Phase III single-blinded study of premexetred + cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma

Reviewer: Ryan Smith, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 19, 2002

Presenter: N.J. Vogelzang
Presenter's Affiliation: U of Chicago
Type of Session: Plenary


    Mesothelioma is an aggressive malignancy with no consistent, proven benefit to any traditional treatment: surgery, radiation therapy, or any combination of chemotherapy. Premexetred is an anitfolate, targeting key enzymes in the purine and pyrimidine synthesis that has shown efficacy in phase I data. This is a phase III study randomizing patients to premexetred and cisplatin (PC) vs. cisplatin alone (C).

Materials and Methods

  • 472 patients entered the study. 452 were randomized, with 448 eligible for analysis.
  • All had unresectable mesothelioma, well-balanced with respect to KPS, gender, and histology.
  • All patients analyzed had at least 1 cycle of chemotherapy with a minimum follow up of 9 months
  • Arm A-Premexetred 500 mg/m2 over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 delivered every 3 weeks
  • Arm B-Ciplatin 75 mg/m2 alone every 3 weeks
  • As enrollment reached close to 150 patients, it was noted that there was a high rate of death and severe toxicity due to febrile neutropenia and diarrhea in the PC group. Investigation linked these toxicities to increased homocysteine and methylmalonic acid levels
  • After this toxicity was noted, the remainder of patients in both groups received folic acid (350-1000 mcg) q day and vitamin B12 (1000 mcg)q 9 weeks beginning 21 days prior to chemotherapy
  • Distribution of patients: Pre-vitamin supplementation-PC=58 patients, C=59 patients. After vitamin supplementation-PC=168, C=163. Total was PC=226 patients, C=222 patients


  • MST (total): PC=12.2 mo, C=9.3 mo (p=.02). MST (supplemented patients): PC=13.3 mo, C=10.1 mo (p=.05)
  • Time to progression (total): PC=5.7 mo vs. C=3.9 mo (p=.001). Time to progression (supplemented patients): PC=6.1 mo vs. C=3.9 mo (p=.008)
  • Risk reduction (total): PC=44% vs. C=17%. Risk reduction (supplemented patients): PC=46% vs. C=20% (p<.001)
  • Median cycles of chemotherapy delivered was 2 in the non-supplemented patients vs. 6 in the supplemented patients
  • There was a 28% rate of severe neutropenia in the PC group, though it decreased from 41% to 23% with supplementation
  • Severe nausea and vomiting decreased from 21% to 11% with supplementation
  • Lung function began improving with the start of the 2nd cycle of chemotherapy. There was more extensive improvement in the PC group. This objective improvement translated to a subjective improvement in patients' dyspnea.

Author's Conclusions

  • There was a significant improvement in survival, TTP, RR, lung function, and subjective indicators of quality of life
  • There was a reduction in toxicity with supplementation with folic acid and vitamin B12
  • This should be considered standard chemotherapy in mesothelioma

Clinical/Scientific Implications

    Mesothelioma has been a frustating disease to treat, as there has been no therapy that has consistently improved the outcome in patients. This study shows a definite improvement in survival, TTP, and RR with PC chemotherapy. Therefore, this should be the standard chemotherapy used, as it supercedes the results with all single agent chemotherapies, and is likely better than the recently popular gemcitabine and cisplatin. However, the toxicity is moderate, with the MST still around 1 year. Therefore, patients should be selected carefully to undergo this therapy. Also, investigations should continue to be made into different chemotherapy regimens. In addition, experimental treatments should continue to be investigated, as survival even with this improved regimen is low. Again, although there is evidence of symptom improvement with this regimen, the potential toxicity should still be weighed against the relatively short life span of most of these patients.

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