Toxicity Profiles of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Importance: The recent development of targeted therapy and immunotherapy has made neoadjuvant therapy an attractive option for patients with hepatocellular carcinoma (HCC). However, surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries. Objective: To summarize the current evidence regarding toxicity profiles for tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) among patients with HCC. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1990 and December 2021. Study Selection: Single-group, placebo-controlled, and dual-agent clinical trials comparing TKIs and ICIs in patients with HCC were eligible for inclusion. Data Extraction and Synthesis: Following the Preferred Reporting Items in Systematic Reviews and Meta-analysis guideline, 2 reviewers independently extracted data. A random-effects model was used. Main Outcomes and Measures: The primary outcome was the proportion of patients with clinically significant liver-related adverse events. Secondary outcomes included the proportion of patients who experienced clinically relevant (grade 3 or higher) adverse events and significant adverse events (ie, those that were life threatening, required hospitalization, or prolonged disability) as well as the risk ratio (RR) of these complications. Results: Overall, 30 studies with 12 921 patients were included. Patients had a mean (range) age of 62 (18-89) years; a mean (SD) 84% (3) were male; a mean (SD) 82% (16) had Barcelona Clinic Liver Cancer stage C HCC; and a mean (SD) 97% (6) had Childs A cirrhosis. Overall, 21% (95% CI, 16%-26%) of patients receiving TKIs had liver toxic effects compared with 28% (95% CI, 21%-35%) of patients receiving ICIs. Severe adverse events occurred in 46% (95% CI, 40%-51%) of patients receiving TKIs compared with 24% (95% CI, 13%-35%) of patients receiving ICIs. Compared with patients receiving sorafenib, other TKIs were associated with similar rates of liver toxic effects (RR, 1.06; 95% CI, 0.92-1.24) but higher rates of severe adverse events (RR, 1.24; 95% CI, 1.07-1.44). Comparing ICIs with sorafenib, there were similar rates of liver toxic effects (RR, 1.10; 95% CI, 0.86-1.40) and severe adverse events (RR, 1.19; 95% CI, 0.95-1.50). Conclusions and Relevance: In this systematic review and meta-analysis, serious adverse events were lower with ICIs than with TKIs, while liver toxic effects were similar. Combination therapy with novel ICIs is an appealing option in trials of neoadjuvant therapy for patients with HCC, requiring evaluation in preoperative trials.

Perioperative optimization with nutritional supplements in patients undergoing gastrointestinal surgery for cancer: A randomized, placebo-controlled feasibility clinical trial.

BACKGROUND: Perioperative nutritional supplementation may improve outcomes. Trials have not investigated the role of combination strategy using different types of nutritional supplements. METHODS: We conducted a single-site randomized pilot trial, among gastrointestinal cancer patients undergoing surgery, comparing perioperative nutritional supplements versus placebo (1 placebo to each supplement), to determine feasibility of a larger trial. Intervention, administered in sequence, included: protein supplementation (preoperative day 30-6), protein supplementation rich in arginine and omega-6 (preoperative day 5-1, and postoperative day 1-5), and carbohydrate loading (surgery day). Primary outcome was enrollment. Secondary outcomes included participant compliance with study supplements (target ≥70% of total packets). We planned protocol modifications to improve enrollment and compliance. Postoperative complications were described. RESULTS: Over 18 months, 495 patients were screened, 144 were deemed eligible, and 71 consented to participate, resulting in an enrollment fraction of 71/144 (49%, 95% confidence interval: 41%-57%). 'Too much burden' was the most common reason for refusal to participate (34%). Participants' median overall compliance with study packets was 80%. Protocol modifications (decreasing the interval from enrollment to surgery from 4 to 2 weeks and decreasing length of baseline assessment) did not impact enrollment or compliance. Postoperative complications were similar between control (18/31 [58%, 95% confidence interval: 4-74]), and intervention (22/34 [65%, 95% confidence interval: 48-79]) arms, with a higher proportion of infectious complications in the control arm (16/31, 52% vs 12/34, 35%). CONCLUSION: Results from this pilot suggest a larger phase III trial is feasible. Postoperative infectious complications were common, making this a suitable outcome of interest.

Effect of Perioperative Nutritional Supplementation on Postoperative Complications-Systematic Review and Meta-Analysis.

BACKGROUND: Perioperative carbohydrate loading, increased protein intake, and immunonutrition may decrease postoperative complications. Studies on the topic have led to controversial results. METHODS: We searched Medline, EMBASE, and CENTRAL up to August 2018 for randomized trials comparing the effect of perioperative nutritional supplements (intervention) versus control on postoperative complications in patients undergoing gastrointestinal cancer surgery. Secondary outcomes included infectious complications and length of hospital stay (LOS). Random effects model was used to estimate the pooled risk ratio (RR) of treatment effects. Pooled mean difference (MD) was used to compare LOS. Heterogeneity was assessed using I2. Sources of heterogeneity were explored through subgroup analysis by nutritional supplementation protocol, type of surgery, and type of nutritional supplement. Risk of bias and quality of the evidence were assessed. RESULTS: Of 3951 articles, we identified 56 trials (n = 6370). Perioperative nutrition was associated with a lower risk of postoperative complications (RR 0.74, 95% confidence interval (CI) 0.69-0.80); postoperative infections (RR 0.71, 95% CI 0.64-0.79, n = 4582); and postoperative non-infectious complications (RR 0.79, 95% CI 0.71-0.87, n = 4883). There were no significant heterogeneity outcomes analyzed (I2 = 14%, 1%, and 7%, respectively). LOS was shorter for the intervention group, MD - 1.58 days; 95% CI - 1.83 to - 1.32; I2 = 89%). Subgroup analysis did not identify sources of heterogeneity. The quality of evidence for postoperative complications was high and for LOS was moderate. CONCLUSION: Perioperative nutritional optimization decreases the risk of postoperative infectious and non-infectious complications. It also decreases LOS in patients undergoing gastrointestinal cancer surgery, but these findings should be taken with caution given the high heterogeneity.