Raltitrexed in mesothelioma

Our plain-English summary of Raltitrexed in mesothelioma, by V.F. Surmont, J.P. van Meerbeeck (Expert Review of Anticancer Therapy, 2011).

The study

• Authors: V.F. Surmont, J.P. van Meerbeeck
• Journal: Expert Review of Anticancer Therapy
• Published: 2011;11(10):1481-90
• Type of article: Review
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Raltitrexed is a cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other agents, raltitrexed inhibits thymidylate synthase directly and specifically in a mixed, noncompetitive manner, which may lead to an improved toxicity profile. After promising Phase II trials exploring the activity of raltitrexed either as a single agent or in combination with a platinum agent, a Phase III randomized study demonstrated that the combination of raltitrexed and cisplatin improves overall survival in malignant pleural mesothelioma (MPM) and is superior compared with cisplatin alone, without harmful effect on health-related quality of life. Moreover, the cost-effectiveness analysis found raltitrexed plus cisplatin to be cost effective compared with cisplatin and compared with active supportive care. Based on these results, raltitrexed is registered for the treatment of MPM in several European countries. MPM is hard to treat and has a poor prognosis. New treatment options, such as a combination of cisplatin and raltitrexed, which improve patient outcomes with no detrimental effect on quality of life, are a welcome addition to our therapeutic portfolio.

In plain English

This article was a review, written as a drug profile, of raltitrexed in malignant pleural mesothelioma (MPM). Raltitrexed is a chemotherapy drug that blocks the enzyme thymidylate synthase. In a Phase II trial of raltitrexed alone, five of 24 patients (20.8%, 95% CI 7.1 to 42.2%) had a partial response. In a Phase II trial of raltitrexed with oxaliplatin in 70 patients, some untreated and some previously treated, 20% (14 patients; 95% CI 11.4 to 31.3%) had a partial response. A Phase II trial in 14 previously treated patients found no objective responses. A Phase III trial randomized 250 patients. Median overall survival was 8.8 months (95% CI 7.8 to 10.8) with cisplatin alone and 11.4 months (95% CI 10.1 to 15) with raltitrexed plus cisplatin (p = 0.048). Severe neutropenia and vomiting were about twice as common with the combination, and no difference in quality of life was seen. A later analysis of that trial gave a hazard ratio of 0.77 (95% CI 0.6 to 1) in favor of the combination. The authors concluded that raltitrexed with cisplatin is a welcome addition to treatment options for MPM.

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 (drug profile) of published laboratory, Phase I, Phase II and Phase III studies of raltitrexed, focusing on mesothelioma
• Who was studied: No new patients were studied. The main trial reviewed was a Phase III trial that randomized 250 chemonaive patients with histologically proven advanced MPM. The review also covered Phase II trials of 24 patients, 70 patients and 14 previously treated patients.
• Exposure: The exposure was the chemotherapy drug raltitrexed: alone at 3 mg/m2, with oxaliplatin, or with cisplatin 80 mg/m2 compared with cisplatin alone. Asbestos exposure was not the subject of the review, although a table lists the number of trial patients with asbestos exposure.
• Main results:
  • In the Phase II trial of single-agent raltitrexed, 5 of 24 patients (20.8%) achieved a partial response. Table 1 gives a 95% CI of 7.1 to 42.2%.
  • In the Phase II raltitrexed plus oxaliplatin trial, 70 patients were enrolled, both chemonaive and previously treated. In this overall population, 20% (14 patients) had a partial response (95% CI 11.4 to 31.3% in Table 1), and 46% (32 patients) had stable disease.
  • In a Phase II trial of raltitrexed plus oxaliplatin in 14 previously treated patients, there were no objective responses.
  • In the Phase III trial, the response rate was 13.6% in the cisplatin arm and 23.6% in the raltitrexed plus cisplatin arm (p = 0.056).
  • In the Phase III trial, median overall survival was 8.8 months (95% CI 7.8 to 10.8) with cisplatin alone and 11.4 months (95% CI 10.1 to 15) with raltitrexed plus cisplatin. One-year survival was 40% and 46% respectively (p = 0.048).
  • In the Phase III trial, grade 3 or 4 neutropenia and emesis (vomiting) occurred twice as often in the combination arm.
  • In the Phase III trial, no toxic deaths were seen and no difference in health-related quality of life was found between arms.
  • An updated analysis of the Phase III trial, with median follow-up of 98.17 months, gave a hazard ratio of 0.77 (95% CI 0.6 to 1) in favor of raltitrexed plus cisplatin.
  • A cost-effectiveness analysis put raltitrexed plus cisplatin at a cost per quality-adjusted life-year of GB£13,454 compared with cisplatin, and GB£27,360 compared with active supportive care.
• The authors' conclusion: The authors concluded that raltitrexed combined with cisplatin is a welcome addition to the treatment options for patients with MPM.
• Limitations the authors state:
  • About the raltitrexed plus oxaliplatin Phase II trial, the authors said results in previously treated patients may have been influenced by patient selection bias.
  • The authors noted that the raltitrexed Phase III trial reached a weaker level of statistical significance than the pemetrexed trial, which they attributed to its smaller sample size.

Topics

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

Medical terms in this study, explained in our Lexicon: Raltitrexed, Mesothelioma, Cisplatin, Overall Survival, Pleural Mesothelioma, Quality of Life, Prognosis.

Related studies

• Raltitrexed: current clinical status and future directions — E. Van Cutsem, D. Cunningham, et al. (2002)
• Raltitrexed Inhibits HepG2 Cell Proliferation via G0/G1 Cell Cycle Arrest — H. Zhao, Y. Zhang, et al. (2016)
• Combination raltitrexed (Tomudex(R))-oxaliplatin: a step forward in the struggle against mesothelioma? The Institut Gustave Roussy experience with chemotherapy and chemo-immunotherapy in mesothelioma — K. Fizazi, R. Caliandro, et al. (2000)
• Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma — B. Woods, N. Paracha, et al. (2012)
• Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer — K. Fizazi, M. Ducreux, et al. (2000)
• Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study — R. Maisano, N. Caristi, et al. (2001)

Browse more research in Expert Review of Anticancer Therapy, or return to medical research.