Bladder cancer is the fifth most common malignancy, with an estimated 63,210 newly diagnosed cases and 13,180 deaths in the United States in 2005.[1] Approximately 75% of patients present with superficial disease[1] and are managed primarily by urologists with cystoscopy and transurethral resection (TUR) with or without intravesicular therapy, depending on grade, presence of carcinoma in situ, and depth of invasion. The remaining patients- approximately 25%-have muscleinvasive disease on a biopsy specimen and have a worse prognosis. Outcomes in these patients are dependent upon tumor stage and grade, and high recurrence rates are seen even with disease confined to the bladder wall managed with cystectomy or primary radiotherapy. Patients who subsequently develop metastatic disease or present with it can expect a median survival of about 14 months with combination systemic chemotherapy. 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, as mounting evidence suggests a role for chemotherapy in the perioperative setting. Work continues toward the de velopment of multimodality, bladdersparing 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. Management of Locally Invasive Disease Surgery
The current standard approach for treatment of muscle-invasive bladder cancer involves radical cystectomy and bilateral pelvic lymphadenectomy. Long-term survival in this setting has been evaluated in multiple surgical series (Table 1).[2-4] The 5-year survival rate is 68% for patients with pathologically organ-confined bladder cancer (pT2), compared with about 25% to 30% for those with extravesicular extension.[3] Analysis of subsets of patients with muscle-invasive disease has determined that both extravesicular disease and node-positive disease are predictive of decreased survival.[4] The poor outcomes seen with surgical resection alone have provided the rationale for investigating a multimodality approach to the management of invasive bladder cancer patients. Learning from the positive outcomes with the utilization 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 survival via the "eradication" of micrometastatic disease. There are several potential advantages to the neoadjuvant approach, including the facilitation of bladdersparing strategies. In addition, because patients have the bladder in place, oncologists are able to monitor for response during treatment, which has prognostic value.[5] 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 following a major surgical procedure. One of the disadvantages of this approach is that patients with chemoresistant disease may progress while receiving neoadjuvant treatment and, therefore, risk progressing to a nonoperable stage due to the delay in providing definitive local therapy. Several randomized clinical trials have been performed to evaluate the use of neoadjuvant platinum-based regimens (Table 2).[6-15] Most of these trials failed to demonstrate a survival advantage, but many of the studies have shortcomings. They included small numbers of patients and are underpowered 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 two modalities have not been directly compared. Poor local control may impact overall outcomes and affect the results of these studies. Three of these trials, however, strongly suggest an advantage for neoadjuvant chemotherapy.
  • International Collaboration-A multi-institutional trial randomized 976 patients to either local therapy alone or three cycles of CMV (cisplatin, methotrexate, vinblastine) followed by local therapy.[6] 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 T2-4a, N0 or NX, M0 disease, and T3 patients comprised 58% of the study population. Eighty percent of patients in the chemotherapy arm were able to receive all three cycles of neoadjuvant chemotherapy. Study results showed a 3-year absolute survival difference of 5.5% (P = .075).[6] The survival rate was 55.5% in the chemotherapy arm vs 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 in abstract form only, after 7.4 years, a 6% statistically significant improvement in overall survival was observed in patients treated with neoadjuvant chemotherapy (P = .048).[16]
  • INT-0080-In 2003, Grossman et al reported the results of a Southwest Oncology Group (SWOG)-intergroup randomized neoadjuvant trial, which also suggested a trend toward a survival advantage with combination therapy.[9] In this study, 307 patients with invasive bladder cancer were randomized to either radical cystectomy alone or to three cycles of MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) followed by radical cystectomy. The study included patients who had T2-4a 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 in the surgery arm was 46 months and in the combinationtherapy arm was 77 months, but this trend failed to reach statistical significance when evaluated by a two-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 one-sided stratified log-rank test. At the time of cystectomy, a significant difference in residual disease was noted between the two groups. While 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 to the surgery-alone arm they did not experience an increase in postoperative complications. This study demonstrated the feasibility of neoadjuvant MVAC in patients with muscle-invasive muscle bladder cancer. A strong trend toward a survival advantage was identified, as well as a reduction in risk of death and an increased disease- free rate at cystectomy.
  • Nordic Trials-Trials-A more recent publication by Sherif et al presented the combined results of two Nordic trials that evaluated neoadjuvant platinum- containing regimens prior to cystectomy.[ 12] 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 vs no chemotherapy, followed by radiation therapy and then surgery.[10] In this right, the second trial included 309 patients and compared cisplatin plus methotrexate followed by surgery to surgery alone.[13] Overall survival at 5 years in the neoadjuvant chemotherapy group was 56% and in the surgery-alone group was 48% (P = .049). Although this report is a combination of two 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.
  • Meta-analysis-A meta-analysis of data for 2,688 individual patients with T2-4a transitional cell carcinoma from 10 trials demonstrated a non- statistically significant 9% reduction in the relative risk of death for patients treated with neoadjuvant chemotherapy, equivalent to an absolute survival increase of 3% at 5 years.[7] While no benefit for neoadjuvant chemotherapy was observed in patients treated with cisplatin alone, patients treated with platinum-based combination chemotherapy regimens had a statistically significant 13% reduction in relative risk of death, equivalent to an absolute survival benefit of 5% at 5 years. Five-year overall survival 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 indicate 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 to improve 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 postcystectomy, and difficulties in the delivery of chemotherapy in the adjuvant setting due to surgical complications and decreased patient tolerance.
  • Randomized Trials-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 CISCA (cisplatin, cyclophosphamide, doxorubicin [Adriamycin]).[17] No significant difference in 5-year overall survival was identified, but patients in the chemotherapy arm had a prolonged disease- free survival of 51% vs 34% for cystectomy alone 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 pattern reflects the fact that the chemotherapy regimen was ineffective for curing disease and merely delayed progression. The subgroup of patients with only one positive lymph node had an improved disease-free survival and overall survival with adjuvant chemotherapy, but no survival benefit was found if two or more lymph nodes were involved.[17] Numerous aspects of this study have been criticized, including its retrospective use of subgroup analyses, small sample size, and questionable statistical methodology. Another small trial was reported by Stockle et al, who randomized patients with pT3-pT4a disease postcystectomy to either observation, three cycles of MVAC, or three cycles of MVEC (methotrexate, vinblastine, epirubicin [Ellence], cisplatin).[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, as compared to 92% of those treated with surgery alone. In 2000, Sylvester et al published a review of four previously conducted adjuvant chemotherapy trials, including the two described above. The authors determined that these trials contained significant flaws in methodology and are therefore insufficient to justify the routine use of adjuvant chemotherapy.[19] 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 guidelines from the National Comprehensive Cancer Network (NCCN) therefore recommend the use of adjuvant chemotherapy to radiation in patients at high risk for relapse.[20]
Combined-Modality Therapy
Not all patients are candidates for radical cystectomy, either because of significant comorbidities or due to 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, as data indicate that up to 70% of these patients may experience a local recurrence and 5-year survival rates are generally suboptimal.[21] The addition of chemotherapy to radiation has been shown to improve local control but not overall survival.[8] Typically, a trimodality approach is used in which a maximum transurethral resection (TUR) is performed followed by bladder irradiation concurrent with radiosensitizing chemotherapy. In addition, either neoad- juvant 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, there has not been a randomized trial to address the issue of bladder preservation adequately.
  • Clinical Trials-Rodel et al evaluated 415 patients with high-risk T1 and T2-4 disease treated with transurethral resection of bladder tumor (TURBT) followed by radiation or radiochemotherapy.[22] The patients underwent restaging TUR 6 weeks after completion of adjuvant therapy, and 72% achieved a complete response. Combination radiation and chemotherapy resulted in higher rates of complete response and survival than radiotherapy alone. Overall survival for all patients was 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 a complete response following 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 muscleinvasive T2-4a disease.[23] Following TURBT and radiochemotherapy, only 35% of patients required radical cystectomy, either because of inability to achieve complete response or because of disease recurrence. The 5- 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. A total of 104 patients with T2-4, N0, M0 bladder cancer were treated with three cycles of neoadjuvant MVAC.[24] Patients then underwent treatment with TURBT, partial cystectomy, or radical cystectomy based on response to chemotherapy. Of the 52 patients who underwent TURBT, 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 were staged as T0 following chemotherapy.
  • Limitations of Bladder Preservation-Despite encouraging outcomes, there are concerns regarding bladderpreservation 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 necessitating cystectomy,[23] 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 a lack of up-front pathologic staging and a significant rate of understaging of patients by clinical measures. As many as 30% of clinically T0 tumors following chemotherapy have been found to have residual disease at cystectomy.[25]
  • Conclusions-Until definitive data are available, it is reasonable to conclude that bladder preservation may be a suitable alternative to radical 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. While 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, rates of functioning bladder, development of new bladder primaries, 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 carcinoma in situ, have small-volume unifocal disease, have no poor risk features such as hydronephrosis, have undergone maximum TUR,[22,23] and are motivated to participate in regular follow-up.
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