MIAMI--In terms of randomized trial results, the M-VAC (methotrexate,
vinblastine, Adriamycin, cisplatin) regimen should probably be
considered the standard of treatment for metastatic bladder cancer,
but the overall outlook with this regimen is not optimal, and newer
treatments are needed.
"I think its entirely appropriate for us to be using some
of the newer agents in patients with metastatic bladder cancer
because the long-term results with M-VAC have been so
disappointing," said Derek Raghavan, MD. Some of those newer
agents include paclitaxel (Taxol), gemcitabine (Gemzar), ifosfamide
(Ifex), and gallium nitrate.
Speaking at the 13th meeting of the Network for Oncology
Communication and Research (NOCR), Dr. Raghavan, head of the Oncology
Department at the University of Southern California Norris
Comprehensive Cancer Center, focused his talk on paclitaxel and
gemcitabine regimens, as well as trials of neoadjuvant chemotherapy.
An ECOG study (Roth et al), he said, is showing that a conventional
24-hour infusion of paclitaxel (250 mg/m²) results in a high
single-agent response rate in previously untreated patients of about
25% to 30%. "The issue of complete vs partial response is going
to depend on the selection of patients," he said.
He noted that with both paclitaxel and M-VAC, median survival is
about 1 year. "So really paclitaxel is a very reasonable
treatment to be using. Paclitaxel is also active in patients who have
failed theM-VAC regimen," he added.
Paclitaxel appears to work better in patients who have lymph node and
soft tissue metastases rather than in those with liver or bone
metastases. Dr. Raghavan pointed out that this is the same as in the
M-VAC randomized trials, which showed that patients with liver and
bone involvement had a shorter median survival time and a lower
"In my practice, Ive seen responses in liver metastases,
but Ive not used pacli-taxel as a single agent; Ive used
it in context with the platinum complexes," he said.
Dr. Raghavan said that researchers are now looking at combination
regimens with paclitaxel. At Vanderbilt University Cancer Center, a
study under the direction of Dr. Barbara Murphy is using paclitaxel
plus carboplatin (Paraplatin) (ECOG URO 2896).
Investigators from Memorial Sloan-Kettering and M.D. Anderson have
done studies combining paclitaxel and cisplatin (Platinol) with
either ifosfamide or methotrexate and are getting response rates of
70% to 80%. Preliminary data of the ITP (ifosfamide, Taxol, Platinol)
regimen at Sloan-Kettering were presented at ASCO last year, showing
responses in four of four patients. "When the series was updated
with a more respectable number of cases, the response rate dropped
somewhat," he said.
Still, Dr. Raghavan concludes that "paclitaxel is an active drug
with a high response rate when used in previously treated and
Dr. Raghavan said that he has had more experience with gemcitabine in
his own clinical practice. He pointed out that gemcitabine is a
prodrug that gets into tumor cells with greater facility and
"interestingly stays in there longer so there is a greater
period of exposure to tumor tissue."
Two nearly identical studies (published in J Clin Oncol,
November 1997) looked at using gemcitabine in previously untreated
bladder cancer. Dr. Raghavan pointed out that neither study seemed to
have a selection bias, as the median age for the studies was about
As a single agent, gemcitabine showed a 25% to 30% response rate.
"This is no better or worse than paclitaxel or cisplatin, which
makes it another drug that can be added to the lexicon of active
agents in bladder cancer," he said. "Of great importance,
gemcitabine is one of the gentlest drugs for this elderly population."
Dr. Raghavan said that while most of his experience is with
gemcitabine and paclitaxel, ifosfamide and gallium nitrate are also
being studied for use in bladder cancer. ECOG has shown ifosfamide to
be a very active single agent with a response rate of 20% in patients
previously treated with M-VAC.
The studies on gallium nitrate are also showing it to be a fairly
active agent in bladder cancer. "Ive never worked with
it," he said, "and I have always been a little uneasy about
a drug that tends sporadically and unpredictably to cause
Preliminary trials of neoadjuvant chemotherapy in bladder cancer are
not yet showing great promise. The EORTC-MRC trial, presented at ASCO
in 1996, was a huge international trial looking at the use of CMV
(cisplatin, methotrexate, vinblastine) plus definitive treatment in
nearly 1,000 bladder cancer patients with high-grade invasive
"Each institution could choose either radiotherapy or surgery as
the definitive treatment, but then had to stay with that choice,"
he explained. The cohort was split about 50/50 between cystectomy
and radiotherapy. There was virtually no significant difference in
disease-free survival at 2 years. Neoadjuvant chemotherapy did show a
downstaging of disease.
From this study, it may appear that neoadjuvant chemotherapy simply
does not work. "But its important to note that this study
did not have a central pathologic review, and there may have been
nonrandom bias with T1, T2 tumors," he said. "Further, this
has only tested the CMV regimen. It is quite possible that the US
randomized trial of M-VAC will be positive, since the Swedish study
showed a survival benefit from AC [Adriamycin, Cisplatin]."
US Intergroup Study
Another ongoing study of neoadjuvant chemotherapy in bladder cancer,
however, may show different results, he said. The US Intergroup Study
is looking at 400 cases. This study is similar to the EORTC trial but
with the addition of being rigorously controlled and having a
pathologic review. "My hunch is that it is going to be a
positive study," Dr. Raghavan said.
Whatever the results of the Intergroup study, it will be another
stone upturned on the pathway to finding better treatment for bladder
cancer. Dr. Raghavan explained that if the results are negative, then
it has to simply be accepted that neoadjuvant chemotherapy does not
work. However, if the results are positive, then the results from the
EORTC study need to be reevaluated.
"At present, there is no defined evidence for neoadjuvant
chemotherapy," he said. "The correct thing to say to
patients is watch this space because I think the key will
come from the US Intergroup Study."
What about adjuvant chemotherapy after cystectomy? The best study,
according to Dr. Raghavan, comes from Stanford University (Freihau et
al). All patients underwent cystectomy. Patients with node-positive
disease were given four cycles of adjuvant CMV (with a cisplatin dose
of 100 mg/m²) and no Adriamycin. Simple observation of the
patients treated with CMV followed at the time of relapse. There was
a clear benefit in disease-free survival, but not in median overall
survival. "However," he said, "the study was
dreadfully underpowered, with fewer than 100 cases randomized."
Many patients ask about adjuvant paclitaxel or gemcitabine. "My
answer is that they are untested in the adjuvant setting, and I say
to leave it to the academic centers to test the hypothesis," Dr.
Raghavan said. "At present, the standard adjuvant
treatment is M-VAC or CMV."
He also emphasized that oncologists need to place an increased demand
on their pathologists to look for the p53 mutation and microvessel
density in making their diagnoses. The p53 mutation has been shown to
be an adverse prognostic marker in bladder cancer patients.
"It doesnt matter if you believe that radiotherapy,
cystectomy, chemotherapy, or a combination is the way to go," he
said. "The problem is that invasive bladder cancer is a systemic
disease, and without an effective strategy, up to half the patients
are going to die in 5 years."