Recent Developments in Chemotherapy for Bladder Cancer

Drs. Vaughn and Malkowicz haveprovided us with a succinct,thorough, evidence-based overview of the current role of chemotherapy inadvanced bladder cancer. Their discussion highlights the veritable explosion ofnew chemotherapy agents with impressive activity in advanced urothelial cancer,the evidence against the routine administration of chemotherapy in theneoadjuvant setting, and in contrast, the paucity of data in the adjuvantsetting. They also provide a look into the future with a brief review ofevolving molecular prognostic factors.

Chemotherapy for Advanced Bladder Cancer

The M-VAC regimen (methotrexate, vinblastine, doxorubicin[Adriamycin], cisplatin [Platinol]) is now over 15 years old. Its introductioninto clinical practice in the 1980s represented the first significantdevelopment in the management of advanced urothelial cancer. M-VAC is clearlyamong the most toxic chemotherapy combinations in our armamentarium, and yet ithas only a modest impact on survival (3.7% survival at 6 years’ medianfollow-up in the Intergroup study).[1]

A large number of new chemotherapy agents introduced intoclinical practice in the late 1980s and 1990s have demonstrated significantactivity in advanced urothelial cancer. Phase II evaluations of paclitaxel(Taxol), gemcitabine (Gemzar), and ifosfamide (Ifex) as single agents and incombination with other active agents have demonstrated intriguing response rateswith some suggestion of improved median survival.[2-4]

Significant activity of the gemcitabine/cisplatin (Platinol)combination in phase II trials led to an important industry-sponsored,multicenter, international phase III trial comparing gemcitabine/cisplatin toM-VAC.[5] This trial impressively accrued over 400 patients in 2 years, andwhile it was not powered as an equivalency trial, its results suggest that thegemcitabine/cisplatin combination is a viable alternative to M-VAC. However, onemust not lose sight of the fact that the median survival in thegemcitabine/cisplatin arm was 13.8 months, compared with 14.8 months for M-VAC,suggesting that real progress has not yet been achieved.

One of the most challenging aspects of our current surplus ofactive chemotherapy agents is the increasingly competitive environment in whichphase II trials are performed. An even greater task is the selection of optimalregimens to take into phase III studies. This quandary exists due to the limitednumber of available patients (approximately 12,000 new advanced bladder cancerdiagnoses each year in the United States, with less than 3% enrolling inclinical trials).[6] The traditional method of basing optimal regimens for phaseIII studies on comparisons of overall response rates in phase II studies isproblematic in urothelial cancer, because the vast majority of trials reportresponse rates with overlapping confidence intervals.

Another confounding issue is the distribution of patients withknown poor prognostic features (eg, poor performance status, visceral metastaticdisease, renal insufficiency) that can negatively affect response rates,resulting in a clinically relevant bias when compared across variousphase II studies. Drs. Vaughn and Malkowicz refer to recent work by Bajorinet al, in which a method of quantitating these risk factors can be appliedacross phase II studies in an attempt to control for known prognosticfactors in urothelial cancer.[7]

Ongoing Challenges

A myriad of important questions remain unanswered. The relativerole of carboplatin (Paraplatin) vs cisplatin in urothelial cancer remainsunclear. Although there are suggestions that cisplatin is superior, no studieshave formally addressed this controversy to date. Other issues include theutility of two- vs three-drug combinations. This question will be addressed bythe proposed European Organization of Research and Treatment of Cancer/SouthwestOncology Group phase III trial comparing gemcitabine/cisplatin vsgemcitabine/cisplatin/paclitaxel.

Cisplatin-based regimens are typically contraindicated inpatients with renal insufficiency, who represent 10% to 20% of patients withadvanced bladder cancer, and as such, present a significant therapeutic dilemmato clinicians. Dr. Vaughn has taken a leadership role in this area by directinga series of Eastern Cooperative Oncology Group phase II trials ofnephron-sparing combinations (E2896, carboplatin/paclitaxel; E5899,gemcitabine/paclitaxel) in this subset of patients. These trials may demonstratethe utility of therapy, albeit with a lower response rate.

Conclusions

Although clinicians who treat patients with advanced urothelialcancer today have an ever-increasing armamentarium from which to choose, thereremains no compelling evidence that significant progress has been made. Manyliken our current state of therapeutics in advanced urothelial cancer to that ofsmall-cell lung cancer in the early 1990s, with high response rates but limitedimpact on overall survival. Drs. Vaughn and Malkowicz’s discussion ofprognostic biomarkers highlights the current drive to develop biologically basedtreatment strategies.

Perhaps the most pressing issue before us today is to selectspecific agents from a host of novel small molecules (eg, farnesyl transferaseinhibitors, proteosome inhibitors) for clinical trials in advanced urothelialcancer. Additional challenges will follow, as the integration of these novelagents into established chemotherapy regimens will likely require phase IIIdesigns to determine the relative benefit of these new molecules.

References:

1. Saxman SB, Propert KJ, Einhorn LH, et al: Long-term follow-upof a phase III intergroup study of cisplatin alone or in combination withmethotrexate, vinblastine, and doxorubicin in patients with metastaticurothelial carcinoma: A Cooperative Group study. J Clin Oncol 15:2564-2569,1997.

2. Roth BJ, Dreicer R, Einhorn LH, et al: Significant activityof paclitaxel in advanced transitional cell carcinoma of the urothelium: A phaseII trial of the Eastern Cooperative Oncology Group. J Clin Oncol 12:2264-2270,1994.

3. Moore MJ, Tannock IF, Ernst DS, et al: Gemcitabine: Apromising new agent in the treatment of advanced urothelial cancer. J Clin Oncol15:3441-3445, 1997.

4. Bajorin DF, McCaffrey JA, Dodd PM, et al: Ifosfamide,paclitaxel, and cisplatin for patients with advanced transitional cell carcinomaof the urothelial tract: Final report of a phase II trial evaluating two dosingschedules. Cancer 88:1671-1678, 2000.

5. Von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabineand cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin inadvanced or metastatic bladder cancer: Results of a large, randomized,multinational, multicenter , phase III study. J Clin Oncol 17:3068-3077, 2000.

6. Greenlee RT, Hill-Harmon MB, Murray T, et al: CancerStatistics 2001. CA Cancer J Clin 51:15-36, 2001.

7. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival inmetastatic transitional cell carcinoma and prognostic factors predicting outcometo chemotherapy. J Clin Oncol 17:3173-3181, 1999.