Taxol, Gemzar, Other Therapies Studied in Metastatic Bladder Cancer

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 it’s 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 response rate.

"In my practice, I’ve seen responses in liver metastases, but I’ve not used pacli-taxel as a single agent; I’ve 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 untreated patients."

Gemcitabine Trials

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 70.

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. "I’ve never worked with it," he said, "and I have always been a little uneasy about a drug that tends sporadically and unpredictably to cause blindness."

Neoadjuvant Chemotherapy

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 disease.

"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 it’s 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 doesn’t 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."