Occult distant micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced muscle-invasive transitional cell carcinoma of the bladder. Cisplatin-based combination chemotherapy enhances survival in patients with metastatic urothelial cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power. However, randomized clinical trials have demonstrated a survival benefit for neoadjvuant cisplatin-based combination chemotherapy, which should be considered a standard of care. In addition, neoadjuvant therapy may assist in the rapid development of novel systemic therapy regimens, since pathologic complete remission appears to be a powerful prognostic factor for long-term outcomes. Patients who are either unfit for or refuse radical cystectomy may benefit from neoadjuvant chemotherapy with or without radiation to enable bladder preservation.
An estimated 67,160 cases of bladder cancer (~25% of which are muscle-invasive) and 13,750 deaths from this disease are predicted for 2007 in the Unites States. Radical cystectomy achieves excellent long-term outcomes in muscle-invasive transitional cell carcinoma (TCC) of the bladder (Table 1). The overall long-term progression-free survival (PFS) rate is 60% to 70% in large retrospective reports from the University of Southern California (USC), Germany, Switzerland, and the Bladder Cancer Research Consortium.[2-7] Extravesical disease confers a relatively poor PFS of 40% to 60%, whereas lymph node involvement is associated with a PFS of 15% to 35%.
Risk Factors for Recurrence Following Radical Cystectomy
A postoperative nomogram was developed by the International Bladder Cancer Nomogram Consortium, based on > 9,000 postoperative patients and including age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the nomogram (concordance index = 0.75) was significantly better than standard staging (concordance index = 0.68; P < .001) or standard pathologic subgroupings (concordance index = 0.62; P < .001).
The quality of radical cystectomy appears to have a major impact. Extended pelvic lymph node dissection (regardless of pathologic tumor involvement) up to the aortic bifurcation (as opposed to the iliac bifurcation or inferior mesenteric artery), lymph node density (number of pathologically positive lymph nodes/total number of lymph nodes removed), and margin status each appear to have a significant impact on outcome.[9-11] The total number of lymph nodes involved, pathologic stage of the primary tumor, and adjuvant chemotherapy also appear to be risk factors.
The majority of bladder cancer recurrences are distant (Table 1). The high incidence of distant recurrence implies the frequent presence of distant micrometastasis (especially in those with pathologic extravesical and lymph node–positive disease), which perioperative systemic chemotherapy may eradicate and thereby enhance survival. Perioperative radiotherapy is likely to play a smaller role in enhancing outcome since local recurrences are less common.
Systemic Chemotherapy for Metastatic Urothelial Cancer
Randomized trials have demonstrated significantly improved outcomes with MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) compared to single-agent cisplatin, CISCA (cisplatin, cyclophosphamide, doxorubicin), or cisplatin/docetaxel (Table 2).[12-14] The median PFS and overall survival (OS) for MVAC are 8 and 14 months, respectively. However, MVAC largely remains a palliative regimen producing a suboptimal long-term survival rate of 4% to 15%.
Conventional MVAC compared with dose-dense MVAC (DD-MVAC) every 2 weeks with recombinant human granulocyte colony-stimulating factor (G-CSF, Neupogen) demonstrated nearly identical median survivals (15.1 vs 14.9 months), while the 5-year survival rate was superior for DD-MVAC (21.8% vs 13.5%, P = .042). DD-MVAC was also superior for overall response rate (RR = 72% vs 58%, P = .016) and complete response (CR) rate (25% vs 11%, P = .006) (Table 2). Owing to the modest size of this trial, it is suggestive but cannot be considered definitive for the superiority of DD-MVAC.
A European randomized trial that accrued 405 patients compared GC (gemcitabine [Gemzar], cisplatin) with MVAC. The median survival (13.8 months for GC vs 14.8 months for MVAC), RR (49% for GC vs 46% for MVAC) and time to progression (7.4 months for both GC and MVAC) were similar. The toxicity profile favored GC, with a significant reduction in the incidence of grade 3/4 mucositis (1% vs 22%), neutropenic sepsis (1% vs 12%), neutropenic fever (2% vs 14%), and alopecia (11% vs 55%). Although the median survivals were similar, the study was underpowered to detect equivalence. However, given the significantly better toxicity profile for GC and the superimposed survival curves, GC has been recognized as an acceptable new standard for metastatic TCC.
A recently reported randomized trial did not demonstrate an improved OS with the addition of paclitaxel to GC. The median survival (12.8 vs 15.7 months, P = .1) and progression-free survival (7.7 vs 8.8 months, P = .109) were not statistically different for GC and PCG (paclitaxel/cisplatin/gemcitabine). The RR was superior for PCG compared to GC (57% vs 46%, P = .02). PCG was more toxic, producing a greater incidence of neutropenic fevers (12.5% vs 3.8%), diarrhea (18.9% vs 8.9%), and alopecia (50.6% vs 15.6%). However, thrombocytopenic hemorrhage was less common with PCG (6.8% vs 11.4%). PCG has not replaced GC as a standard, owing to the lack of survival improvement. Thus, front-line chemotherapy for advanced urothelial cancer can be chosen la carte from MVAC, DD-MVAC, and GC.
A phase III trial planned by the Cancer and Leukemia Group B (CALGB) will examine the benefit of combining GC and bevacizumab (Avastin). Ongoing early phase I/II trials are evaluating novel chemotherapeutic (vinflunine, nab-paclitaxel [Abraxane], E7389) and biologic agents (sunitinib [Sutent], sorafenib [Nexavar], vandetanib, pazopanib, lapatinib [Tykerb], cetuximab [Erbitux], trastuzumab [Herceptin], VEGF Trap), alone or in combination therapy.
Renal dysfunction, usually defined as a calculated creatinine clearance (CrCl) of < 60 mL/min by the Cockroft-Gault (CG) equation, appears to be quite common in patients with urothelial carcinoma and renders patients ineligible for cisplatin therapy. Renal dysfunction may be attributable to advanced age, comorbidities, or ureteric obstruction. In a retrospective study, the probability of ineligibility for cisplatin increased with age, with > 40% of postoperative patients aged > 70 years found ineligible for cisplatin by the CG equation. However, current formulas may underestimate CrCl, especially in those over 65. Both carboplatin-based and nonplatinum regimens have been employed in patients with renal dysfunction or poor performance status. However, small randomized trials suggest that carboplatin regimens are inferior to cisplatin regimens.[20-22] Therefore, patients ineligible for treatment with cisplatin require a special focus.
Adjuvant Chemotherapy for Bladder Cancer
Studies employing adjuvant chemotherapy were conducted in muscle-invasive and locally advanced bladder cancer before neoadjuvant or preoperative chemotherapy was studied (Table 3). All of the patients in these studies were pathologically staged since they had undergone radical cystectomy and pelvic lymph node dissection. Problems in the interpretation of these trials include the lack of statistical power due to their small size, as well as early termination.
The single largest published randomized clinical trial enrolled 91 patients at USC. Patients with deeply muscle-invasive and/or node-positive disease were randomized to observation or chemotherapy including a CISCA-like regimen, single-agent cisplatin, and regimens selected by clonal assays. The median survival was significantly improved in the chemotherapy arm (4.3 vs 2.4 years, P = .0062), but the 3-year survival rate was not statistically superior (66% vs 50%, P = .09). Of the 44 patients randomized to chemotherapy, 11 refused treatment. Accrual of patients was extremely slow, with the study taking 8 years to accrue 91 patients. The trial also employed Wilcoxon statistics for analysis, which emphasize early, but often nonsustained, differences.
A German randomized trial of 49 patients included those with extravesical and/or node-positive disease. Patients received observation or adjuvant MVAC or MVEC (methotrexate, vinblastine, epirubicin [Ellence], cisplatin). A significant improvement in relapse-free survival (P = .0012) was observed without a difference in overall survival. The cystectomy-alone arm fared worse than expected, with 18 of 23 patients exhibiting progression. Most patients who progressed in the cystectomy group did not receive chemotherapy on progression. Of the 26 patients in the chemotherapy group, 8 did not receive it.
Other small prospective randomized trials from Stanford and Switzerland evaluated CMV (cisplatin, methotrexate, vinblastine) or high-dose cisplatin, respectively, and did not demonstrate improved survival.[25,26] The German multicenter trial AUO-AB 5/95 randomized 327 patients with extravesical and/or lymph node–positive disease to adjuvant CM (cisplatin/methotrexate) or MVEC, with the goal of proving noninferiority of CM. The hazard ratio (HR) for PFS (1.13) supported the noninferiority of CM. The 5-year progression-free, disease-specific, and overall survival rates were similar. Grade 3/4 leukopenia occurred in 7% of patients treated with CM and 22.2% of patients treated with MVEC (P < .0001). However, in the absence of definitive data supporting adjuvant chemotherapy, an arm receiving no adjuvant therapy compared to MVEC may have been the optimal design.
The Advanced Bladder Cancer Meta-analysis Collaboration analyzed 491 patients from six trials, representing 90% of all patients randomized in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The overall HR for survival of 0.75 suggests a 25% relative reduction in the risk of death for chemotherapy compared to the control group. However, this meta-analysis is clearly flawed due to the inclusion of poorly conducted trials.
Ongoing Large Cooperative Group Trials of Adjuvant Chemotherapy
The major advantage of adjuvant therapy is that it treats a population of patients whose risk of relapse is clearly defined by their pathologic stage at cystectomy. Ideally, a large, adequately powered, and well-designed study is necessary to definitively prove the efficacy of adjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) is currently conducting a prospective randomized study comparing adjuvant chemotherapy with delayed chemotherapy at clinical relapse. Eligibility includes extravesical disease with or without lymph node involvement. The chemotherapy regimens allowed are MVAC, DD-MVAC, or GC.
Unfortunately, many physicians appear to have already concluded that adjuvant chemotherapy does have a real impact on survival, and consider further randomized comparisons of adjuvant chemotherapy with observation to be inappropriate. Selection of candidates for adjuvant chemotherapy based on molecular factors is being explored.
Overexpression of p53 appears to correlate with an increased risk of progression as well as chemosensitivity. The Southwest Oncology Group (SWOG) has just closed a prospective randomized trial to assess adjuvant MVAC in patients with p53-overexpressing T1 and T2 (invasion of the lamina propria or muscle layer) bladder cancer.
The Cancer and Leukemia Group B (CALGB) and Eastern Cooperative Oncology Group (ECOG) have accepted adjuvant GC as standard, and an Intergroup study was planned to enroll 800 patients with extravesical or node-positive TCC at cystectomy to GC or dose-dense AG (doxorubicin/gemcitabine) followed by PC (paclitaxel/cisplatin). Unfortunately, this trial closed prematurely due to poor accrual.
Dr. Sonpavde is a member of the speakers bureau for Sanofi-Aventis, Pfizer, and Novartis, and has received research support from Pfizer, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, and Cytogen. Dr. Lerner has received research support from Pfizer, Eli Lilly, Bristol-Myers Squibb, Cytogen, Photocure, and Cell Genesys.
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