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. 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.
Transitional cell carcinoma of the urothelium is a chemotherapy-sensitive tumor. Significant response rates have been demonstrated with the single agents cisplatin(Drug information on cisplatin) (Platinol), methotrexate(Drug information on methotrexate), cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin), and vinblastine(Drug information on 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.
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. 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). 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). 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. 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.
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).
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. 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 activebut toxicregimen 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(Drug information on gemcitabine) (Gemzar) and paclitaxel(Drug information on paclitaxel) (Taxol).
Gemcitabine for Advanced Bladder Cancer
Gemcitabine (2´2´-difluorodeoxycytidine) is a cytosine analog with a structure that is similar to cytarabine(Drug information on 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. In phase I studies of gemcitabine, responses were reported in patients with bladder cancer. 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%). Stadler et al and Moore et al 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. 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. 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. 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. 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.