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Recent Developments in Chemotherapy for Bladder Cancer

Recent Developments in Chemotherapy for Bladder Cancer

ABSTRACT: Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials. [ONCOLOGY 15(6):763-780, 2001]

Introduction

An estimated 54,300 new cases
of bladder carcinoma will be
diagnosed in the United States in 2001, with 12,400 deaths attributable to this
cancer.[1] The majority of these tumors will be superficial, confined to the
mucosa and lamina propria of the bladder. Although these superficial bladder
cancers frequently recur and may be multifocal, survival is excellent. To
decrease rates of recurrence and progression, these tumors are best approached
with cystoscopic surgery and, in select cases, intravesical drug therapy with,
for example, bacillus Calmette-Guérin or chemotherapeutic agents.

When a tumor invades the muscular wall of the bladder, the
prognosis markedly worsens because of the increased risk of metastatic
progression. For this reason, there is a clear need for effective systemic
chemotherapy for bladder cancer. Systemic chemotherapy may be used for the
palliation of metastatic disease, and in a select minority of these patients, to
achieve long-term survival. In the earlier-disease, perioperative setting,
chemotherapy may be considered to eradicate microscopic metastases and increase
surgical cure rates. This article will discuss recent developments in
chemotherapy for invasive bladder cancer.

Chemotherapy for Advanced Bladder Cancer

Transitional cell carcinoma of the urothelium is a
chemotherapy-sensitive tumor. Significant response rates have been demonstrated
with the single agents cisplatin (Platinol), methotrexate, cyclophosphamide
(Cytoxan, Neosar), doxorubicin, and vinblastine, among others. Cisplatin-based
combination regimens, such as M-VAC (methotrexate, vinblastine, doxorubicin
[Adriamycin], cisplatin) and CMV (cisplatin, methotrexate, vinblastine), have
been studied extensively.

M-VAC-Based Treatment

Investigators at Memorial Sloan-Kettering Cancer Center (MSKCC)
developed M-VAC in the 1980s, and a phase II investigation suggested response
rates as high as 72%, with a 36% complete response rate.[2] Randomized trials
have demonstrated that M-VAC is superior to both single-agent cisplatin and
CISCA (cisplatin, cyclophosphamide, Adriamycin).[3,4]

The Intergroup phase III trial in 246 evaluable, previously
untreated patients with advanced urothelial carcinoma who had been randomized to
single-agent cisplatin vs M-VAC revealed the combination to have a higher
response rate (39% vs 12%; P = .0001) and improved overall survival (12.5 vs 8.2
months; P = .0002).[3] When investigators at the M. D. Anderson Cancer Center
randomized patients with advanced disease to M-VAC vs CISCA, M-VAC was shown to
be superior with respect to response rate (65% vs 46%; P < .05) and overall
survival (46 vs 36 weeks; P = .000315).[4] Based on these randomized trials,
M-VAC has emerged as the standard treatment
for patients with metastatic urothelial carcinoma.

The most important limitation of M-VAC is toxicity and poor
patient tolerance. In the Intergroup trial, the combination showed substantially
more toxicity, including mucositis, myelosuppression, and treatment-related
deaths, than single-agent cisplatin. Additionally, some patients with advanced
urothelial carcinoma have age- and/or disease-related renal dysfunction that
makes cisplatin-based regimens problematic. Nevertheless, M-VAC remains an
important milestone in the development of chemotherapy for bladder cancer.

In an effort to improve the therapeutic index of M-VAC, studies
have been conducted to find ways to improve the tolerability or increase the
efficacy of the regimen. The addition of granulocyte colony-stimulating factor
(G-CSF [Neupogen]) to M-VAC has been shown to abrogate some of the toxicities,
including mucositis and granulocytopenia.[5] Several studies have attempted dose
intensification of M-VAC by using hematopoietic growth factors; however, the
results have generally been disappointing.[6-8] At the 2000 meeting of the
American Society of Clinical Oncology (ASCO), the European Organization for the
Research and Treatment of Cancer (EORTC) reported the results of a phase III
trial that failed to demonstrate a survival advantage for high-dose-intensity
M-VAC and G-CSF, compared to standard M-VAC.[9]

Early phase II trials of M-VAC suggested that this regimen had
the potential to cure patients with advanced urothelial cancer. But the
effectiveness of M-VAC with respect to long-term survival, and which patients
were most likely to derive a long-term benefit, was unknown. A recent study by
Bajorin et al from MSKCC addressed these issues. In this series, in which 203
patients with advanced bladder cancer were treated with M-VAC, the presence of
visceral (lung, liver, or bone) metastases and a baseline Karnofsky performance
status less than 80% predicted independently for a poor outcome. Patients with
both of these risk factors had a 5-year survival of 0% (median survival: 9.3
months). However, if patients had neither risk factor, the probability of
achieving 5-year survival jumped to 33% (median survival: 33 months).[10]

At 6-year follow-up of the previously described Intergroup trial
comparing M-VAC and single-agent cisplatin in patients with advanced urothelial
cancer, the chance of long-term, cancer-free survival in patients treated with
M-VAC was only 3.7%. Predictors for poor outcome in this study included
nontransitional histology, poor performance status, and/or bone/visceral
metastasis.[11] Thus, the probability of long-term survival for many patients
treated with M-VAC is small. The identified poor prognostic factors are
clinically useful in predicting the potential for a long-term benefit from
combination chemotherapy regimens such as M-VAC. This information can also be
used when evaluating reported trials of new chemotherapy regimens, since patient
selection may significantly influence results.

In summary, M-VAC is an active—but toxic—regimen for
advanced bladder cancer. Given the small chance for long-term survival for most
patients treated with this regimen, efforts to identify new agents and
combinations with improved efficacy or tolerability have been ongoing. Newer
agents with significant activity include gemcitabine (Gemzar) and paclitaxel
(Taxol).

Gemcitabine for Advanced
Bladder Cancer

Gemcitabine (2´2´-difluorodeoxycytidine) is a cytosine analog
with a structure that is similar to cytarabine. Gemcitabine is approved by the
US Food and Drug Administration for the palliative treatment of patients with
advanced pancreatic cancer, but it has broad antitumor activity, including
activity in bladder cancer.

A review of gemcitabine in bladder cancer was recently
published.[12] In phase I studies of gemcitabine, responses were reported in
patients with bladder cancer.[13] Based on this activity, phase II studies were
initiated in advanced urothelial cancer. Lorusso et al treated 31 evaluable
patients who had previously received cisplatin with gemcitabine, 1,200 mg/m2
administered on days 1, 8, and 15 every 28 days. A response rate of 22.5% was
demonstrated (95% confidence interval [CI] = 8%-37%).[14] Stadler et al[15]
and Moore et al[16] performed phase II trials in patients with advanced bladder
cancer who were previously untreated with chemotherapy. Patients received
gemcitabine, 1,200 mg/m2, on days 1, 8, and 15 every 28 days. Response rates in
these trials were 28% (95% CI = 15%-45%) in the Stadler trial and 24% (95% CI
= 12%-41%) in the Moore trial. Median survival was 12.5 and 8 months,
respectively. In all these phase II trials, this therapy was well tolerated;
toxicity was generally mild and reversible.

Gemcitabine/Cisplatin: Based on the significant single-agent
activity and the acceptable toxicity profile of gemcitabine in patients with
bladder cancer, combination trials with cisplatin were performed subsequently.
Three phase II trials of the combination of gemcitabine/cisplatin have been
reported (Table 1).[17-20]

Von der Masse et al treated 44 patients with gemcitabine, 1,000
mg/m2, and cisplatin, 35 mg/m2, on days 1, 8, and 15 every 28 days.[17] A
response rate of 41% (95% CI = 25%-58%) was reported. Toxicities included
grade 3/4 granulocytopenia in 46% and thrombocytopenia in 71% of patients. Moore
et al treated 31 patients with gemcitabine, 1,000 mg/m2, on days 1, 8, and 15,
and cisplatin, 70 mg/m2, on day 2 every 28 days.[18] An overall response rate of
57% was demonstrated in this study (95% CI = 37%-76%). Toxicity was
principally hematologic with grade 3/4 granulocytopenia reported in 39% and
grade 3/4 thrombocytopenia in 55% of patients. Median survival for all patients
was 13.2 months. Kaufman et al reported the results of a multi-institutional
phase II trial of the combination of gemcitabine/cisplatin.[19] A total of 46
patients were treated in this study. Initial doses were gemcitabine, 1,000 mg/m2
on days 1, 8, and 15 every 28 days, with cisplatin, 100 mg/m2, on day 2. Due to
excessive hematologic toxicity in the first cohort of 11 patients, the cisplatin
dose was reduced to 75 mg/m2 for the duration of
the trial. The objective response rate was 41% with a median survival of 14.3
months. Toxicity included grade 3/4 granulocytopenia in 74% and grade 3/4
thrombocytopenia in 65% of patients.

Gemcitabine/Cisplatin vs M-VAC: Given the promising
results noted in the phase II trials of gemcitabine/cisplatin, an
industry-sponsored phase III trial comparing combination gemcitabine/cisplatin
with the standard M-VAC regimen in patients with previously untreated, advanced
bladder cancer has been performed in Europe and the United States.[20] This
trial was initiated in 1996 and reached its accrual goal of 405 patients in
1998. Patients with previously untreated, locally advanced disease (T4b, N2, N3)
or metastatic transitional cell carcinoma of the urothelium were randomized to
receive gemcitabine, 1,000 mg/m2, on days 1, 8, and 15, and cisplatin
70 mg/m2, on day 2 every 28 days vs
M-VAC. The primary end point was overall survival, and the study was
sufficiently powered to detect a 4-month improvement in survival. Secondary end
points included response rate, time to tumor progression, toxicity, quality of
life, and resource utilization. The median age of the study population was 63
years, and the arms were well balanced with respect to prognostic risk factors,
performance status, and presence of visceral metastases.

The overall survival for the group treated with
gemcitabine/cisplatin was 13.8 months vs 14.8 months for those treated with
M-VAC (not a statistically significant difference). The response rate (49% for
gemcitabine/cisplatin vs 46% for M-VAC) and complete response rates (12% for
gemcitabine/cisplatin vs 12% for M-VAC) were also not significantly different.
The M-VAC regimen was associated with significantly more grade 3/4 mucositis and
granulocytopenic fever and sepsis. Gemcitabine/cisplatin was associated with
significantly more grade 3/4 anemia and thrombocytopenia. Quality-of-life
measures demonstrated that more patients in the gemcitabine/cisplatin arm fared
well with respect to weight, performance status, and fatigue. Use of supportive
measures (eg, G-CSF, antibiotics, antifungals, and number of days of
hospitalization) was greater with M-VAC. Thus, this trial demonstrates that
gemcitabine/cisplatin is associated with similar survival to M-VAC. (The study
was not sufficiently powered to demonstrate equivalent survival between the two
arms.) In addition, gemcitabine/cisplatin showed a more favorable toxicity
profile than M-VAC. This trial establishes gemcitabine/cisplatin as an
alternative to M-VAC for the treatment of patients with advanced urothelial
carcinoma.

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