Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a

Our plain-English summary of Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a, by P. Soulié, P. Ruffié, L. Trandafir, et al (Journal of Clinical Oncology, 1996).

The study

• Authors: P. Soulié, P. Ruffié, L. Trandafir, I. Monnet, A. Tardivon, P. Terrier, E. Cvitkovic, T. Le Chevalier, J.P. Armand
• Journal: Journal of Clinical Oncology
• Published: 1996;14(3):878-85
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM).

Patients And Methods: Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression.

Results: Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively).

Conclusion: The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.

In plain English

This was a small, open phase I-II study at a French cancer institute. It tested two drugs given together, cisplatin by weekly infusion and interferon alfa-2a injected under the skin four days a week, in 26 previously untreated patients with advanced diffuse malignant mesothelioma (23 pleural, 3 peritoneal) enrolled between August 1991 and December 1992. Fifteen of the 26 patients had a history of asbestos exposure. The first 12 patients tolerated a 5-weeks-on, 3-weeks-off schedule poorly, so the remaining 14 received 4 weeks on, 4 weeks off. Side effects were mainly loss of appetite, fatigue and prolonged nausea and vomiting. Of 25 patients assessable for response, 10 had a partial response, and none had a complete response. The overall response rate was 40% (95% confidence interval, 20% to 60%). Median survival was 12 months for all patients, 25 months for responders and 8 months for nonresponders. The authors concluded that the combination showed encouraging activity but that the specific contribution of interferon remained speculative. They cautioned that the results came from a small group of patients.

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: Open, pilot phase I-II treatment study (single-arm, consecutive patients)
• Who was studied: 26 previously untreated patients with advanced diffuse malignant mesothelioma (23 pleural, 3 peritoneal), enrolled August 1991 to December 1992 at Institut Gustave Roussy and associated centres in France. 29 patients were referred; 3 were excluded after pathology review reclassified their tumor as adenocarcinoma. There were 21 men and 5 women, median age 56.
• Exposure: Treatment with weekly cisplatin 60 mg/m2 (day 2) plus interferon alfa-2a 3 x 10^6 IU subcutaneously on days 1 to 4 each week. Asbestos exposure was recorded by occupational history: 15 of 26 patients were listed as exposed. No fiber types are given.
• Main results:
  • 15 of 26 patients were listed as having asbestos exposure (patient characteristics table)
  • Increasing vomiting and cumulative fatigue limited treatment in the first 12 patients (group A, 5 weeks on/3 weeks off). Later patients (group B) received 4 weeks on/4 weeks off.
  • Toxicity was mainly clinical: progressive anorexia, asthenia, and prolonged nausea/vomiting
  • No episodes of febrile neutropenia were observed or reported
  • Objective responses, all partial, occurred in 10 patients (95% CI, 20% to 60%) among 25 assessable for response
  • The authors described an overall response rate of 40% (10 of 25 assessable patients; 95% CI, 20% to 60%)
  • Among pleural tumors, 6 of 12 epithelial tumors responded (50%), 2 of 8 biphasic tumors (25%), and none of 3 sarcomatous tumors
  • Median survival was 12 months (range 5 to 32) for all patients: 25 months (range 9 to 32) for responders and 8 months (range 5 to 24) for nonresponders
  • Median time to progression for the whole cohort was 6 months
  • Response rates did not differ between group A (5 of 11, 45%) and group B (5 of 14, printed as 35%)
• The authors' conclusion: The authors concluded that this pilot study showed encouraging antitumor activity in a traditionally resistant tumor, although the specific contribution of interferon remained speculative and needed further clinical research.
• Limitations the authors state:
  • The results must be interpreted cautiously because the patient cohort was small
  • There is no formal proof that interferon added benefit; weekly high-dose cisplatin alone might have produced similar activity
  • Sample sizes were too small for the comparison of tolerance between groups A and B to reach statistical significance

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Cisplatin, Histopathology, confidence interval, Median Survival.

Related studies

• Weekly systemic combination of cisplatin and interferon alpha 2a in diffuse malignant pleural mesothelioma — A. Purohit, L. Moreau, et al. (1998)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)
• Safety, feasibility and therapeutic activity of intrapleural autologous lymphocyte conditioned medium followed by systemic recombinant interleukin-2 and interferon-alpha in a patient with malignant pleural mesothelioma — S. Duensing, H. Hamm, et al. (1997)
• 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)
• Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma — S.C. White, H. Anderson, et al. (2000)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)

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