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

Our plain-English summary of Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy, by R. Kotecha, R. Tonse, M. Rubens, et al (Cancers, 2021).

The study

• Authors: R. Kotecha, R. Tonse, M. Rubens, H. Appel, F. Albrecht, P. Kaywin, E.W. Alley, M.C. Tom, M.P. Mehta
• Journal: Cancers
• Published: 2021;13(9)
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article was a systematic review and meta-analysis of published first-line drug-treatment trials for locally advanced or metastatic malignant pleural mesothelioma. It did not examine asbestos exposure. The authors pooled 29 trials (24 phase II, five phase III) covering 2534 patients. In ten trials (1303 patients) using platinum-pemetrexed chemotherapy, pooled median progression-free survival was 6.7 months (95% CI 6.2 to 7.2) and overall survival 14.2 months (95% CI 12.7 to 15.9). In nineteen negative trials (1231 patients) of 15 experimental regimens, pooled overall survival was 13.5 months (95% CI 12.6 to 14.6). Using study-level age, sex, performance status, stage and tumor subtype, the authors built a nomogram (scoring chart) predicting platinum-pemetrexed survival. For the MAPS trial's experimental-arm patient mix, it predicted 15.76 months (95% CI 13.96 to 17.81); the trial reported 18.8 months. For CheckMate 743's experimental arm, it predicted 13.65 months (95% CI 11.41 to 16.33); 18.1 months was reported. Both reported results fell outside the predicted intervals. The authors concluded these estimates provide baseline comparison values for future trials. They noted subgroup-specific outcomes were seldom reported.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review and meta-analysis of published phase II and phase III clinical trials, with meta-regression used to build a prognostic nomogram
• Who was studied: Patients with locally advanced or metastatic malignant pleural mesothelioma receiving first-line systemic therapy in 29 published trials (24 phase II, 5 phase III), 2534 patients in total
• Exposure: Not asbestos. The article studied chemotherapy treatments: platinum (cisplatin or carboplatin) plus pemetrexed, compared with other experimental regimens
• Main results:
  • The pooled analysis covered 2534 patients from 24 phase II and five phase III trials
  • Ten trials (1303 patients) used a platinum-pemetrexed-based regimen
  • Platinum-pemetrexed group: pooled progression-free survival was 6.7 months (95% CI 6.2 to 7.2 months) and overall survival was 14.2 months (95% CI 12.7 to 15.9)
  • Platinum-pemetrexed group: pooled grade 3 to 4 neutropenia was 22% (95% CI 15 to 30%)
  • Nineteen negative trials tested 15 experimental regimens in 1231 patients
  • Experimental regimens group: pooled progression-free survival was 6.6 months (95% CI 6.2 to 7.0 months) and overall survival was 13.5 months (95% CI 12.6 to 14.6 months)
  • No publication bias was detected for the primary outcomes
  • MAPS trial: for the patient population of the experimental arm, the nomogram predicted overall survival with platinum-pemetrexed of 15.76 months (95% CI 13.96 to 17.81 months), compared with 18.8 months reported in the trial
  • CheckMate 743 trial: the nomogram predicted overall survival of 13.65 months (95% CI 11.41 to 16.33 months), compared with 18.1 months reported in the experimental arm
  • For both MAPS and CheckMate 743, the reported experimental-arm results fell outside the confidence interval predicted from historical data
  • STELLAR trial: the nomogram predicted 16.95 months (95% CI 10.49 to 27.38 months), and because of the wide interval this potentially overlapped the 18.2 months reported
• The authors' conclusion: The authors concluded that survival estimates from prior studies could support innovative trial designs with weighted randomization toward experimental regimens, and that their study provides baseline comparative values that can account for differing proportions of prognostic variables
• Limitations the authors state:
  • Outcome data specific to each subgroup (for example, male-specific and female-specific survival) were seldom reported and were difficult to extract
  • Other prognostic variables, such as hemoglobin, weight loss and albumin, could not be extracted from the publications
  • Patient characteristics, demographics and treatment information were not uniformly reported across the trials
  • The meta-regression used study-level covariates rather than individual patient data

Topics

Medical terms in this study, explained in our Lexicon: Meta-Analysis, Pleural Mesothelioma, Chemotherapy, Unresectable, Systematic Review, Systemic Therapy, Overall Survival, Platinum-Pemetrexed.

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