Advancing Treatment of
Bladder Cancer
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Managing Muscle-Invasive Bladder Cancer
Current areas of clinical research for urothelial carcinomas are focused on improving the outcomes of patients with muscle-invasive disease with the use of local and systemic therapy, because mounting evidence suggests a role for chemotherapy in the perioperative setting. Work continues toward development of multimodality, bladder-sparing approaches that incorporate surgery, radiotherapy, and chemotherapy with the intent of avoiding radical cystectomy. For patients with metastatic disease the focus has been on new cytotoxic agents and combinations that have better therapeutic and toxicity profiles in addition to investigating the role of targeted therapies.
Patient Assessment and Disease Staging
Patients with a diagnosis of muscle-invasive bladder cancer should have general laboratory tests to assess organ function, including a complete blood cell count and chemistry profile. They should also undergo imaging to assess disease extent, including a chest x-ray examination, computed tomography or magnetic resonance imaging of the abdomen and pelvis, a bone scan (if bone metastases are suspected clinically or by laboratory tests), and imaging of the upper urinary tract. All patients should also undergo a cystoscopy with examination while under anesthesia and transurethral resection of the bladder tumor (TURBT).
Treatment
Surgery
The current standard approach for treatment of muscle-invasive bladder cancer is radical cystectomy and bilateral pelvic lymphadenectomy. The long-term survival for patients with muscle-invasive bladder cancer has been evaluated in multiple surgical series (Table 1)2-4.
Table 1. Radical Cystectomy: 5-year Overall Survival Rate
The 5-year survival rate for patients with pathologically organ-confined bladder cancer (pT2) is 68%, whereas those with extravesicular extension or lymph node involvement have approximately a 25% to 30% 5-year survival rate3. Analysis of subsets of patients with muscle-invasive disease has determined that both extravesicular disease and node-positive disease are predictive of decreased survival4. The poor outcomes seen with surgical resection alone have provided the rationale for investigating a multimodality approach to the management of patients with invasive bladder cancer. Learning from the positive outcomes of trials of adjuvant or neoadjuvant chemotherapy for a variety of other solid tumors, such trials evaluating perioperative chemotherapy for invasive bladder cancer have been conducted.
Neoadjuvant Chemotherapy
The goal of neoadjuvant chemotherapy is to improve patient survival via the "eradication" of micrometastatic disease. There are several potential advantages to the neoadjuvant approach, including facilitating bladder-sparing approaches. In addition, because patients have their bladders in place, oncologists are able to monitor for response during treatment that has prognostic value5. Patients may also be better able to tolerate chemotherapy before surgery when their performance status is higher, whereas they may not be good candidates for chemotherapy after a major surgical procedure. One of the theoretical disadvantages is that patients with chemoresistant disease may experience disease progression while receiving neoadjuvant treatment and therefore risk progression to a nonoperable stage due to delaying definitive local therapy. However, the data thus far do not support this concern.
Several randomized clinical trials have been performed to evaluate the use of neoadjuvant platinum-based regimens (Table 2)6-15.
Table 2. Neoadjuvant Chemotherapy Trials
Most of these trials failed to demonstrate a survival advantage, but many of the studies have shortcomings, including small numbers of patients and lack of power to detect a difference in survival. Some trials evaluated single-agent chemotherapy, which is known to be less efficacious than combination regimens. Other trials allowed patients to receive either radiation or cystectomy for local therapy, and these 2 modalities have not been directly compared. Poor local control may affect overall outcomes and affect the results of these studies.
Three of these trials, however, strongly suggest an advantage for neoadjuvant chemotherapy. A multi-institutional trial randomized 976 patients to either local therapy alone or 3 cycles of cisplatin, methotrexate, and vinblastine (CMV) followed by local therapy6. Local therapy consisted of either cystectomy or radiation therapy at the treating physician's discretion, and a portion of patients received both radiation and surgical resection. Eligible patients had clinical stage T2-T4a N0 or NX M0 disease, and patients with T3 disease comprised 58% of the study population. Eighty percent of patients in the chemotherapy arm were able to receive all 3 cycles of neoadjuvant chemotherapy. Results showed a 3-year absolute survival difference of 5.5% (P = .075). The survival rate was 55.5% in the chemotherapy arm versus 50% in the local therapy-only arm. A trend toward improved overall survival with neoadjuvant chemotherapy was demonstrated, although these differences did not reach statistical significance. In a follow-up published only in abstract form, after 7.4 years of follow-up a 6% statistically significant improvement in overall survival was observed in patients treated with neoadjuvant chemotherapy (P = .048) 16.
In 2003, Grossman et al reported the results of a Southwest Oncology Group (SWOG) intergroup randomized neoadjuvant trial that also suggested a trend toward a survival advantage with combination therapy9. In this study, 307 patients with invasive bladder cancer were randomized to either radical cystectomy alone or 3 cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by radical cystectomy. The study included patients who had clinical stage T2-T4a disease without evidence of lymph node involvement or distant metastasis, and 60% of patients had more advanced disease, either T3 or T4a. By intent-to-treat analysis, the median survival time was 46 months in the surgery arm and 77 months in the combination-therapy arm, but this trend failed to reach statistical significance when evaluated by a 2-sided stratified log-rank test (P = .06). Similar results were found for 5-year overall survival rates. Of note, the study was initially designed to be analyzed using a 1-sided stratified log-rank test. At the time of cystectomy, a significant difference in residual disease was noted between the 2 groups. Although only 15% of the cystectomy group were without residual disease, 38% of the combination-therapy group were disease free at cystectomy (P<.001), and 85% of patients with pT0 disease at the time of surgery were alive at 5 years. In patients who received neoadjuvant MVAC, the toxicity profile was acceptable with no associated toxic deaths reported, and compared with the surgery-alone arm they did not experience an increase in postoperative complications. This study revealed a strong trend toward a survival advantage, a reduction in risk of death, and increased disease-free rate after cystectomy, thereby demonstrating the feasibility of neoadjuvant MVAC in patients with muscle-invasive muscle bladder cancer.
A more recent publication by Sherif et al presented the combined results of 2 Nordic trials that evaluated neoadjuvant platinum-containing regimens before cystectomy12. A total of 620 patients with grade 3 T1 disease or T2-4a NX disease were included, and 51% of enrolled patients had T3 or T4a disease. The first trial included 311 patients and evaluated cisplatin plus doxorubicin versus no chemotherapy, followed by radiation therapy and then surgery10. The second trial included 309 patients and compared cisplatin plus methotrexate followed by surgery to surgery alone13. The overall survival rate at 5 years was 56% in the neoadjuvant chemotherapy group and 48% in the surgery alone group (P = .049). Although this report is a combination of 2 trials that differ both in the chemotherapeutic agents used and in the use of radiation therapy, the results support the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.
A meta-analysis of data for 3005 individual patients with invasive transitional cell carcinoma from 11 randomized controlled trials demonstrated a statistically significant disease-free and overall survival benefit, with a 14% reduction in the relative risk of death for patients treated with neoadjuvant cisplatin-based combination chemotherapy, equivalent to an absolute survival increase of 5% at 5 years7. The 5-year overall survival rate increased from 45% to 50%, an effect that was seen regardless of the local treatment modality.
In summary, although no single trial has conclusively demonstrated the benefit of neoadjuvant chemotherapy, the preponderance of the evidence from multiple randomized trials indicates that neoadjuvant combination chemotherapy should be offered to all patients with muscle-invasive bladder cancer.
Adjuvant Chemotherapy
Adjuvant chemotherapy has also been evaluated in an attempt at improving outcome in patients with muscle-invasive bladder cancer. By treating patients postoperatively, definitive local treatment is provided up-front without delay. Because the surgery is performed first, complete pathologic staging information can be obtained for making treatment decisions, allowing better patient selection. Some of the limitations of the adjuvant approach include delay in initiating systemic therapy directed toward micrometastatic disease, an inability to assess response to chemotherapy after cystectomy, and difficulties in the delivery of chemotherapy in the adjuvant setting due to surgical complications and decreased patient tolerance.
Two randomized trials suggested a benefit for adjuvant therapy for bladder cancer. Skinner et al randomized 91 high-risk patients to cystectomy alone or to cystectomy and adjuvant cisplatin, doxorubicin, and cyclophosphamide (CISCA)17. No significant difference in 5-year overall survival was identified, but patients in the chemotherapy arm had a prolonged disease-free survival rate of 51% versus 34% for the cystectomy-alone group at 5 years (P = .011). Although this difference in disease-free survival reached statistical significance, the disease-free survival curves crossed after 7 years. Investigators have suggested that this reflects that the chemotherapy regimen was ineffective in curing disease and merely delayed progression. The subgroup of patients with only 1 positive lymph node had an improved disease-free survival and overall survival with adjuvant chemotherapy, but no survival benefit was found if 2 or more lymph nodes were involved17. Numerous aspects of this study have been criticized, including its retrospective use of subgroup analyses, small sample size, and statistical methods.
Another small trial was reported by Stockle et al, who randomized patients with pT3 to pT4a disease after cystectomy to observation, 3 cycles of MVAC, or 3 cycles of methotrexate, vinblastine, epirubicin, and cisplatin (MVEC)18. After 3.5 years the study was halted because an interim analysis of 49 patients demonstrated a large difference in disease-free survival at 3 years. In an intention-to-treat analysis, the 3.5-year disease-free survival rate was 63% with adjuvant therapy and only 13% with cystectomy alone. A significant benefit was noted for patients with lymph node-positive disease who received adjuvant chemotherapy. Only 27% of patients who received chemotherapy had evidence of disease progression compared with 92% treated with surgery alone.
In 2000, Sylvester et al published a review of 4 major adjuvant chemotherapy trials previously conducted, including the 2 described above, and determined that they contain significant methodological flaws and therefore are insufficient to justify the routine use of adjuvant chemotherapy19. Although the studies performed have included small numbers of patients and are underpowered to demonstrate a survival benefit, current data demonstrate that adjuvant chemotherapy delays recurrence of disease. Current National Comprehensive Cancer Network (NCCN) guidelines therefore recommend the use of adjuvant chemotherapy in patients at high risk for relapse20.
Combined-modality Therapy
Not all patients are candidates for radical cystectomy because of either significant comorbidities or unresectable disease. Other patients refuse surgery for fear of compromising quality of life. As an alternative, these patients may be treated with definitive radiotherapy, but radiation alone has poor curative potential because data indicate that up to 70% of these patients may experience a local recurrence and 5-year survival rates are generally suboptimal21. The addition of chemotherapy has been shown to improve local control but not overall survival8.
Typically, a trimodality approach is used in which a maximum TUR is performed followed by bladder irradiation concurrent with radiosensitizing chemotherapy. In addition, either neoadjuvant or adjuvant chemotherapy is sometimes given. Periodic cystoscopies are performed to monitor for disease, and if recurrence is noted, patients undergo salvage radical cystectomy. To date, no randomized trials have adequately addressed the issue of bladder preservation.
Rodel et al evaluated 415 patients with high-risk T1 and T2-T4 disease treated with TURBT followed by radiation or radiochemotherapy22. The patients underwent restaging TUR 6 weeks after completing adjuvant therapy, and 72% achieved complete response. Combination radiation and chemotherapy resulted in higher rates of complete response and survival than radiotherapy alone. Overall survival rates for all patients were 51% and 31% at 5 and 10 years, respectively. Patients with muscle-invasive tumors had 5- and 10-year overall survival rates of 45% and 29%, respectively. Of surviving patients, 80% maintained their bladders. Patients who did not achieve complete response after initial therapy underwent radical cystectomy. The major limitation of this series is that patients were not prospectively randomized, hence limiting the conclusions regarding outcome.
Shipley et al performed a similar study of 190 patients with muscle-invasive T2-4a disease23. After TURBT and radiochemotherapy, only 35% of patients required radial cystectomy because of either inability to achieve complete response or disease recurrence. Five- and 10-year overall survival rates were 54% and 36%, respectively, similar to results reported for radical cystectomy.
Sternberg et al investigated an alternative approach. One hundred four patients with T2-4 N0 M0 bladder cancer were treated with 3 cycles of neoadjuvant MVAC24. Patients then underwent treatment with transurethral resection of the bladder (TURB), partial cystectomy, or radical cystectomy based on response to chemotherapy. Of the 52 patients who underwent TURB, 44% maintained an intact bladder and 60% were alive at a median follow-up of 56 months. The subset of patients who underwent radical cystectomy after chemotherapy had a survival rate of 38% at a median follow-up of 45 months. In both cohorts, patients had higher survival rates if they had stage T0 disease after chemotherapy.
Despite encouraging outcomes, many investigators have several concerns regarding bladder preservation approaches. Critics of bladder preservation fear that with an intact bladder, metachronous bladder cancers remain and are a source for recurrent and possibly fatal disease. In the series by Shipley et al, 13% of patients experienced recurrent invasive disease that necessitated cystectomy23, but similar outcomes were observed whether cystectomy was performed for incomplete initial response or for recurrence, suggesting that even with recurrent disease, bladder preservation protocols can achieve similar outcomes to primary cystectomy. The use of neoadjuvant chemotherapy is associated with lack of up-front pathologic staging and a significant rate of understaging of disease by clinical measures. As many as 30% of clinically staged T0 tumors after chemotherapy have been found to have residual disease at cystectomy25.
Until definitive data are available, it is reasonable to conclude that bladder preservation may be a suitable alternative to radial cystectomy for a select group of patients who achieve complete response to initial therapy. No randomized trials comparing radical cystectomy to a bladder-sparing approach have been conducted. Although prospective studies are needed to address the important question regarding the efficacy of organ preservation relative to cystectomy-based therapy, it is important to establish several key metrics to judge the success and suitability of the preservation approaches. Possible measures include not only survival and rates of adequate local control, but also primary disease relapse rates, functioning bladder rates, development of new bladder primary tumor, systemic disease control, and feasibility in the general bladder cancer population. Patients must be carefully selected for bladder preservation protocols. Ideal candidates have minimal or no CIS, small-volume unifocal disease, and no poor risk features such as hydronephrosis, have undergone maximum TUR22-23, and are motivated to participate in regular follow-up.
Molecular Predictive and Prognostic Markers for Localized and Metastatic Disease
In various stages of bladder cancer, molecular markers are being evaluated as potential novel prognostic factors to better classify patients' risk of progression to invasive disease or systemic recurrence, and some are being evaluated as therapeutic targets (Table 3)33-37.
Table 3. Tumor Markers
Other reviews have dealt with this subject in more detail37-38. Briefly, multiple genes have been evaluated33-36, but the most extensive data pertain to mutations of the tumor suppressor p53, which are associated with genomic instability and formation of carcinoma. Accumulation of p53 within tumor nuclei, when detected by immunohistochemical staining, has been associated with increased risk of recurrence from bladder cancer in some studies39 but not others33, 40. In a multivariate analysis stratified for tumor grade, pathologic stage, and nodal status, alteration in p53 was found to be an independent prognostic factor associated with increased recurrence and reduced survival39. Other studies of p53 accumulation in both locally advanced and node-positive disease, however, have not demonstrated a correlation with disease-free survival33-40. Based on these observations, a National Cancer Institute (NCI)-sponsored trial was conducted randomizing patients with invasive bladder cancer and mutations in p53 to adjuvant chemotherapy versus observation after radical cystectomy.
The epidermal growth factor receptor (EGFR) and Her-2/neu are tyrosine kinases involved in cell proliferation, cell survival, angiogenesis, and metastasis37, 41. The EGFR is overexpressed in high-grade invasive transitional cell carcinomas and is associated with more aggressive clinical behavior37. Another member of the EGFR family, Her-2/neu, has also been studied in urothelial tumors. In patients with metastatic bladder cancer, Jimenez et al demonstrated Her-2/neu overexpression in 37% (22 of 60) of primary tumors, 63% (20 of 32) of regional lymph node metastases, and 86% (6 of 7) of distant metastases42. Absence of overexpression of Her-2/neu in the primary tumor failed to predict absence of Her-2/neu overexpression in distant metastases. The increased expression in distant sites suggests that overexpression is an acquired feature during the metastatic process.
Agents exist that target EGFR and Her-2/neu, making these targets potentially have therapeutic value and prognostic significance. Preclinical studies in a murine model have suggested that the anti-EGFR antibody cetuximab (Erbitux) has activity in bladder cancer43. On the basis of prior results that showed enhancement of antitumor activity of chemotherapy with the addition of trastuzumab (Herceptin) in patients with metastatic breast cancer overexpressing Her-2/neu, studies are under way in advanced bladder cancer to evaluate both single-agent trastuzumab and the addition of trastuzumab to chemotherapy. The Cancer and Leukemia Group B (CALGB) is currently evaluating single-agent trastuzumab, and accrual has recently been completed for an NCI-sponsored trial that was designed to prospectively evaluate the frequency of Her-2/neu overexpression and the feasibility of the combination of trastuzumab with paclitaxel, carboplatin, and gemcitabine44.