Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma

Our plain-English summary of Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma, by R.K. Goudar (Therapeutics and Clinical Risk Management, 2008).

The study

• Author: R.K. Goudar
• Journal: Therapeutics and Clinical Risk Management
• Published: 2008;4(1):205-11
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is a resistant form of lung cancer, and its incidence continues to rise in Europe and Australia. Until recently, chemotherapy had not been shown to be effective in the treatment of this slowly progressive disease. In 2004, the combination of pemetrexed and cisplatin was shown to induce high response rates in MPM. This article reviews the published literature describing the development and testing of this therapeutic combination in mesothelioma, and examines in detail the key phase III clinical trial that led to the approval of pemetrexed by the US FDA. Ongoing research will further define the role of pemetrexed plus cisplatin in the treatment of MPM.

In plain English

This article was a single-author review of published research on pemetrexed plus cisplatin for malignant pleural mesothelioma. The author described it as a systematic review of the literature, plus selected references and conference abstracts. It did not study asbestos exposure; asbestos appeared only as background. Most of the review examined the EMPHACIS phase III trial (Vogelzang et al 2003), which randomized 448 patients who had not previously received chemotherapy to pemetrexed with cisplatin or to cisplatin alone. As the review reported it, median survival was 12.1 months with the combination versus 9.3 months with cisplatin alone. Final 2005 data gave 12.8 versus 9.0 months, with a hazard ratio for death of 0.74 (95% CI 0.60 to 0.90). Response rates were 41.3% versus 16.7%. Among patients given folate and vitamin B12 throughout, the survival difference (13.3 versus 10.0 months) was not statistically significant (p = 0.051). The author noted criticisms of the trial, including its cisplatin-only control and unexpectedly poor results in that arm. The author concluded that EMPHACIS showed improved outcomes with the combination.

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: Review (described by the author as a systematic review of the published literature, plus selected references and conference abstracts)
• Who was studied: Published studies of pemetrexed plus cisplatin, centred on the EMPHACIS phase III trial of 448 patients with malignant pleural mesothelioma who had not received prior chemotherapy (chemonaive). Twelve percent had received radiation therapy before enrollment.
• Exposure: Not asbestos. The review studied a treatment: pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 every 21 days, compared with cisplatin alone. Asbestos is mentioned only as background (about 80% of cases linked to prior asbestos exposure, citing Robinson et al 2005).
• Main results:
  • In EMPHACIS as reported in the review, median survival was 12.1 months in the pemetrexed plus cisplatin arm versus 9.3 months in the cisplatin-only arm (p = 0.02).
  • Final EMPHACIS data (2005): median survival 12.8 months with pemetrexed plus cisplatin versus 9.0 months with cisplatin alone, with a hazard ratio for death of 0.74 (95% CI 0.60 to 0.90) for the combination arm.
  • Among patients who received vitamin supplementation throughout, median survival was 13.3 months in the combination arm versus 10.0 months in the cisplatin-only arm. The difference was not statistically significant (p = 0.051).
  • Median time to progression was 5.7 months in the combination arm versus 3.9 months with cisplatin alone (p = 0.001). The total response rate was 41.3% versus 16.7%, with no complete responses.
  • Grade 3 or 4 neutropenia was reported by 52% of unsupplemented or partially supplemented patients, compared with 9.4% of patients fully supplemented with folate and vitamin B12.
  • On retrospective review, the FDA confirmed 47 of the 94 partial responses that the study authors reported in the combination arm. Pemetrexed was approved for malignant pleural mesothelioma in the US on 4 February 2004.
  • On the LCSS-Meso symptom questionnaire in EMPHACIS, the overall symptom score favored the combination arm after 6 cycles (p = 0.004).
• The authors' conclusion: The author concluded that the EMPHACIS trial showed improved outcomes with cisplatin plus pemetrexed compared with cisplatin alone, and that ongoing and future testing would likely expand the role of this regimen.
• Limitations the authors state:
  • Limitation of the reviewed EMPHACIS trial: using cisplatin alone as the control has been criticized, because cisplatin doublets were considered standard care before the trial.
  • Limitation of the reviewed EMPHACIS trial: outcomes in the cisplatin-only arm were unexpectedly poor compared with other trials, which may have made the combination look more effective.
  • Limitation of the reviewed EMPHACIS trial: it enrolled patients with good performance status, while most patients are more symptomatic and less functional at presentation, which may limit how far the results apply to other patients.
  • Limitation of the reviewed EMPHACIS trial: the small number of never or partially supplemented patients complicates understanding the effect of vitamin supplementation.
  • Limitation of the reviewed EMPHACIS trial: chemotherapy given after the study may have affected survival times.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Lung Cancer, Chemotherapy, Mesothelioma, Clinical Trial.

Related studies

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• Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma — J. Green, Y. Dundar, et al. (2007)
• Genetic variability of HIF1A and response to treatment with cisplatin in combination with pemetrexed or gemcitabine in patients with malignant mesothelioma — M. Setina, E. Setina, et al. (2025)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma — A.K. Nowak, A.M. Cook, et al. (2015)
• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)

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