Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation

Our plain-English summary of Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation, by B. Hasan, L. Greillier, A. Pallis, et al (European Journal of Cancer, 2014).

The study

• Authors: B. Hasan, L. Greillier, A. Pallis, J. Menis, R. Gaafar, R. Sylvester, D.A. Fennell, P. Baas, V. Surmont, J.P. Van Meerbeeck, M.E. O'brien
• Journal: European Journal of Cancer
• Published: 2014;50(16):2771-82
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Response criteria have always been difficult to apply to malignant pleural mesothelioma (MPM), due to its unique pattern of growth. We developed some models to show that progression free survival rate (PFSR) could be a better predictor of overall survival (OS) than the response rate (RR) in MPM patients. The results were validated independently in the European Organisation for Research and Treatment of Cancer (EORTC) 08052, a phase II study in MPM.

Methods: Individual patient data from 10 EORTC-Lung Cancer Group (LCG) studies of first-line chemotherapy in MPM were pooled. Response to therapy was assessed according to World Health Organisation (WHO) criteria in all except the two most recent trials, which used Response Evaluation Criteria in Solid Tumours (RECIST). Landmark analyses (LA) at 9 weeks and 18 weeks after registration/randomisation were performed to assess the association between PFSR and OS. Independent validation of the results was conducted in EORTC 08052 study (82 patients) employing the same LA.

Results: All 10 studies (N=523 patients) were included in the LA of PFSR at 9 and 18 weeks (PFSR-9 and PFSR-18). PFSR-9 and PFSR-18 were confirmed as predictors of OS, with hazard ratio (HR) of 0.37 (95% confidence interval (CI), 0.30-0.47) and 0.50 (0.38-0.65) and C-index of 0.62 and 0.58, respectively. In the validation study, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-9 and PFSR-18 weeks were both strongly correlated with OS (HR of 0.35 [80% CI, 0.25-0.49] and 0.46 (0.32-0.67) and C-index of 0.66 and 0.60, respectively).

Conclusion: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier end-point, PFSR-9 was also strongly correlated to OS with better discriminating capacity. The results were independently validated.

Copyright © 2014 Elsevier Ltd. All rights reserved.

In plain English

This study pooled data on 523 patients with malignant pleural mesothelioma from 10 chemotherapy trials run by the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group. It then checked the results in a separate trial, EORTC 08052, of 82 patients given cisplatin and bortezomib. It asked whether being free of disease progression 9 or 18 weeks after trial entry predicted overall survival. In the pooled trials, patients without progression at 9 weeks had a median survival of 12.4 months, against 6.2 months for those who had progressed (hazard ratio 0.37, 95% confidence interval 0.30 to 0.47). At 18 weeks the figures were 12.6 versus 8.4 months (hazard ratio 0.50, 0.38 to 0.65). In the validation trial the hazard ratios were 0.35 at 9 weeks and 0.46 at 18 weeks (80% confidence intervals 0.25 to 0.49 and 0.32 to 0.67). The authors concluded that progression-free status at 9 weeks, rather than tumour response rate, should be the end-point for future phase II mesothelioma trials. They noted that this did not establish it as a substitute for survival. Asbestos exposure was not studied.

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: Pooled analysis of individual patient data from 10 clinical trials (nine phase II and one randomised phase III), using landmark analyses at 9 and 18 weeks, with independent validation in a separate phase II trial
• Who was studied: 523 patients with malignant pleural mesothelioma in 10 EORTC Lung Cancer Group trials conducted between 1984 and 2001 (83% male, median age 58). Validation used 82 patients in the EORTC 08052 trial (67.1% male, median age 55).
• Exposure: Not an asbestos exposure study. Patients received first-line chemotherapy: mitoxantrone, 4-epidoxorubicin, etoposide, paclitaxel, gemcitabine, pegylated liposomal doxorubicin, temozolomide, raltitrexed, or cisplatin alone versus raltitrexed and cisplatin. The validation trial used cisplatin and bortezomib.
• Main results:
  • Pooled 10 trials, 435 patients eligible at 9 weeks: median overall survival was 12.4 months (95% CI 11.4 to 13.7) for those without progression at 9 weeks versus 6.2 months (5.2 to 7.8) for those who had progressed. Hazard ratio was 0.37 (95% CI 0.30 to 0.47), C-index 0.62.
  • Pooled 10 trials, 377 patients eligible at 18 weeks: median overall survival was 12.6 months for those without progression versus 8.4 months for those who had progressed. Hazard ratio was 0.50 (95% CI 0.38 to 0.65), C-index 0.58.
  • Head-to-head comparison in six trials (369 patients). At 9 weeks, the hazard ratio was 0.41 (95% CI 0.30 to 0.55) for no progression and 0.51 (0.36 to 0.72) for tumour response (complete or partial response). The C-indexes were 0.60 and 0.58.
  • Validation trial (EORTC 08052), progression-free status at 9 weeks: median overall survival was 16.9 months without progression versus 6.8 months with progression. Hazard ratio was 0.35 (80% CI 0.25 to 0.49), C-index 0.66, positive predictive value 73%, negative predictive value 68%.
  • Validation trial, progression-free status at 18 weeks: median overall survival was 16.9 months without progression versus 11.9 months with progression. Hazard ratio was 0.46 (80% CI 0.32 to 0.67), C-index 0.60.
  • Validation trial, tumour response at 9 weeks: hazard ratio was 0.49 (80% CI 0.29 to 0.82), log-rank p 0.07, C-index 0.59, positive predictive value 77%, negative predictive value 50%.
• The authors' conclusion: The authors concluded that progression-free status at 18 weeks, and even more so at 9 weeks, was strongly correlated with overall survival. They concluded that progression-free status at 9 weeks rather than response rate should be the end-point for future phase II mesothelioma trials.
• Limitations the authors state:
  • The analysis does not establish progression-free rate or response rate as a surrogate end-point for overall survival. That would require several phase III studies, and most of the included studies were phase II.
  • Patients in the validation trial had a slightly better prognosis than those in the development trials, because performance status 0 or 1 was required.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Overall Survival, Pleural Mesothelioma, Meta-Analysis, Lung Cancer, Chemotherapy, Hazard Ratio, confidence interval, Prognosis.

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• Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials — X. Wang, X. Wang, et al. (2017)
• Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients — A.A. Bahnassy, A.R. Zekri, et al. (2012)
• Prognostic factors for progression-free and overall survival in malignant pleural mesothelioma — J. Guzmán-Casta, S. Carrasco-CaraChards, et al. (2021)
• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group — K. Mattson, G. Giaccone, et al. (1992)

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