Commentary (Dotan/Herr): Management of Patients With Muscle-Invasive and Metastatic Bladder Cancer

Optimal therapy for locally advanced bladder cancer aims to prevent local recurrence, reduce the probability of distant metastasis, and improve survival. Radical cystectomy coupled with a pelvic lymph node dissection is the mainstay treatment of locally invasive bladder cancer, curing the majority of patients with organ-confined bladder tumors, about half with extravesical disease, and a significant minority with lymph node metastases. Although radical cystectomy provides good local and regional control of invasive bladder cancer, the recurrencefree and overall survival rates are still only 63%-72% and 59%-66%, respectively, among all patients. The major predictors for disease-specific survival of patients following radical cystectomy for bladder cancer are the pathologic stage of the primary tumor and status of lymph nodes at time of cystectomy. Freedom from recurrence at 5 years after cystectomy is 63%- 72% for patients with organ-confined disease and only 25%-37% for non- organ-confined disease. Quest for Optimal Treatment
Despite radical cystectomy for muscle-invasive bladder cancer, half the patients still succumb to occult metastases. And despite reasonably effective chemotherapy regimens against metastatic bladder cancer, virtually all patients eventually relapse and die of their disease. Given that single treatments fail in many patients, combining therapeutic modalities may provide more optimal treatment. In the current paper, Henry, MacVicar, and Hussain provide an excellent overview of neoadjuvant and adjuvant chemotherapy for locally advanced bladder cancer, chemotherapy for metastatic disease, and molecular prognostic factors that may ultimately identify targets for more specific therapy. While the authors concentrate on chemotherapy, we believe that integrating chemotherapy with local treatment to optimize therapy for advanced bladder cancer requires a more comprehensive discussion than provided by the authors. Chemotherapy is only one part of integrated therapy, and even that is in desperate need of improvement. We address three additional aspects based on current published data that we believe help to define optimal treatment strategy for both locally advanced and metastatic bladder cancer. Surgical Factors in the Treatment of Invasive Bladder Cancer
First, accumulating data in many neoplasms (including bladder cancer) show that the quality of surgery is critical to achieving a successful outcome. The curative aim of radical cystectomy is to remove all cancer in the bladder, pelvis, and regional lymph nodes. The goal is to achieve a negative soft-tissue margin around the bladder and to remove sufficient lymph nodes for staging and control of micrometastatic tumor. A recent review of the Southwest Oncology Group (SWOG) 8710 (Intergroup 0080) trial-which demonstrated a survival benefit of neoadjuvant chemotherapy among patients undergoing cystectomy[1]- showed that the quality of surgical resection was an independent predictor of survival, with or without chemotherapy.[ 2] Among 268 patients who underwent cystectomy, local recurrence developed in 68% with positive surgical margins compared to only 7% with negative surgical margins. Virtually all patients with a local recurrence died of their disease. Further, the extent of lymph node dissection and the number of nodes retrieved had an impact on survival outcome. Patients who underwent a thorough pelvic lymph node dissection removing at least 10 to 14 nodes had better local control and 5-year survival rates than patients after a limited or no-node dissection and fewer node counts. This was true for both node-negative and node-positive tumors, independent of whether neoadjuvant chemotherapy was given. Urologic oncologists operating in high-volume academic medical centers also tended to achieve better results than general urologists who did fewer cases in low-volume community hospitals. We believe that both neoadjuvant and adjuvant chemotherapy improves the survival of patients with locally advanced bladder cancer, but only if chemotherapy is integrated with a high-quality operation performed by an experienced surgeon. Who performs surgery and how well it is done is just as important as the use of chemotherapy. Postchemotherapy Surgery for Unresectable Bladder Cancer and Metastatic Disease
Platinum-based combination chemotherapy is the primary treatment for inoperable or metastatic bladder cancer, achieving overall and complete response rates of 39%-72% and 20%- 36%, respectively.[3] Postchemotherapy surgery in responding patients helps to define pathologic complete responses and may be therapeutic since relapse in sites of responding metastatic tumor is common. Complete response to chemotherapy, including surgery to remove residual viable disease, is the most important predictor of survival. Among 207 patients with unresectable or metastatic disease, 80 (39%) underwent postchemotherapy surgery with intent to cure following cisplatinbased chemotherapy, 12 (6%) refused to undergo surgery despite complete clinical response to chemotherapy, and 115 (55%) did not undergo cystectomy or metastasectomy owing to tumor progression or poor performance status. Of the 80 patients who underwent surgery, 34 (42%) survived up to 5 years, including 20 (41%) of 49 with resection of residual viable disease. Five-year survival rates were similar among patients who achieved a complete response to chemotherapy alone, or with chemotherapy plus surgery. Only one patient who refused surgery survived longer than 1 year and died at 3 years after chemotherapy.[4] A recent study also confirmed that none of the patients failing to undergo surgery after chemotherapy survived longer than 14 months.[5] Additional information on benefit of a complete pathologic response can also be derived from the SWOG 8710 trial. Patients who achieved a complete response (defined as no evidence of disease in the pathology specimen) had a 5-year survival rate of 85%; 38% of patients were pT0 after neoadjuvant chemotherapy vs 15% with cystectomy alone. Cumulative data show that postchemotherapy surgery is critical to achieving complete responses by eradicating all disease, reduces both local and systemic relapses, and appears to improve survival even in patients with locally advanced or metastatic bladder cancer. Improved Chemotherapy Regimens for Locally Advanced/ Metastatic Urothelial Cancer
Cisplatin-based combination chemotherapy is currently used for perioperative and metastatic bladder cancer. The two most common regimens are MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) and GC (gemcitabine [Gemzar], cisplatin). A randomized trial that compared the two regimens showed similar response rates (49% vs 46% for GC and MVAC, respectively), time to progression (7.4 months for both) and overall survival (13.8 vs 14.8 months for GC and MVAC, respectively), although GC was better tolerated than MVAC. However, few patients (less than 5%) with metastatic disease survive up to 5 years with such chemotherapy. In order to improve responses over those seen with MVAC and GC, newer chemotherapy regimens are sorely needed. For example, a combination of ifosfamide, paclitaxel, and cisplatin with growth factor support was used to treat 44 patients with either unresectable or metastatic urothelial cancer; 68% of patients responded, including complete responses in 23%. Equally important, the duration of responses was superior to that following MVAC (20 vs 13 months, respectively).[6] Further, based on the Norton- Simon hypothesis, non-cross-resistant dose-dense sequenced chemotherapy has improved outcomes in breast cancer. Phase II testing of sequential gemcitabine/ doxorubicin followed by paclitaxel/cisplatin in patients with locally advanced and metastatic urothelial cancer demonstrated an overall response proportion of 86%, including a 43% durable complete response rate for more than 2 years.[7] Based on that favorable safety and benefit profile, the Cancer and Leukemia Group B will conduct a prospective randomized trial to compare the efficacy of sequenced chemotherapy consisting of gemcitabine/doxorubicin followed by paclitaxel/ cisplatin vs a standard regimen of GC as adjuvant treatment for high-risk bladder cancer (T3-T4, N0 or any T, N+) after cystectomy, with survival as the end point. In summary, the treatment of both locally advanced and metastatic bladder cancer has improved in recent years by the integration of effective chemotherapy regimens with better surgery. Optimal therapy and better cure rates will require advances in both systemic and local therapeutic strategies combined for most, if not all, patients with advanced bladder cancer.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.
2. Herr HW, Faulkner JR, Grossman HB, et al: Surgical factors influence bladder cancer outcomes: A cooperative group report. J Clin Oncol 22:2781-2789, 2004.
3. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 97:3173- 3181, 1999.
4. Herr HW, Donat SM, Bajorin DF: Postchemotherapy surgery in patients with unresectable or metastatic bladder cancer. J Urol 165:811-814, 2001.
5. Nieuwenhuijzen JA, Bex A, Meinhardt W, et al: Neoadjuvant MVAV for histologically proven lymph node positive bladder cancer. J Urol 174:80-85, 2005.
6. Bajorin DF, McCaffrey JA, Dodd PM, et al: ITP for patients with advanced transitional cell carcinoma of the urothelial tract. Cancer 88:1671-1678, 2000.
7. Maluf FL, Bajorin DF: Sequential chemotherapy in advanced urothelial cancer. Semin Urol Oncol 19:2-8, 2001.