COPENHAGENFor patients with locally advanced or metastatic
bladder cancer (transitional cell carcinoma of the urothelium), the
combination of gemcitabine (Gemzar) and cisplatin (Platinol) may
offer a less toxic regimen, according to a presentation at the ASCO meeting.
MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin), the only
regimen with proven survival benefit for this population, is
associated with considerable toxicity, especially neutropenic sepsis
and mucositis, according to Hans Von der Maase, MD, Aarhus University
Hospital, Copenhagen, Denmark.
Dr. Von der Maase led a phase III multicenter trial in 19 countries
(mostly European), following phase II studies demonstrating that the
gemcitabine/cisplatin combination is active, safe, and well
The primary endpoint of the trial was overall survival and the result
was 4-month improvement. Secondary endpoints included response, time
to disease progression, time to treatment failure, toxicity, changes
in quality of life, and utilization of various medical resources.
No Prior Chemotherapy
None of the 405 patients (median age, 63; 79% male) in the study had
Patients were randomized to receive either gemcitabine/cisplatin
(with gemcitabine at 1,000 mg/m² on days 1, 8, and 15, and
cisplatin at 70 mg/m² day 2) or MVAC every 28 days, for a
maximum of six cycles.
The MVAC regimen consists of 28-day cycles of methotrexate at 30
mg/m² days 1, 15, and 22; vinblastine 3 mg/m² days 2, 15,
and 22; Adriamycin 30 mg/m² day 2; and cisplatin 70 mg/m²
day 2. As in the other arm of the study, cisplatin was given at 70
mg/m² on day 2.
Eighty-four percent of gemcitabine/cisplatin and 82% of MVAC patients
had the bladder as primary tumor site. In addition, 70% of
gemcitabine/cisplatin and 64% of MVAC patients had metastatic disease.
After a median follow-up of 19 months, overall survival was 13.8
months in the gemcitabine/cisplatin arm and 14.8 months in the MVAC
arm. There were 274 deaths.
Complete responses were reported in 12% of both groups, and partial
responses were found in 37% of gemcitabine/cisplatin patients and 34%
of MVAC patients, for overall rates of 50% of gemcitabine/cisplatin
patients and 46% of MVAC patients.
Time to progressive disease, which occurred among 334 participants,
was 7.4 months for both study arms. None of the differences were
statistically significant, Dr. Von der Maase said.
Negative prognostic factors included Karnofsky index less than 80,
elevated alkaline phosphatase levels, and the presence of rhizome
metastases. Adjusting for these factors did not reveal any
differences in outcomes, Dr. Von der Maase pointed out.
Toxicity Rates Vary
Grade 3-4 anemia occurred more frequently in the
gemcita-bine/cisplatin group (26%) than in the MVAC group (17%), as
did thrombocytopenia56% in the gemcitabine/cisplatin group and
21% in the MVAC group. Grade 3-4 neutropenia, however, occurred more
often in the MVAC group (82%) than in the gemcitabine group (71%). In
the MVAC group, 65% of neutropenia cases were grade 4.
More importantly, Dr. Von der Maase said, we should
look not at the lab values, but at the hematologic
He pointed out that hemorrhage rates were the same for both arms at
2%, but neutropenic fever was reported in 5% of gemcitabine patients
and in 22% of MVAC patients. Also, neutropenic sepsis was found in 1%
of gemcitabine patients and 12% of MVAC patients. Toxic death rates
were 1% and 3%, respectively.
Nonhematologic toxicities were more common for MVAC, Dr. Von der
Maase said. The infection rate was 2.5% for gemcita-bine vs 15% for
MVAC; mucositis 1% vs 22%; diarrhea 3% vs 7.5%; and alopecia 11% vs
55%. There were no differences in nausea and vomiting and other
While improvements in emotional function and pain were noted in both
arms, and quality of life, in general, was maintained, fatigue scores
worsened in the MVAC arm.
Medical resource utilization was higher for MVAC with increases in
need for G-CSF (Neupogen), antifungals, antivirals, and antibiotics.
Need for transfusions was slightly higher with gemcitabine/cisplatin.
Most striking was the increase in admissions in the MVAC group for
neutropenic fever49 admissions, totaling 272 days. For the
gemcitabine group, there were only 9 admissions, for a total of 33 days.
Positive or Negative Result?
Dr. Von der Maase concluded that efficacy was similar between
treatment arms, but that toxicities were higher for MVAC. The
risk-benefit profile in this large randomized trial support the use
of the combination of gemcitabine and cisplatin as a new standard in
patients with locally advanced and/or metastatic transitional cell
carcinoma of the urethelium.
Following Dr. Von der Maases presentation, some objections were
raised over considering the trials outcomes to be sufficient to
merit proclaiming a new standard of practice. It was pointed out that
the trials primary objective was, indeed, survival benefit,
making the trial a negative one.
Dr. Von der Maase replied, I consider it a positive trial
The objection was also raised that G-CSF was not given routinely to
MVAC patients, which might have accounted for the increased toxicities.
Howard Scher, MD, Memorial Sloan-Kettering Cancer Center, the ASCO
session discussant, reviewed the positive aspects of the trial and
the objections noted above and concluded, My own bias is toward
the former, that if a regimen is easier and appears to be similar in
terms of survival it should at least be offered as an
He added, however, There is really no cause for celebration. We
have made no impact on survival time.