203 Controversies in the Management of Bladder Cancer
There are a multitude of issues in the treatment of bladder cancer (BC) without a true management consensus. To aid the reader we have provided some cases that illustrate common and important management questions that are likely to appear in practice.
Case 1: A 53-year-old male presents with T2N0M0 bladder cancer.
Question 1: Do all cases of muscle invasive bladder cancer need radical cystectomy?
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) state that organ preservation can be considered for patients with T2a to T3 BC. There is no consensus on how to accomplish this. Modalities may include transurethral resection of bladder tumor (TURBT), chemotherapy, radiation and/or partial cystectomy. Bladder preservation is more accepted for nonsurgical candidates, although it still may be underutilized (1). However, for those patients who do not desire radical cystectomy (RC) and are otherwise surgical candidates, the physician recommendations are challenging. Part of this dilemma is that there is a high rate of discordance between clinical tumor stage and pathological stage at the time of RC. Because of this controversy, the NCCN recommends that for surgical candidates, bladder preservation options should only be chosen in the context of clinical trials or if patients refuse surgery (1).
Of the preservation options mentioned, chemoradiation has the most supportive data. TURBT alone should only be considered in select cases with tumors less than 2 cm, 204minimal muscle invasion, no in situ disease, no palpable mass, and no hydronephrosis. Chemotherapy alone is considered inadequate, as the pathologic complete response (CR) rate in the bladder is low. Similarly, radiation alone is not recommended unless patients cannot tolerate chemotherapy, as results are inferior to those of combined modality treatment. Chemoradiation should only be considered in potential surgical candidates if complete resection can be obtained with TURBT. The category 2A recommendations for chemotherapy given as part of combined modality treatment in this situation are: cisplatin, cisplatin + 5-fluorouracil (5-FU), cisplatin + paclitaxel, and 5-FU + Mitomycin C (1).
Six Radiation Therapy Oncology Group (RTOG) studies have examined chemoradiation in bladder preservation. Five of them were phase 2 trials and one was a phase 3 trial. In a meta-analysis of these trials, the 5-year- and 10-year overall survival (OS) were 57% and 36%, respectively. Disease-specific survival, muscle-invasive local-regional failure, nonmuscle invasive local regional failure, and distant metastasis at 5 and 10 years were 71% and 65%, 13% and 14%, 31% and 36%, and 31% and 35%, respectively. Some of these trials utilized a neoadjuvant (NA) chemotherapy approach prior to concurrent chemoradiation; however, this has not been shown to provide additional benefit. In these trials, there were no excess high-grade acute or long-term toxicities (2).
A meta-analysis of retrospective and prospective studies examining chemoradiation and bladder preservation in muscle invasive BC was recently published. There were 13,396 patients. It is suggested that this approach may actually have a survival advantage compared to RC upfront or after NA chemotherapy. The 5-year OS rate for the bladder preservation group was 57%, compared to 52% (51% for RC alone and 53% for RC + chemotherapy) in those who did not undergo bladder preservation (P = .04, hazard ratio [HR] 1.22 for RC) (3).
It is important to remember that these bladder preservation strategies are for the most part dependent on having a clinical CR to combined modality therapy. Since the survival outcomes are in many cases similar or better than those who have undergone RC, what may be happening is that this approach selects 205for patients with biologically less aggressive tumors that are more responsive to chemoradiation. To further understand the true effect of these bladder-preservation strategies, we need to await the results of further trials where patients who attain a clinical CR to NA combined modality treatment are randomized to either bladder preservation or RC.
Case 2: A 67-year-old male presented with 3 months of gross hematuria. He was found to have T4bN1M0 urothelial carcinoma of the bladder. He was deemed not a surgical candidate because of nodal involvement and T4b disease.
Question 2: After NA therapy, could he become an operative candidate?
Bladder cancer that is clinically T4b and/or has positive lymph nodes is generally considered unresectable, and the median OS without surgery is a little over a year. However, the NCCN Guidelines® suggest that in select cases RC may be considered in these patients after NA therapy. In these cases, the guidelines suggest chemotherapy and/or radiation may be used in the NA setting (1).
Small cohort and retrospective studies have suggested that in certain patients with T4 disease and/or clinically positive lymph nodes undergoing RC after NA chemotherapy, improved survival may be achieved. One such retrospective study looked at the response to NA chemotherapy in 304 patients who were initially felt to be unresectable due to clinically positive lymph nodes and who received mainly cisplatin-based regimens followed by RC. Interestingly, the median OS for the whole cohort was 22 months, although the median follow-up was only 13 months. Forty-eight percent of patients achieved pN0 disease. For those with pN0 disease, the median OS was 71 to 84 months, depending on the initial number of clinically positive nodes (4). When interpreting this and other retrospective analyses, it is important to keep in mind that these were nonrandomized, very select patient populations. Such studies may not be representative of all patients with clinically positive lymph nodes and the particular study discussed in detail earlier did not include patients with T4b disease.
206Case 3: After NA chemotherapy, a patient is to undergo RC. His initial stage was T3N0M0.
Question 3: What extent of lymphadenectomy should the patient receive at the time of surgery?
According to the NCCN Guidelines, pelvic lymphadenectomy is an essential component in the surgical treatment of bladder cancer. An extended pelvic lymphadenectomy that includes the common iliac and sometimes the lower para-aortic nodes is associated with improved survival (1). However, there is some controversy as to how extensive such lymphadenectomy really needs to be, since the supporting evidence is retrospective or nonrandomized prospective data. Our patient should, at a minimum, undergo a bilateral pelvic lymph node dissection that includes the obturator fossa, internal and external iliac basin, the fossa of Marcille, and the lymph nodes around the common iliac artery. However, the optimal superior extent of such dissection (ureteropelvic junction or aortic bifurcation) is not known. Additionally, there is no specific number of lymph nodes that should be removed (5).
Case 4: A 64-year-old female is diagnosed with a high grade T1N0M0 transitional cell carcinoma of the urothelium. She undergoes a repeat TURBT 6 weeks after the initial one and is found to have residual nonmuscle invasive disease.
Question 4: Should this patient now receive treatment with intravesicular Bacillus Calmette-Guérin (BCG) or RC?
The NCCN Guidelines state that for residual disease in this setting, intravesicular BCG is a category 1 option. A second option, which carries a 2A recommendation, is to perform RC (1). Performing an RC in these patients instead of intravesicular therapy is controversial because of the morbidity associated with the procedure. Part of the impetus for this approach is that there is a significant amount of clinical understaging in BC. This understaging may be part of why some reports suggest that as many as 53% of high-grade T1 lesions will progress to muscle invasive disease. Additionally, some data suggest that intravesicular BCG may not delay progression in these patients, as an estimated 34% will die of BC within 15 years (6).However, there has been no trial showing a survival benefit to RC over intravesicular therapy in these patients.