A phase II trial of dose-escalated doxorubicin and ifosfamide/mesna in patients with malignant mesothelioma

Our plain-English summary of A phase II trial of dose-escalated doxorubicin and ifosfamide/mesna in patients with malignant mesothelioma, by L.Y. Dirix, J. van Meerbeeck, D. Schrijvers, et al (Annals of Oncology, 1994).

The study

• Authors: L.Y. Dirix, J. van Meerbeeck, D. Schrijvers, B. Corthouts, A. Prové, E. van Marck, P. Vermeire, A.T. van Oosterom
• Journal: Annals of Oncology
• Published: 1994;5(7):653-5
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: This study investigated the feasibility and efficacy of doxorubicin dose-escalated chemotherapy in combination with ifosfamide in patients with malignant mesothelioma.

Patients And Methods: In this single institution phase II study, 24 chemotherapy-naive, eligible patients were entered. The chemotherapy regimen consisted of doxorubicin 75 mg/m2 in combination with ifosfamide 5 gr/m2 given as a continuous 24 hour infusion, every 21 days with either rhG-CSF (5 micrograms/kg) or rhGM-CSF (250 micrograms/m2) as haematopoietic support from d3 to d14. Cycles were repeated every 3 weeks.

Results: We treated 24 patients, of whom 22 are evaluable for tumour response. One of the two inevaluable patients died from a cerebral haemorrhage during a period of grade III thrombocytopenia after the second course. In 7 patients a partial response was observed, resulting in a response rate of 32% (95% confidence interval 13%-51%). Median response duration was 6 months (range 1-13) and median survival was 7 months (range 1-18).

Conclusions: The high-dose regimen with growth factor support is feasible in this group of patients and leads to an interesting response rate. The limiting toxicity for further dose increments and more courses of treatment, was cumulative thrombocytopenia. There seems to be a subgroup of patients with malignant mesothelioma which is less susceptible to develop thrombocytopenia. However, the overall toxicity and the poor response duration limit the use of this schedule in the treatment of malignant mesothelioma.

In plain English

This single-hospital phase II trial at University Hospital Antwerp, Belgium, tested a high-dose chemotherapy combination in people with malignant mesothelioma who had not had chemotherapy before. Between March 1990 and December 1992, 24 patients (18 men, 6 women) received doxorubicin 75 mg/m2 with ifosfamide 5 gr/m2 and mesna every three weeks, for up to six cycles. They also received a blood-cell growth factor: GM-CSF for the first 12 patients and G-CSF for the next 12. Of the 22 patients who could be assessed for response, 7 had a partial response, a response rate of 32% (CI 13%-51%). Median response duration was 6 months, and median overall survival was 7 months (range 2-18). Side effects were frequent. Grade III or IV low white cell counts occurred in 64 of 84 cycles, and grade III or IV low platelet counts occurred in 24 of 84 cycles, worsening with more cycles. One patient died of a brain haemorrhage while platelet counts were low. The authors concluded the regimen was feasible, but that its overall toxicity and short responses limit its use. They noted the trial was not randomised.

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-institution phase II (non-randomised) treatment trial
• Who was studied: 24 previously untreated patients (18 men, 6 women) with histologically proven malignant mesothelioma, University Hospital Antwerp, Belgium, entered March 1990 to December 1992; 22 evaluable for response, all 24 for toxicity
• Exposure: Chemotherapy: doxorubicin 75 mg/m2 as an i.v. bolus plus ifosfamide 5 gr/m2 as a 24-hour infusion, with mesna, every 21 days for up to six cycles, with rhGM-CSF (first 12 patients) or rhG-CSF (latter 12 patients) as growth factor support. Table 1 lists 'Known asbestos exposure', but the scanned table does not show how many patients this applied to.
• Main results:
  • Among the 22 response-evaluable patients, 7 had a partial response (response rate 32%, CI 13%-51%); there were no complete responses
  • Median response duration among responders was 6 months (range 1-13)
  • Median overall survival of the 22 evaluable patients was 7 months (range 2-18); 6 months (2-10) in non-responders and 7 months (range 7-18) in responders
  • Grade III/IV leukopenia and/or neutropenia occurred in 64 of 84 cycles, and grade IV in 40 of 84 cycles
  • Grade III/IV thrombocytopenia (low platelets) occurred in 24 of 84 cycles, with evidence of cumulative toxicity
  • One patient had a cerebral haemorrhage during grade III thrombocytopenia after the second cycle (the one toxic death)
  • Initial platelet count correlated linearly with the lowest platelet count after the first cycle (r = 0.811, p = 0.0001) and the second cycle (r = 0.821, p = 0.0001)
• The authors' conclusion: The authors concluded that the high-dose regimen with growth factor support was feasible and gave an interesting response rate. Cumulative thrombocytopenia limited further dose increases. They also concluded that the overall toxicity and poor response duration limit the use of this schedule in malignant mesothelioma, and that their results gave no argument that the higher response rate was clinically significant.
• Limitations the authors state:
  • The trial was not randomised, and the authors stated that comparisons with earlier (historical) results are not a reliable way to judge whether a regimen is superior

Topics

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

Medical terms in this study, explained in our Lexicon: Doxorubicin, Mesothelioma, Chemotherapy, confidence interval, Median Overall Survival.

Related studies

• High-dose doxorubicin, dexrazoxane, and GM-CSF in malignant mesothelioma: a phase II study-Cancer and Leukemia Group B 9631 — M.P. Kosty, J.E. Herndon, et al. (2001)
• Treatment of malignant mesothelioma with epirubicin and ifosfamide: a phase II cooperative study — M.D. Magri, S. Foladore, et al. (1992)
• Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study — A. Scherpereel, T. Berghmans, et al. (2011)
• Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study — G. Hillerdal, J.B. Sorensen, et al. (2008)
• Phase-II study with the combination of cisplatin and doxorubicin in advanced malignant mesothelioma of the pleura — H. Henss, H.H. Fiebig, et al. (1988)
• Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors — C.A. Johnson, D. Kilpatrick, et al. (1997)

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