CHICAGONo overall gain was seen with ranpirnase (Onconase) compared with doxorubicin(Drug information on doxorubicin) in unresectable malignant mesothelioma, but there was a trend toward ranpirnase benefit in good-prognosis patients.
In reporting these results at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO), Nicholas Vogelzang, MD, of the University of Chicago School of Medicine, said that combination ranpirnase/doxorubicin will now be tested against doxorubicin alone in a new phase III study.
Ranpirnase is an antineoplastic ribonuclease derived from frog eggs. Of 157 patients enrolled in the trial, 85 were randomized to 480 mg/m² of ranpirnase as an IV infusion over 30 minutes every week until progressive disease or toxicity occurred, and 72 were randomized to doxorubicin 60 mg/m² every 3 weeks. Tumor assessment was done every 8 weeks and toxicity assessment every 9 weeks.
Study objectives were to compare the overall survival, response rates, safety profile, and quality of life (QOL) of the two regimens. The trial was powered to detect a 50% or greater increase in median survival.
All patients had a performance status (PS) of 0 or 1, Dr. Vogelzang said, adding that 70% had epithelial disease, 15% had nonpleural primary disease, and about 15% had received prior chemotherapy.
Median survival was 7.7 months with ranpirnase vs 8.2 months with doxorubicin. One-year survivals were 30.7% vs 32.3%, and 2-year survivals were 17.8% vs 6.4% (30% of patients were censored in each arm). These differences were not statistically significant.
Patients were initially stratified only by performance status. Dr. Vogelzang explained that stratifying mesothelioma patients by stage is largely meaningless. The protocol was later amended to stratify by epithelial or nonepithelial histology.
After randomization, 25 of the 70 doxorubicin patients refused treatment or received doxorubicin locally off protocol. Minimal follow-up information is available on those patients. Only 1 of the 84 patients randomized to ranpirnase refused treatment, Dr. Vogelzang said.
Analysis by CALGB prognostic groups (Chest 113:723,1998) revealed a marked excess of poor-prognosis patients in the ranpirnase arm. Of the 85 patients randomized to ranpirnase, 38% were in the poor-prognostic groups. Of the 72 patients randomized to doxorubicin, only 17% were in the poor-prognostic groups. This difference is significant, and the randomization failed to control for this important variable, Dr. Vogelzang said.
In a subgroup analysis that excluded these patients with a poor prognosis (CALGB groups 5 and 6), Dr. Vogelzang found a median survival of 11.6 months with ranpirnase vs 9.6 months with doxorubicin. Additional subset analysis of patients with epithelial histology showed that treatment with ranpirnase had a modest effect (P = 0.1).
There was significantly more peripheral edema, arthralgia, paresthesia, myalgia, flu-like syndrome, and hypotension in patients treated with ranpirnase. There was more nausea, mucositis, constipation, and alopecia in patients treated with doxorubicin.
More patients discontinued ran-pirnase due to toxicity than did patients randomized to doxorubicin, Dr. Vogelzang commented. There were no drug-related deaths, he added.
Quality-of-life data and the independent central assessment of objective tumor response are not yet complete.
In this largest phase III trial in malignant mesothelioma, we have demonstrated that survival following ranpirnase is comparable to that of a commonly used standard therapy, doxorubicin, Dr. Vogelzang stated.
Based on these data, a second phase III trial with the aim of demonstrating a survival advantage for ranpirnase has begun. This trial will compare ranpirnase/doxorubicin to doxorubicin alone and be restricted to CALGB prognostic groups 1-4, PS 0-1.
Buzz on the Internet
The session discussant, Karen Antman, MD, of Columbia University College of Physicians and Surgeons, noted: Mesothelioma is an uncommon disease, but it is no longer rare. A reasonable estimate is about 2,000 new cases per year in the United States. There is no standard therapy. Even our best cytotoxic chemotherapy has only modest activity.
Because more ranpirnase patients refused further therapy, Dr. Antman said she would predict that the QOL data, if available, would favor doxorubicin. It is interesting that the QOL data were not available to the authors, she said.
She also noted that in the absence of survival benefits, we would ordinarily fall back on response rates in evaluating new drugs. Again, these essential data are not available to the authors.
Dr. Antman also commented on the high refusal rate of patients on the doxorubicin arm, which she attributed to the buzz on the Internet about ranpirnase.
While ranpirnase and doxorubicin appear roughly equivalent in this study, Dr. Antman raised questions about the efficacy of doxorubicin. Does doxorubicin prolong median survival over supportive care alone? Probably not. No randomized study of doxorubicin vs best supportive care exists, she said.