Malignant pleural mesothelioma (MPM)

A randomized phase III study of cisplatin with or without raltitrexed in patients (pts) with malignant pleural mesothelioma (MPM)


Abstract:
Background: MPM is characterized by an increasing incidence and refractoriness to available cytostatic drugs. Phase I and II trials in mesothelioma pts using raltitrexed- a thymidine synthase inhibitor- with and without platinum showed an ORR of 20-35% (Fizazi, 2000 and 2003) and of 21%(Baas, 2003) respectively and provide the rationale for the design of this randomized study.

Methods: Eligible pts had to have histologically proven unresectable MPM, not pretreated with chemotherapy, WHO PS ≤ 2, and adequate hematological, renal and hepatic function. Stratification was by institution, PS (0 vs.1-2) and WBC (< 8.3 109/l vs. ≥ 8.3 109/l). After written informed consent, pts were randomized between cisplatin 80 mg/m2 iv on day 1, without (Arm A) or with (Arm B) preceding infusion of raltitrexed 3 mg/m2. Treatment was continued q3 weeks unless refusal, progression or unacceptable toxicity occurred. Appropriate dose reductions were made in case of toxicity. In pts with measurable disease, response was monitored using RECIST criteria. The study was powered to detect a 50% increase in median survival with a 2 sided alpha error of 0.05 and a beta error of 0.2 (sample size of 240 pts).

Results: Between November 1999 and January 2003, 250 pts with following characteristics were randomized: 20% females, median age 58 years (range 19-80), PS 0/1/2: 25/62/13% and histological subtype epithelial/non-epithelial: 68/24%.The median number of cycles in arm A was 4 (range 1-9) and in B 5 (range 1-9). Comparable relative dose intensities of cisplatin were obtained. There were no toxic deaths. The main gr ¾ toxicities observed were (in % of pts of arm A/B respectively): neutropenia 8/16, TRC-penia 0/2, fatigue 5/12, nausea 10/14, emesis 7/13, pleuritic pain 10/6, dyspnea 8/10. Among 207 pts with measurable disease, 14 PR in arm A, 1 CR and 24 PR in arm B were observed (ORR 14 vs 23% respectively). Presently, all of the 195 events required for intention to treat analysis have occurred. Median overall and 1 year survival in arm A and B are 8.8 months (95%CI: 7.7-11.4) vs 11.2 months (95%CI: 10.0-13.9) and 40 vs 45% respectively (p= 0.06).

Conclusion: the present study shows a trend toward improved survival with a combination of raltitrexed and cisplatin as compared to cisplatin alone in pts with MPM, although this does not reach statistical significance.