Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma

Our plain-English summary of Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma, by J. Green, Y. Dundar, S. Dodd, et al (The Cochrane Database of Systematic Reviews, 2007).

The study

• Authors: J. Green, Y. Dundar, S. Dodd, R. Dickson, T. Walley
• Journal: The Cochrane Database of Systematic Reviews
• Published: 2007;2007(1):CD005574
• Type of article: Systematic review
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy whose incidence is expected to increase in the United Kingdom, Western Europe, and Australia over the next 20 years as a result of occupational exposure to asbestos fibres. Surgery is feasible in only a small proportion of cases, and radiotherapy and cytotoxic chemotherapy are used in palliation. Pemetrexed is the first and only chemotherapy agent that has been granted a marketing approval for use in combination with cisplatin for the treatment of chemo-naïve patients with unresectable MPM.

Objectives: To examine evidence on the clinical effectiveness of pemetrexed disodium used in combination with cisplatin for the treatment of unresectable malignant pleural mesothelioma in chemotherapy naïve patients compared with other cytotoxic agents used alone or in combination, or supportive care.

Search Strategy: CENTRAL (Issue 2, 2005), EMBASE (1980-2005), MEDLINE (1980-2005), HTA database (1990-2005), Web of Knowledge (1990-2005) and handsearching (including reference lists of retrieved articles and the pharmaceutical company submission to to NICE), up to October 2005.

Selection Criteria: Randomised Controlled Trials (RCTs) where the use of pemetrexed disodium in combination with cisplatin is compared with other cytotoxic agents, or supportive care for the treatment of malignant pleural mesothelioma (or non-RCTs, in the absence of RCT data ).

Data Collection And Analysis: Outcomes included overall survival, tumour response, progression-free survival, toxicity and quality of life. Data extraction and quality assessment of included trials was completed independently. Trial data and quality assessment were tabulated and presented narratively.

Main Results: One RCT involving 448 patients and comparing pemetrexed plus cisplatin versus cisplatin alone for the treatment of unresectable malignant mesothelioma was included in the review. In the intention-to-treat study population, the median survival was statistically significantly longer in the combination arm of pemetrexed plus cisplatin when compared with the cisplatin alone arm. (12.1 and 9.3 months, respectively, p=0.002). The incidence of grade 3/4 toxicities was higher in the combination arm compared with the cisplatin alone arm.

Authors' Conclusions: Pemetrexed disodium in combination with cisplatin and with folic acid and vitamin B(12 )supplementation may improve survival when used in combination with cisplatin in good performance status patients. Further studies including patients with poor performance status are needed in order to generalise the treatment findings. Further studies are also needed into the optimum chemotherapy, and a clear definition of what constitutes best supportive care.

In plain English

This was a Cochrane systematic review of trials of the chemotherapy drug pemetrexed combined with cisplatin in people with malignant pleural mesothelioma that could not be removed by surgery and who had not had chemotherapy before. It did not study asbestos exposure. Searches ran to October 2005. One randomised trial, EMPHACIS, met the criteria. In it, 448 patients received either pemetrexed plus cisplatin (226) or cisplatin alone (222). No studies compared pemetrexed with other regimens or with supportive care alone. In the trial's main analysis, median survival was 12.1 months with the combination and 9.3 months with cisplatin alone. Tumours partly shrank in 41.3% versus 16.7% of patients. Serious side effects, such as low white blood cell counts, were more common with the combination. Folic acid and vitamin B12 supplements lowered some of them. The authors concluded the combination with these supplements may improve survival in patients in good general condition. They noted several limits: only fitter patients took part, cisplatin alone is not universally accepted as standard care, and the doctors assessing outcomes knew which treatment patients received.

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 (Cochrane review) of randomised controlled trials. One randomised, multicentre, single-blind trial (EMPHACIS) was included. Seven non-comparative studies were described but excluded.
• Who was studied: The included trial had 448 randomised patients with unresectable malignant pleural mesothelioma who had not had chemotherapy before: 226 received pemetrexed plus cisplatin and 222 received cisplatin alone. It ran at 20 treatment centres in Europe, the Americas, Asia and Australia. Patients needed a Karnofsky performance status of 70 or greater, and 81% were male. The literature searches covered 1980 to October 2005.
• Exposure: Not an asbestos exposure study. The treatment studied was pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, compared with cisplatin 75 mg/m2 alone, given on day one of each 21-day cycle. After a protocol change, most patients also received folic acid and vitamin B12 supplements.
• Main results:
  • Intention-to-treat population, median survival: 12.1 months with pemetrexed plus cisplatin (n=226) versus 9.3 months with cisplatin alone (n=222), log-rank P 0.020 (figures from the article's Table 3).
  • Fully supplemented patients only, median survival: 13.3 months with the combination (n=168) versus 10.0 months with cisplatin alone (n=163), P 0.051. The review called this borderline significance.
  • Intention-to-treat population, median time to progressive disease: 5.7 months in the combination arm versus 3.9 months in the cisplatin-only arm (P=0.001).
  • Partial response rate: 41.3% with pemetrexed plus cisplatin versus 16.7% with cisplatin alone (P less than 0.001). No patient had a complete response.
  • Grade 3/4 neutropenia (low neutrophil count): 63 of 226 patients (27.9%) with the combination versus 5 of 222 (2.3%) with cisplatin alone. Other grade 3/4 effects, such as nausea and vomiting, were also more frequent with the combination.
  • Among combination-treated patients, grade 3/4 neutropenia occurred in 39 of 168 fully supplemented patients (23.2%) versus 24 of 58 partially or never supplemented patients (41.4%), P 0.011.
  • Quality of life results were published only as a conference abstract. Patients on the combination showed greater improvement in global quality of life than those on cisplatin alone (P=0.0012). The review advised caution in interpreting this.
  • The searches found no studies comparing pemetrexed with other commonly used chemotherapy regimens (MVP, vinorelbine) or with supportive care.
• The authors' conclusion: The authors concluded that pemetrexed with folic acid and vitamin B12 supplementation may improve survival when used with cisplatin in patients with good performance status. They added that patient selection should take account of the expected toxicity, and that any improvement over best supportive care is only an indirect assessment.
• Limitations the authors state:
  • The trial did not report why 118 (about 20%) of the 574 consenting patients were found ineligible.
  • Supplementation was added only after the first 70 patients. The survival gain in the fully supplemented subgroup was of borderline significance.
  • Single-agent cisplatin, the comparison arm, is not universally accepted as the standard of care for advanced disease.
  • Only relatively fit patients (Karnofsky performance status 70 or greater) were enrolled, so results may not apply to the expected patient population.
  • Patients in the combination arm received more treatment cycles (median 6 versus 4), which may have contributed to the survival difference.
  • Outcome assessors were not blinded, which may have biased investigator assessments. An FDA review could confirm tumour response for only about 50% of responders (47 of 94) in the combination group.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Occupational Exposure, Chemotherapy, Unresectable, Overall Survival, Progression-Free Survival.

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• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)
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