CHICAGONo overall gain was seen with ranpirnase (Onconase)
compared with doxorubicin in unresectable malignant mesothelioma, but
there was a trend toward ranpirnase benefit in good-prognosis
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
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
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.
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.
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
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.