per day. The total duration intervention varied widely across the studies, with the shortest involving three months of BCAA supplementation. Six studies evaluated BCAAs administration during the preoperative and postoperative periods, while five RCTs gave BCAAs only postoperatively. Overall, the studies demonstrated beneficial effects of BCAAs, especially in terms of reducing postoperative morbidity. BCAAs were found to have a beneficial effect on several outcomes. To begin, there was a 38% decreased relative risk of postoperative infections in the BCAA group compared to controls. The studies’ follow-up times ranged from from seven to 513 days. Infections reported included wound infection, sepsis, biliary fistula (septic), central-catheter sepsis, infected ascites, postoperative pulmonary infection, postoperative subphrenic abscess, urinary tract infection, surgical site infection, liver abscess, infectious complications, chest infection, intraabdominal abscess, and pneumonia. Additionally, BCAA supplementation was also associated with a 45% decreased relative risk of ascites compared to controls. BCAAs improved hospitalization length of stay, shortening it by two days compared to controls. BCAAs were also found to be beneficial for body weight, as participants were 3 kg heavier in the BCAA group compared to controls. With respect to immune cells and inflammatory markers, follow-up times ranged from seven to 15 days. One study reported significant improvements in C-reactive protein and white blood cell counts. Another study, however, found no difference in antibodies (i.e., IgA, IgG, IgM). With respect to other outcomes, there were no differences between BCAAs and controls for mortality, recurrence, other postoperative complications (e.g., liver failure, edema, pleural effusion), perioperative blood loss, quality of life, ammonia level, and prothrombin time. Furthermore, none of the RCTs provided data on cancer treatment response, metastasis, remission, stable disease, fatigue, pain, general wound healing, and cancer biomarker levels. The majority of the studies (6/13 of the RCTs and all six observational studies) did not report any adverse events. However, those that reported adverse events found no serious adverse effects due to BCAAs. Reported adverse events included hyperglycemia, diuresis, nausea, vomiting, diarrhea, abdominal distension, hypertension, and abdominal pain. One RCT reported two adverse events related to the use of intravenous catheters (i.e., poorly positioned catheter and catheter sepsis).Critical analysis
One strength of this study was that it provided a very comprehensive review on the effects of BCAA supplementation during the perioncological period. They analyzed a wide variety of outcomes including postoperative complications, body weight, markers of immune function, as well as quality of life. This helped to provide insight into the many different ways that BCAA supplementation could help support a patient during a perioncological operative period. Additionally, the meta-analyses conducted used rigorous statistical methods, and there was transparent reporting of the methods and results. The study also had several limitations. The authors reported that, overall, the findings were of low quality evidence, as most of the included RCTs had a high risk of bias. RCT risk of bias was appraised using the Cochrane Risk-of-Bias tool, and the observational studies’ quality assessment was conducted with Newcastle-Ottawa Scale. Most of the RCTs had selective reporting and potential selection bias. Some studies had an unclear or high risk regarding blinding of participants and outcome assessment, as well as possible attrition bias. In addition, the exclusion of non-English studies may have introduced language bias into the present study. The substantial heterogeneity that existed between the included studies also makes it difficult for specific implications to be deduced from this review. Another limitation is that the findings of this study may not necessarily be generalizable to other sexes or types of cancer, as the studies mostly involved males and liver cancers. Furthermore, a majority of the studies did not report on adverse events related to BCAAs, which limits the safety data that was able to be obtained from this review. Though there appears to be benefits to BCAAs, the meta-analysis does not provide indication of potential dosing and administration information.The bottom line
This study demonstrated the great potential of BCAAs to reduce surgical morbidity and improve outcomes for patients. Trials of higher methodological quality are needed to confirm the results as well as determine the most effective administration and dosage of BCAA supplementation. These findings can potentially help inform current Enhanced Recovery After Surgery (ERAS) guidelines, which are aimed at improving recovery after major surgery. The guidelines currently involve nutritional supplementation preoperatively (12) and postoperatively (9) for patients at risk of malnutrition. Therefore, further research in this area can help optimize outcomes for these patients.Save time.
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References
- Calder PC. (2006). Branched-chain amino acids and immunity. J Nutr. 136:288s-293s.
- Charlton M. (2006). Branched-chain amino acid enriched supplements as therapy for liver disease. The Journal of nutrition, 136(1 Suppl), 295S–8S.
- Choudry HA, Pan M, Karinch AM, Souba WW. (2006). Branched- chain amino acid-enriched nutritional support in surgical and cancer patients. J Nutr. 136:314s-318s.
- Cogo, E., Elsayed, M., Liang, V., Cooley, K., Guerin, C., Psihogios, A., & Papadogianis, P. (2021). Are Supplemental Branched-Chain Amino Acids Beneficial During the Oncological Peri-Operative Period: A Systematic Review and Meta-Analysis. Integrative cancer therapies, 20, 1534735421997551.
- Hammad, A., Kaido, T., & Uemoto, S. (2015). Perioperative nutritional therapy in liver transplantation. Surgery today, 45(3), 271–283.
- Nakamura I, Ochiai K, Imai Y, Moriyasu F, Imawari M. (2007). Restoration of innate host defense responses by oral supplementation of branched-chain amino acids in decompensated cirrhotic patients. Hepatol Res. 37:1062-1067.
- Gluud LL, Dam G, Les I, et al. (2017). Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 5:Cd001939.
- Langer G, Großmann K, Fleischer S, et al. (2012). Nutritional interventions for liver-transplanted patients. Cochrane Database Syst Rev. 8:Cd007605.
- Melloul E, Hübner M, Scott M, et al. (2016). Guidelines for perioperative care for liver surgery: Enhanced Recovery After Surgery (ERAS) society recommendations. World J Surg. 40:2425-2440.
- Nakamura, I., Ochiai, K., & Imawari, M. (2004). Phagocytic function of neutrophils of patients with decompensated liver cirrhosis is restored by oral supplementation of branched-chain amino acids. Hepatology research : the official journal of the Japan Society of Hepatology, 29(4), 207–211. https://doi.org/10.1016/j.hepres.2004.04.005
- Soeters, P. B., & Fischer, J. E. (1976). Insulin, glucagon, aminoacid imbalance, and hepatic encephalopathy. Lancet (London, England), 2(7991), 880–882.
- Weimann A, Braga M, Harsanyi L, et al. (2006). ESPEN guide- lines on enteral nutrition: surgery including organ trans- plantation. Clin Nutr. 25:224-244.