High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma

Our plain-English summary of High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma, by M. Halme, A. Knuuttila, T. Vehmas, et al (British Journal of Cancer, 1999).

The study

• Authors: M. Halme, A. Knuuttila, T. Vehmas, L. Tammilehto, M. Mäntylä, J. Salo, K. Mattson
• Journal: British Journal of Cancer
• Published: 1999;80(11):1781-5
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Twenty six patients with pleural mesothelioma of UICC stage I-IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-alpha (3 MIU days 2-10) and recombinant IFN-gamma1b (50 microg m(-2) on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13-51%). Median duration of response was 10 months (range 3-24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1-2 renal toxicity). The combination of high dose MTX and IFN-alpha and IFN-gamma is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.

In plain English

This phase II drug trial at Helsinki University Central Hospital, Finland, did not study asbestos exposure. From March 1992 to May 1997, 26 previously untreated patients (23 men, 3 women) with malignant pleural mesothelioma took part. Twenty-one had known occupational asbestos exposure. The plan was six high-dose 3 g methotrexate doses with calcium folinate rescue, each followed by interferon-alpha and interferon-gamma injections, continued as maintenance until progression. Patients received one to six scheduled doses (mean 5.1); 18 received all six, and two of these then received six more because of continuing response. Of 24 patients whose response could be judged, seven had a partial response (29%, 95% confidence interval 13 to 51%) and none a complete response. Among all 26 patients, median survival was 17 months; 62% survived 1 year and 31% 2 years. Seven patients had grade 3 low white blood cell counts. One patient developed reversible one-sided weakness, and treatment stopped. The authors concluded high-dose methotrexate was active and the survival figures encouraging, but no benefit could be attributed to interferon; judging its effect would need a randomized trial.

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: Single-arm clinical phase II treatment study
• Who was studied: 26 patients with previously untreated, histologically confirmed malignant pleural mesothelioma, aged 18 to 70 (mean 55), 23 male and 3 female, treated at Helsinki University Central Hospital, Finland, between March 1992 and May 1997. 12 had stage I, 2 stage II, 10 stage III and 2 stage IV disease.
• Exposure: The study tested a treatment. The planned regimen was methotrexate 3 g intravenously on days 0, 14, 28, 49, 70 and 91 with calcium folinate rescue. Natural interferon-alpha 3 MIU was injected under the skin on days 2 to 10 after each methotrexate dose. Recombinant interferon-gamma 1b 50 micrograms per square metre was injected on days 2, 6 and 10. Both interferons were to continue as maintenance until disease progression. As background, 21 of 26 patients (81%) were known to have been occupationally exposed to asbestos. Fiber types were not reported.
• Main results:
  • Patients received between one and six methotrexate doses of the scheduled course (mean 5.1), and 18 received all six scheduled cycles. Two of these 18 received an additional six doses because of continuing response. Two patients received only one dose, and two received reduced doses (1.5 to 2 g).
  • Among 24 patients evaluable for response, there were no complete responses and seven partial responses (objective response rate 29%, 95% CI 13 to 51%).
  • Among the seven responders, the median duration of response was 10 months (range 3 to 24 months). Median time to progression for all patients was 4 months.
  • For all 26 patients, median survival was 17 months (range 3.5 to 36+ months). The 1-year survival rate was 62% and the 2-year rate 31%.
  • Two-year survival was 57.1% for responders (n = 7) and 11.8% for non-responders (n = 17), p less than 0.05. One-year survival was 85.7% versus 64.7%, which was not significant.
  • Toxicity in all 26 patients: 7 patients (27%) had WHO grade 3 leukopenia. Three had grade 3 transaminase elevation. Renal toxicity led to methotrexate dose reductions in two patients. One patient had WHO grade 4 neurological toxicity (hemiparesis), which was reversible and led to stopping treatment.
  • During interferon maintenance, toxicity was described as mild and transient. Flu-like symptoms were common, and one patient stopped interferon because of them.
• The authors' conclusion: The authors concluded that methotrexate at a relatively high dose is active against mesothelioma and that the survival figures were encouraging. They added that, compared with an earlier methotrexate-only study, no benefit could be attributed to adding interferon. Whether the interferons contributed to survival remained open and would require a randomized trial to assess.
• Limitations the authors state:
  • Other treatments given after methotrexate may have affected survival. Seven patients received other chemotherapy and 23 received radiotherapy.
  • The study had no comparison group, so the contribution of interferon could not be assessed without a randomized trial.
  • Response evaluation in mesothelioma is not standardized, which makes comparison between trials difficult.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, UICC, Disease Progression, confidence interval, Median Overall Survival, Immunotherapy.

Related studies

• Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines — A. Hand, K. Pelin, et al. (1995)
• High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study — O.P. Solheim, G. Saeter, et al. (1992)
• Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer — H. Fujie, T. Tanaka, et al. (2011)
• Effects of natural interferon alpha, natural tumor necrosis factor alpha and their combination on human mesothelioma xenografts in nude mice — T. Ohnuma, L. Szrajer, et al. (1993)
• Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a — P. Soulié, P. Ruffié, et al. (1996)
• Despite some expression of folate receptor alpha in human mesothelioma cells, internalization of methotrexate is predominantly carrier mediated — N.Z. Khokhar, A.F. Lam, et al. (2002)

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