Commentary (Quek et al): Management of Patients With Muscle-Invasive and Metastatic Bladder Cancer

Drs. Henry, MacVicar, and Hussain provide a timely review of the current management of muscle-invasive and metastatic urothelial cancer. The emerging role of neoadjuvant chemotherapy and the promise of novel, less toxic targeted therapies are of particular interest in the treatment of a disease in which outcomes remain poor for locally advanced and metastatic involvement despite an aggressive multimodality approach.[1] We wish to briefly comment on three issues raised by the authors:
(1) the role of surgery in the management of invasive disease,
(2) the indiscriminate use of neoadjuvant chemotherapy for clinically localized disease, and
(3) the current status of bladder-sparing approaches. Importance of an Extended Lymphadenectomy
Although the authors briefly discuss the outcomes of radical cystectomy for locally invasive disease, there has recently been renewed interest in the role of surgical factors, particularly the extent of lymphadenectomy, in the comprehensive management of high-grade, invasive bladder cancer. A growing body of evidence suggests that an extended lymph node dissection may provide not only prognostic information, but also a clinically significant therapeutic benefit for both lymph node-positive and -negative patients undergoing radical cystectomy for bladder cancer. Herr and colleagues reported a secondary analysis of the neoadjuvant chemotherapy Southwest Oncology Group (SWOG)-Intergroup 8710 trial, which drew attention to the tremendous variability in the quality of bladder cancer surgery in this country and the impact of surgical factors on cancer-specific outcomes.[2] In particular, the extent of lymphadenectomy (whether 10 or more lymph nodes were removed) proved to be an important prognostic factor independent of whether neoadjuvant chemotherapy was given and regardless of nodal involvement (hazard ratio = 2.0; P = .0001). The inclusion of a standard pelvic lymph node dissection was associated with a lower rate of positive surgical margins as well as a lower local recurrence rate. In our experience, local pelvic recurrences from bladder cancer are uniformly fatal, even with adjuvant systemic chemotherapy.[3] It is clear from this study that a properly performed radical cystectomy with an appropriate lymphadenectomy is critical in decreasing local recurrence rates and improving survival, and that neoadjuvant chemotherapy cannot compensate for an inadequate surgical resection. This sentiment has been echoed by single-institution cystectomy series,[ 4,5] as well as the Surveillance, Epidemiology, and End Results (SEER) cancer registry,[6] which have shown improved postcystectomy survival with the inclusion of a more comprehensive lymph node dissection. Some have advocated standardizing the extent of lymphadenectomy based on the number of lymph nodes removed and examined in order to accurately stage nodal status and to provide a potential therapeutic benefit.[7] Although the boundaries of the lymph node dissection remain a subject of controversy, historical reports confirmed by recent lymphatic mapping studies suggest that the common iliac, presacral, and possibly distal para-aortic and paracaval lymph nodes should be included in the routine lymphadenectomy for bladder transitional cell carcinoma (TCC). For those with pathologic evidence of lymph node metastases, the extent of the primary bladder tumor (p-stage), number of lymph nodes removed, lymph node tumor burden, presence of extracapsular nodal extension, and lymph node density have been shown to be important prognostic variables.[8] Radical cystectomy with an appropriately performed lymphadenectomy arguably provides the best survival outcomes and the lowest local recurrence rates. Although the absolute limits of the lymph node dissection remain to be determined, an evolving body of data supports a more extended lymphadenectomy at the time of cystectomy in patients that are appropriate surgical candidates. Selective Use of Neoadjuvant Chemotherapy
The authors advocate the routine administration of neoadjuvant chemotherapy to all patients with muscleinvasive bladder cancer. This remains controversial, as most studies have shown either no survival advantage or only a marginal benefit (as the authors have outlined). Even in the recent positive SWOG 8710 trial,[9] the greatest benefit was seen primarily in those who had a complete response to the chemotherapy (pathologic pT0 at cystectomy). The problem is that there is no way to reliably predict who will respond to the chemotherapy and who would be better served with an early cystectomy. Delays in definitive surgical management of bladder cancer have been shown to adversely affect cancer-specific survival.[10,11] It has been our preference to offer chemotherapy in the adjuvant setting, basing the decision on definitive highrisk pathologic criteria. Patients with pathologically organ-confined TCC treated with radical cystectomy have 10-year recurrence-free rates of over 80%.[3] The majority of these patients do not require systemic chemotherapy. The indiscriminate use of neoadjuvant therapy for all muscleinvasive tumors would mean that many patients would be overtreated and unnecessarily exposed to the potential side effects of cytotoxic chemotherapy. Neoadjuvant chemotherapy may have a role in treating patients with locally advanced bladder cancer (≥ cT3 or regional nodal involvement) as a means to downstage these tumors to a surgically resectable state. These unfortunate patients are already at high risk for distant metastases with their survival dependent on a favorable response to chemotherapy, which is often better tolerated in the preoperative setting. Bladder Preservation Strategies: A Warning
The authors provide a balanced review of the current status of organpreserving approaches for muscleinvasive TCC. There are obvious inherent problems in comparing the outcomes of trimodality therapy (transurethral resection, systemic chemotherapy, radiation therapy) based on clinical staging and radical cystectomy series, which are typically reported by pathologic stage. No randomized trials have compared the two approaches, and given the ever-evolving technology of radiation delivery and newer chemotherapeutic protocols, such trials might not even provide a definitive answer. Kim and Steinberg have previously reviewed the role of bladder preservation in the treatment of muscle-invasive bladder cancer.[12] There are several points worth highlighting regarding trimodality therapy. First, this strategy is significantly more expensive and requires a dedicated, coordinated multimodality team approach. These patients require intensive routine surveillance for local recurrences. In the era of cost containment, this is clearly an important consideration. Second, as a significant number of patients eventually require cystectomy, delays in definitive surgical management may adversely affect survival outcomes. While the rationale for bladder preservation is to improve quality of life with an intact native bladder, unfortunately, some patients may suffer significant radiation-induced bladder and bowel dysfunction. With the widespread acceptance of orthotopic bladder substitution, quality-of-life issues are now better addressed, thereby weakening this argument. Conclusions
Despite the evolving role of neoadjuvant chemotherapy, radical cystectomy with an extended pelvic lymphadenectomy remains the cornerstone for the treatment of muscleinvasive bladder cancer. Further research into the molecular determinants of bladder carcinogenesis and progression will undoubtedly lead to novel, less toxic targeted therapeutic modalities with the promise of improvements in outcomes, even for high-risk locally advanced and metastatic 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:

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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. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001.
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8. Quek ML, Sanderson KM, Daneshmand S, et al: The importance of an extended lymphadenectomy in the management of high-grade invasive bladder cancer. Expert Rev Anticancer Ther 4:1007-1016, 2004.
9. 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.
10. May M, Nitzke T, Helke C, et al: Significance of the time period between diagnosis of muscle invasion and radical cystectomy with regard to the prognosis of transitional cell carcinoma of the urothelium in the bladder. Scand J Urol Nephrol 38:231-235, 2004.
11. Sanchez-Ortiz RF, Huang WC, Mick R, et al: An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 169:110-115 (incl discussion), 2003.
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