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Non-cytotoxic therapy has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients. With unique mechanisms of action, these agents have decidedly improved survival and have demonstrated an improved toxicity profile. However, the real-life experience of the patient, which is commonly assessed by health-related quality of life (HRQoL) measurement, is not clearly established with this new generation of lung cancer treatments. The heterogeneity created by specific patient subgroups and different therapeutics calls for a tailored-approach to analyzing patient-reported outcomes. The objective of this systematic review was to assess the methodological quality of HRQoL analysis in Randomized Clinical Trials (RCTs) involving biologic agents to treat NSCLC.A systematic literature search was performed using Medline, Embase, and Web of Science databases to identify NSCLC RCTs published between January 1st, 2000 and January 1st, 2020 reporting HRQoL measures. Only RCTs that both enrolled previously untreated patients with advanced NSCLC and had HRQoL analysis were included.4203 abstracts were screened, of which only 85 RCTs met inclusion and exclusion criteria for analysis. The most applied HRQoL assessment tools were the EORTC-QLQ-C30 (47, 55.3 %), and EORTC-QLQ-LC13 (35, 41.2 %). The median number of verified CONSORT-PRO Extension criteria in the included trials was 3, and only in 10 (11.8 %) trials were all criteria well-documented. Notably, only 21 (24.7 %) RCTs performed subgroup analyses to specifically evaluate HRQoL in different patient populations.QoL reporting in clinical trials is inconsistent and the quality of QoL measures adopted in a majority of trials is suboptimal. Considering the fact that NSCLC is a biologically diverse disease and that the treatments differ based on patient and tumor-specifics, efforts should be pursued to tailor QoL measures for different subsets of this patient population in addition to mandating QoL reporting in clinical trials. We believe that this is necessary to understand the real-life experience of lung cancer patients in the era of personalized medicine.

This systematic review and meta-analysis examines randomized clinical trials (RCTs) of modern cancer drugs in the adjuvant setting to determine the incidence of severe adverse events reported in placebo groups., Key Points Question What is the incidence of grade 3 to 4 adverse events in the placebo groups of modern cancer drug trials in the adjuvant setting? Findings In this systematic review and meta-analysis including 11 143 patients and 10 adjuvant, double-blind, randomized, placebo-controlled, phase 3 trials, the incidence of grade 3 to 4 adverse events in the placebo groups was 18%. Meaning This finding suggests that placebo administration may be associated with a substantial incidence of grade 3 to 4 adverse events in modern cancer adjuvant trials and should be considered by investigators and patients., Importance Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials. Objective To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting. Data Sources Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type–related keywords. Study Selection A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion. Data Extraction and Synthesis Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies. Main Outcomes and Measures Incidence of grade 3 to 4 placebo AEs in the placebo groups. Results Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non–small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11 143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2 = 86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (ρ = 0.7; P = .03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%). Conclusions and Relevance Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.