Mortality burden of pre-treatment weight loss in patients with non-small-cell lung cancer: A systematic literature review and meta-analysis

Abstract

Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non-small-cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta-analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre-treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random-effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan-Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016-2021) met the criteria for inclusion in the meta-analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL < 5% (pooled HR [95% confidence interval, CI]: 1.82 [1.47, 2.25]). Although statistical heterogeneity was high (I² = 88%), individual study HRs were directionally aligned with the pooled estimate, and there was considerable overlap in CIs across included studies. A subgroup analysis of studies using the ICC (HR [95% CI]: 2.26 [1.80, 2.83]) or WL ≥ 5% (HR [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Assessments of methodological, clinical and statistical heterogeneity indicated that the meta-analysis was robust. Overall, this analysis found that ICC-defined cachexia or WL ≥ 5% was associated with inferior survival in patients with NSCLC. Routine assessment of both weight and weight changes in the oncology clinic may help identify patients with NSCLC at risk for worse survival, better inform clinical decision-making and assess eligibility for cachexia clinical trials.

Keywords: cachexia; meta‐analysis; muscle wasting; non‐small‐cell lung cancer; systematic literature review; weight loss.

Figure 1

PRISMA diagram of the literature‐screening process for the NSCLC SLR and meta‐analysis. ^aLC types were SCLC (n = 2) or malignant pleural mesothelioma (n = 1). ^bOutcomes were PFS or weight gain. ^cWL analysed as quartiles or as a continuous variable in MVA. ^dWL assessment periods were during treatment rather than at baseline. HR, hazard ratio; IC, international consensus; KM, Kaplan–Meier; LC, lung cancer; MVA, multivariate analysis; NSCLC, non‐small‐cell lung cancer; PFS, progression‐free survival; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analyses; SCLC, small‐cell lung cancer; SLR, systematic literature review; WL, weight loss.

Figure 2

Meta‐analysis of the association between cachexia or weight loss ≥ 5% and overall survival in NSCLC: Base‐case random‐effects model. Sample size reflects patients with NSCLC and OS data, which for some studies is less than the number of patients with baseline data. CI, confidence interval; H², homogeneity statistic; HR, hazard ratio; I², heterogeneity statistic; NSCLC, non‐small‐cell lung cancer; OS, overall survival; Q, Cochrane Q (chi‐square statistic); T², tau‐square; z, normality distribution; θ, overall effect estimate.

Figure 3

Galbraith plot analysis for the base‐case meta‐analysis of the association between cachexia or weight loss ≥ 5% and overall survival in non‐small‐cell lung cancer. θ and σ represent the study‐specific effect size and its standard error. Navy circles represent study‐specific log HR divided by sigma (θ/σ) against study precisions 1/σ. CI, confidence interval; HR, hazard ratio; REML, restricted maximum likelihood; se, standard error; θ, overall effect estimate.

Figure 4

Funnel plot analysis for the base‐case meta‐analysis of the association between cachexia or weight loss ≥ 5% and overall survival in non‐small‐cell lung cancer. CI, confidence interval; HR, hazard ratio; θ, overall effect estimate.