Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy

Abstract

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002-2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2-7.2 months) and OS of 14.2 months (95% CI: 12.7-15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6-14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.

Keywords: first line; mesothelioma; meta-analysis; systematic review.

Figure 1

Forest plots demonstrating the (A) progression-free survival with platinum/pemetrexed; (B) overall survival with platinum/pemetrexed; (C) progression-free survival with other experimental therapies; and (D) overall survival with other experimental therapies. Squares indicate the proportions from individual studies and horizontal lines indicate the 95% confidence interval. The size of the data marker corresponds to the relative weight assigned in the pooled analysis using the random effects model. The diamond indicates the pooled proportion with 95% CI.

Figure 2

Forest plots demonstrating the toxicity outcomes for platinum/pemetrexed regimen based on toxicity category: (A) Anemia; (B) Neutropenia; (C) Thrombocytopenia; (D) Cardiac Toxicity; (E) Gastro-intestinal toxicity; (F) Fatigue; (G) Infections; (H) Skin toxicity; and (I) Nausea and vomiting. Squares indicate the proportions from individual studies and horizontal lines indicate the 95% confidence interval. The size of the data marker corresponds to the relative weight assigned in the pooled analysis using the random effects model. The diamond indicates the pooled proportion with 95% CI.

Figure 3

Forest plots demonstrating the toxicity outcomes for various experimental regimens: (A) Anemia; (B) Neutropenia; (C) Thrombocytopenia; (D) Cardiac Toxicity; (E) Gastro-intestinal toxicity; (F) Fatigue; (G) Infections; (H) Skin toxicity; and (I) Nausea and vomiting. Squares indicate the proportions from individual studies and horizontal lines indicate the 95% confidence interval. The size of the data marker corresponds to the relative weight assigned in the pooled analysis using the random effects model. The diamond indicates the pooled proportion with 95% CI.

Figure 4

Nomogram model developed to predict overall survival (OS) in patients with malignant pleural mesothelioma treated with platinum/pemetrexed therapy. The mean log OS can be calculated by drawing a vertical line connecting the value of each variable with the point score at the top of the nomogram. The point scores for individual variables are then summed to get a total point score. This is then plotted along the total points line at the bottom of the nomogram. This line is projected to the mean log OS of the trial. Then the exponential of mean log OS is calculated to obtain the OS in months.