Trimetrexate in malignant mesothelioma: A Cancer and Leukemia Group B Phase II study

Our plain-English summary of Trimetrexate in malignant mesothelioma: A Cancer and Leukemia Group B Phase II study, by N.J. Vogelzang, L.B. Weissman, J.E. Herndon, et al (Journal of Clinical Oncology, 1994).

The study

• Authors: N.J. Vogelzang, L.B. Weissman, J.E. Herndon, K.H. Antman, M.R. Cooper, J.M. Corson, M.R. Green
• Journal: Journal of Clinical Oncology
• Published: 1994;12(7):1436-42
• Cited by: 61 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Folic acid antagonists are reported to have activity against mesothelioma. The Cancer and Leukemia Group B (CALGB) undertook this phase II study of the new antifolate, trimetrexate (TMTX), to evaluate its response rate and toxicity in chemotherapy-naive patients with malignant mesothelioma.

Patients And Methods: Fifty-two patients were accrued to this protocol. Because of concerns about TMTX toxicity in patients with malignant effusions and/or hypoalbuminemia, the first 17 patients were treated at a dose of 6 mg/m2 daily for 5 days every 21 days. Because minimal toxicity was observed, the subsequent 35 patients were treated at a dose of 10 mg/m2.

Results: Two of 17 patients (12%) in the 6-mg/m2 treatment group had a partial response (PR) and four of 34 eligible patients (12%) in the 10-mg/m2 treatment group had a PR or regression (R) of assessable disease. No patient achieved a complete response (CR). Median survival durations were 5.0 and 8.9 months in the 6- and 10-mg/m2 treatment groups, respectively, while the 2-year survival rates were identical at 18%. At the 10-mg/m2 dose, toxicity was tolerable, with one toxic death from sepsis and a 12% rate of grade 4 thrombocytopenia and granulocytopenia.

Conclusion: In this large trial, TMTX showed minor activity in the treatment of malignant mesothelioma. Myelosuppression was mild and dose-related. Future studies of higher doses of TMTX should be considered.

In plain English

This phase II trial tested trimetrexate in chemotherapy-naive malignant mesothelioma patients. Fifty-two patients enrolled from July 1989 to August 1991; 11 of 17 and 20 of 34 in the two groups were recorded as asbestos-exposed. The first 17 were assigned 6 mg/m2 daily for 5 days every 21 days; eight started at 4 mg/m2 because of low albumin. The next 35 enrolled at 10 mg/m2; one cancelled before treatment. No patient achieved a complete response. Tumors shrank in two of 17 lower-dose patients (12%; 95% confidence interval 2% to 33%), one after escalation to 12 mg/m2, and in four of 34 higher-dose patients (12%; 7% to 29%). Median survival was 5.0 months (95% confidence interval 1.9 to 9.6) at the lower dose and 8.9 months (6.5 to 13.8) at the higher; both had 18% 2-year survival. At the higher dose, one patient died of granulocytopenia and infection; severe (grade 4) white-cell and platelet drops each affected 12%. The authors concluded trimetrexate showed minor activity; they could not determine whether the longer higher-dose survival reflected dose, group differences, or small numbers.

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: Phase II clinical trial (two-stage design for each starting dose) by the Cancer and Leukemia Group B (CALGB)
• Who was studied: 52 patients with histologically confirmed, unresectable malignant mesothelioma (epithelial, sarcomatoid, or mixed histology) who had received no prior chemotherapy, accrued July 1989 to August 1991 at CALGB institutions. 17 patients were in the 6-mg/m2 cohort. 35 were enrolled in the 10-mg/m2 cohort; one cancelled consent before therapy, leaving 34. Most patients had pleural primary tumors.
• Exposure: The treatment studied was trimetrexate (TMTX), an antifolate drug, given as a 5-minute intravenous bolus daily for 5 days every 21 days. The first 17 patients had a starting dose of 6 mg/m2/d, but eight of them actually started at 4 mg/m2/d because of albumin of 2.5 to 3.5 g/dL. Later patients started at 10 mg/m2/d. Dose escalation was allowed.
• Main results:
  • 6-mg/m2 cohort: 2 of 17 patients had a partial response (12%; 95% confidence interval 2% to 33%); no patient in either cohort achieved a complete response
  • 6-mg/m2 cohort: one of the two partial responses was achieved 14 months after study entry, following a dose increase to 12 mg/m2/d
  • 10-mg/m2 cohort: 4 of 34 patients had a partial response or regression (two of each) (12%; 95% confidence interval 7% to 29%); 22 (65%) had stable disease
  • Response durations were 3.5, 4.3, 6.5, and 34.2+ months in the 10-mg/m2 cohort, and 7.4 and 23.8 months in the 6-mg/m2 cohort
  • Median time to treatment failure was 4.4 months (95% confidence interval 3.7 to 6.4) in the 10-mg/m2 cohort and 1.5 months (95% confidence interval 1.3 to 2.5) in the 6-mg/m2 group
  • Median survival was 5.0 months (95% confidence interval 1.9 to 9.6) in the 6-mg/m2 cohort and 8.9 months (95% confidence interval 6.5 to 13.8) in the 10-mg/m2 cohort
  • 2-year survival was 18% in both cohorts
  • 10-mg/m2 cohort: one toxic death from granulocytopenia and infection, at the initial dose level
  • 10-mg/m2 cohort: grade 4 thrombocytopenia occurred in 12% of patients; grade 3 or 4 granulocytopenia occurred in 24%, and was grade 4 in 12%
  • 6-mg/m2 cohort: no lethal events, and only two patients had grade 4 toxicity
  • Asbestos exposure (listed in Table 1 under possible carcinogen exposures) was recorded as 'yes' for 11 of 17 patients (65%) in the 6-mg/m2 cohort and 20 of 34 (59%) in the 10-mg/m2 cohort
• The authors' conclusion: The authors concluded that in this large trial TMTX showed minor activity in the treatment of malignant mesothelioma, that myelosuppression was mild and dose-related, and that future studies of higher doses should be considered. In the discussion they suggested 12 to 14 mg/m2/d for 5 days.
• Limitations the authors state:
  • The authors stated that these data cannot determine whether the longer time to treatment failure and survival in the higher-dose group reflect the higher dose, other prognostic factors, or a misimpression based on the small numbers of patients
  • The authors noted that the low-dose group had a slightly older median age, more weight loss, and more nodal involvement than the high-dose 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: Malignant Mesothelioma, Mesothelioma, Antifolate, Chemotherapy, Median Survival.

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