The Role of Perioperative Chemotherapy in the Treatment of Urothelial Cancer

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Genitourinary Cancer The Role of Perioperative Chemotherapy in the Treatment of Urothelial Cancer Seth M. Cohen, a,e Anupama Goel, a,e John Phillips, d,e Ronald D. Ennis, a,b,e Michael L. Grossbard a,c,e a Department of Medicine, Division of Hematology/Oncology and b Department of Radiation Oncology, St. Luke s-roosevelt Hospital Center, New York, New York, USA; c Department of Medicine, Division of Hematology/Oncology and d Department of Urology, Beth Israel Medical Center, New York, New York, USA; e Continuum Cancer Centers of New York, New York, New York, USA Key Words. Urothelial cancer Transitional cell carcinoma Neoadjuvant Adjuvant Chemotherapy Learning Objectives After completing this course, the reader will be able to: 1. Explain the rationale for perioperative chemotherapy administration in the treatment of operable bladder cancer. 2. Identify the advantages and disadvantages of the preoperative and postoperative administration of chemotherapy in the treatment of operable bladder cancer. 3. Describe the benefits of the perioperative administration of chemotherapy in the treatment of operable bladder cancer shown in randomized clinical trials. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract Cancer of the urothelium is the fourth most common malignancy in men in the U.S. and the ninth most common in women. More than 63,000 Americans will be diagnosed with bladder cancer this year (47,010 men and 16,200 women), and more than 13,000 (8,970 men and 4,210 women) can expect to die of their disease. The approximate 5:1 ratio of incidence to mortality roughly parallels the frequency of superficial to invasive disease. Efforts to improve this ratio have generated a potential paradigm shift in the treatment of urothelial cancer, incorporating increasingly active chemotherapy into treatment regimens for high-risk tumors in both the pre- and postoperative settings. This review summarizes the evolution of chemotherapeutic treatment of urothelial cancer and the rationale for its perioperative administration and addresses the future directions of clinical research in this field. The Oncologist 2006;11: Introduction Cancer of the urothelium is the fourth most common malignancy in men in the U.S. and the ninth most common in women [1]. More than 63,000 Americans will be diagnosed with bladder cancer this year (47,010 men and 16,200 women), and more than 13,000 (8,970 men and 4,210 Correspondence: Seth M. Cohen, M.D., St. Luke s-roosevelt Hospital Center, 1000 Tenth Avenue 11C-02, New York, New York 10019, USA. Telephone: ; Fax: ; secohen@chpnet.org Received January 4, 2006; accepted for publication May 3, AlphaMed Press /2006/$20.00/0 The Oncologist 2006;11:

2 Cohen, Goel, Phillips et al. 631 women) can expect to die of their disease [1]. The approximate 5:1 ratio of incidence to mortality roughly parallels the frequency of superficial to invasive disease [1]. Efforts to improve this ratio have generated a potential paradigm shift in the treatment of urothelial cancer, incorporating increasingly active chemotherapy into treatment regimens for high-risk tumors in both the pre- and postoperative settings. This review summarizes the evolution of chemotherapeutic treatment of urothelial cancer and the rationale for its perioperative administration and addresses the future directions of clinical research in this field. Rationale: Poor Outcomes with Local Treatment Alone Tumors that invade the deep muscle layer of the bladder are assigned stage T2, while T3 and T4 lesions invade the perivesical tissue and local structures, respectively (Tables 1 and 2). Standard treatment of muscle-invasive cancers has historically comprised surgical resection via radical cystectomy, achieving 5-year recurrence-free survival rates of 81%, 68%, 47%, and 44% for pathologic T2, T3a, T3b, and T4a tumors, respectively [2]. The 5-year overall survival rate is 78% for organ-confined, node-negative disease but falls to 45% when lymph nodes are involved, though an extended lymphadenectomy for node-positive disease may achieve a slight survival advantage [3]. The 5-year overall survival rate for extravesical, node-negative patients is 47% but likewise falls to 25% in node-positive disease. Results for localized radiotherapy (RT) of primary and/or unresectable disease were historically less favorable than those for surgery [4 7]. As a result, efforts were made to improve survival by adding RT before and after surgery. Initial retrospective analyses were encouraging of this strategy, so prospective randomized studies were organized [8]. The National Surgical Adjuvant Bladder Project reported a trial of 475 patients with T2 T4 tumors, randomizing participants to preoperative RT followed by cystectomy versus cystectomy alone [9]. Unfortunately, more than 50% of the enrolled patients were not included in the final analysis because of a failure to complete treatment or Table 2. American Joint Committee on Cancer stage groupings for bladder cancer Stage TNM I T1 N0 M0 II T2a N0 M0 T2b N0 M0 III T3b N0 M0 T4a N0 M0 T4b N0 M0 IV T3a N0 M0 any T N1 3 M0 any T any N M1 Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The orginal source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002), published by Springer New York, Table 1. American Joint Committee on Cancer TNM staging system for bladder cancer Primary tumor (T) Regional lymph nodes (N) Distant metastasis (M) Tx Primary tumor cannot be assessed T0 evidence of primary tumor Ta ninvasive papillary carcinoma Tis Carcinoma in situ T1 Tumor invades subepithelial connective tissue T2 Tumor invades muscle pt2a Tumor invades superficial muscle pt2b Tumor invades deep muscle T3 Tumor invades perivesical tissue pt3a Microscopically pt3b Macroscopically T4 Tumor invades adjacent structures pt4a Prostate, uterus, vagina pt4b Pelvic wall, abdominal wall Abbreviation: LN, lymph node. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The orginal source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002), published by Springer New York, Nx Regional LN cannot be assessed N0 regional LN metastases N1 Metastasis in a single LN, <2 cm N2 Metastasis in a single LN, 2 5 cm; multiple LNs <5 cm N3 Metastasis in an LN >5 cm Mx Distant metastasis cannot be assessed M0 distant metastasis M1 Distant metastasis

3 632 Perioperative Chemotherapy for Urothelial Cancer study ineligibility. In the remaining 234 patients, the 5-year survival rates were 43% versus 35% favoring the RT arm, but this was not statistically significant. The 8-year survival rates were 19% in both groups, and the pelvic failure rates were similar. In a multi-institutional intergroup phase III study, 140 patients with muscle-invasive bladder cancer, or rapidly recurring superficial high-grade tumors, were randomized to 20 Gy of pelvic radiation followed by cystectomy or cystectomy alone [10]. The 5-year overall survival rate was 43% (95% confidence interval [CI], 30% 56%) in the RT arm and 53% (95% CI, 41% 65%) in the surgery alone arm (p =.23). Although the study was underpowered, with wide confidence intervals, there was not even a trend toward a difference in outcome. A meta-analysis including these and other randomized studies failed to show a benefit for the use of RT prior to cystectomy, and this strategy has since been abandoned [11]. Unfortunately, no phase III randomized study has been performed evaluating RT in the postoperative setting, most likely related to the findings of a Radiation Therapy Oncology Group phase II study revealing a high rate of small bowel obstruction and fistula formation (37% vs. 8%) [12]. Alternatives to RT have long been sought to improve the results of surgery without affecting the morbidity of the operation. Efforts incorporating chemotherapy into the treatment of high-risk urothelial cancers were undertaken, driven by the finding that cisplatin-based, combination chemotherapy was capable of producing complete responses in an increasing percentage of patients with advanced disease, relative to those seen in patients treated with single-agent regimens. Evolution of the Treatment of Advanced Disease Several chemotherapeutic agents with different mechanisms of action were proven active in urothelial cancer in the 1970s and 1980s. Methotrexate, vinblastine, doxorubicin, and cisplatin elicited objective responses in 29%, 18%, 17%, and 30% of patients, respectively, in a series of studies conducted at Memorial Hospital [13 16]. Doublet and triplet combinations induced higher response rates, but few complete responses. Ultimately, the two most potent doublets, cisplatin doxorubicin and methotrexate vinblastine, were combined, forming the regimen commonly referred to as M-VAC. In a pilot trial, M-VAC produced a 71% overall response rate, including a 50% complete clinical remission rate, and at least a doubling of the median survival time relative to single-agent cisplatin [17]. Toxicity was significant, however, with myelosuppression resulting in nadir sepsis in 4 of 24 patients, drugrelated death in one patient, and varying degrees of anorexia, nausea, emesis, alopecia, and renal dysfunction. A series of randomized controlled studies proved that M-VAC was superior to single-agent cisplatin [18] and other cisplatin-based combinations [19] with respect to the overall response rate and complete response rate (13% vs. 3% and 35% vs. 25%, respectively) and overall survival. Unfortunately, only 3.7% of patients treated with M-VAC experienced long-term, disease-free survival, while up to one fourth of patients experienced nadir fever, >50% had at least grade 2 mucositis, 3% 4% experienced a toxic death, and many patients suffered ototoxicity and peripheral neuropathy [20]. One strategy devised to address the shortcomings of M-VAC involved increasing the dose intensity of both cisplatin and doxorubicin while adding a myeloid growth factor [21]. Although the toxicity (including leukopenia, nadir fever, and mucositis) was ameliorated, the complete response rate was improved, and the progression-free survival time was increased, no overall survival difference was noted. Recently, newer agents, including gemcitabine, paclitaxel, and docetaxel, were shown to be active in transitional cell carcinoma (TCC). Doublet combinations including cisplatin and docetaxel [22], carboplatin and paclitaxel [23], and cisplatin and gemcitabine (GC) [24] have been compared with M-VAC in the phase III setting. While M- VAC was proven to be superior to cisplatin and docetaxel and the randomized trial of M-VAC versus carboplatin and paclitaxel failed to reach accrual goals, GC compares favorably with M-VAC [22, 24 26]. differences were seen with respect to the median or 5-year overall survival rates, but patients treated with M-VAC suffered more high-grade toxicities, including myelosuppression, nadir fever and sepsis, mucositis, and alopecia. Although this widely cited study was not designed as an equivalency trial, most medical oncologists have adopted the CG as a standard of care in advanced urothelial cancer. Finally, three- and four-drug combinations comprising both targeted and classic chemotherapeutic agents are being investigated [27 29]. Neoadjuvant Chemotherapy As chemotherapy in the metastatic setting evolved, prolonging survival and achieving higher complete response rates, it was incorporated into the multimodality treatment of localized but muscle-invasive disease. Neoadjuvant chemotherapy, shown to be effective in rectal cancer [30, 31] and breast cancer [32], was applied to TCC. Advantages of preoperative chemotherapy include better tolerability relative to postoperative treatment and the ability to assess the sensitivity of the primary lesion, shown to be important prognostically. In one trial of postoperative chemotherapy, 30% of patients were unable to complete even one of the three planned cycles of chemotherapy [33]. The Oncologist

4 Cohen, Goel, Phillips et al. 633 By administering chemotherapy prior to surgery, a decline in performance status resulting from operative morbidity is not an obstacle to treatment. In a retrospective analysis, Splinter et al. [34] found that 75% of patients who had a major pathologic response (<pt1) with M-VAC neoadjuvant treatment were alive and disease free after 5 years of follow-up, while only 20% of patients without such a response (>pt2) were alive and disease free. Disadvantages of neoadjuvant treatment include the potential for over- or undertreatment based on imprecise clinical staging, or delays in or noncompliance with recommended cystectomy after chemotherapy. In a study by the Italian Bladder Tumor Study Group comparing neoadjuvant chemotherapy followed by cystectomy with cystectomy alone in clinical T2 4, N0, M0 TCC, the accuracy of clinical versus pathological staging in the control arm was only 42.3%, with 22.5% overstaged and 35.2% understaged [35]. While understaged patients could potentially go on to receive adjuvant treatment, overstaged patients may suffer needless drug-related toxicity. At least 14 randomized controlled trials have been performed evaluating a neoadjuvant strategy in muscleinvasive TCC, and two meta-analyses including these trials have been published in recent years (Table 3) [36, 37]. Although many studies suffer from insufficient power, limited follow-up time, early closure, and suboptimal chemotherapy, at least two large, well-designed trials have been completed and are incorporated into the most recent meta-analysis [36, 38 40]. A study involving cooperative groups from Europe, Scandinavia, Australia, and Canada, coordinated by the Medical Research Council (MRC) and the European Organization for the Research and Treatment of Cancer (EORTC), randomized 976 patients with highgrade clinical T2, or T3 or T4 TCC of the bladder, without biopsy-proven involved lymph nodes, felt to be reasonable candidates for potentially curative local therapy, to an institutionally chosen local treatment comprising cystectomy, external-beam radiation, or both, with or without preoperative cisplatin, methotrexate, and vinblastine (CMV) every 3 weeks for three cycles [40]. The study was powered to detect a 10% improvement (from 50% to 60%) in the primary outcome, overall survival. The calculated absolute 3-year overall survival difference was 5.5%, with a hazard ratio (HR) of 0.85, favoring the use of neoadjuvant chemotherapy. Although the p-value was.075 at the time of initial publication, an update with a median follow-up of 7 years revealed a statistically significant difference in survival (again 5.5%; p =.048). Further, there was an 18% reduction (p =.019) in the risk for locoregional relapse, metastases, or death (i.e., relapse-free survival). Although this trial is large and adequately powered, has sufficient follow-up, and shows a survival benefit, criticisms have been put forth; the lack of doxorubicin (omitted because of a concern for toxicity associated with radiation), high proportion of good-risk patients (34% had ct2 tumors), 20% rate of noncompletion of chemotherapy in patients assigned to the experimental arm, and control group crossover phenomenon may have underestimated the true effect of preoperative chemotherapy. Similarly, an American Intergroup study (INT 0080) was designed to test the efficacy of neoadjuvant chemotherapy in muscle-invasive bladder cancer [38]. Patients with T2 T4a, N0, M0 TCC who were to undergo radical cystectomy were randomized to surgery alone or three cycles of M-VAC prior to surgery. Patients were stratified by age (<65 years vs. 65 years) and stage (T2 vs. T3). The study was powered to detect a 50% difference in the primary end point of median overall survival. Accrual was slow, requiring 11 years to enroll 317 patients (or two patients per month from across the U.S.). With a median follow-up of 8.4 years, the median survival time was longer (77 months vs. 46 months) Table 3. Randomized clinical trials of neoadjuvant cisplatin-based chemotherapy Trial n Clinical TNM stage Chemotherapy Local therapy Survival benefit p-value Wallace et al. [75] Font et al. [76] Martinez-Pineiro et al. [77] Cortesi [35] Malmstrom et al. [78] Hall et al. [39], MRC [40] Bassi et al. [79] Sherif et al. [80] Sengelov et al. [81] Grossman et al. [38] T2 4 Nx M0 T2 3 N0 M0 T2 4a Nx M0 T2 4 N0 M0 T1G3 or T2 4a Nx M0 T2G3 or T3 4a Nx M0 T2 4 Nx M0 T2 4a Nx M0 T2 4b Nx M0 T2 4a N0 M0 C CMV C M-VEC C and A CMV M-VAC C and M C and M M-VAC RT RT & RT or RT or Yes a Yes Yes a Yes for subset with T3 4; p =.03. Abbreviations: A, doxorubicin; C, cisplatin;, cystectomy; E, epirubicin; G, grade; M, methotrexate;, not available; RT, radiation therapy; V, vinblastine.

5 634 Perioperative Chemotherapy for Urothelial Cancer in the chemotherapy arm (p =.06; p =.05 in an unstratified analysis) and the 5-year overall survival rate was greater (57% vs. 43%; p =.06). At the time of surgery, more patients in the experimental arm were found to have no residual disease in the cystectomy specimen, relative to patients in the control arm who had undergone cystoscopic biopsies (38% vs. 15%; p <.001), which was found to be a positive prognostic factor in both groups. Fever, infection, mucositis, and treatment-related death were less frequent with the use of M-VAC in the neoadjuvant setting than in the treatment of advanced disease. Importantly, preoperative chemotherapy did not prevent patients from undergoing potentially curative surgery and did not increase the frequency or severity of operative morbidity. Criticisms have included the long accrual time, suggestive of selection bias, the use of a one-sided p-value (the two-sided p- value was calculated at.088 in one editorial [41]), and the use of medians read from the survival curves as opposed to HRs, which better estimate the whole curves and not just a point in time. In order to address the variability and methodological flaws in the literature on neoadjuvant chemotherapy in invasive TCC, Winquist et al. [36] compiled data from 11 of 16 identified randomized, controlled trials, representing 2,605 patients, and performed a meta-analysis of overall survival. The MRC/EORTC and the INT 0080 trials were both included. The pooled HR for death was 0.90 (95% CI, ; p =.02), a 10% reduction in the risk for death. Focusing on the eight trials that incorporated cisplatin-based combination chemotherapy, the pooled HR was 0.87 (95% CI, ; p =.006), consistent with an absolute survival benefit of 6.5% (50% 56.5%). An earlier meta-analysis did not include the results of INT 0080 but did confirm a 13% reduction in the risk for death (p =.016) and a 5% absolute survival benefit at 5 years for the use of preoperative cisplatin-based combination chemotherapy [37]. In summary, on the basis of two randomized, controlled trials from the MRC/EORTC and an American Intergroup collaboration, as well as subsequent meta-analyses, the standard of care for clinically staged high-risk muscleinvasive bladder TCC is shifting from radical cystectomy alone to a multimodality regimen employing neoadjuvant cisplatin-based combination chemotherapy. Preoperative treatment is tolerable and does not exacerbate operative morbidity or lead to delays in resection. Unfortunately, far too few patients who would otherwise qualify for neoadjuvant chemotherapy are referred for such treatment by their surgeons. The challenge remains to determine the optimal chemotherapeutic regimen and to reduce barriers to referral by identifying reliable predictors of benefit. Adjuvant Chemotherapy An alternative approach to improving survival in muscle-invasive urothelial cancer, and one that may be more acceptable to the surgical community, is the administration of chemotherapy following radical cystectomy. The benefits of chemotherapy in this setting include: (a) the availability of accurate pathological staging prior to systemic therapy, precluding overtreatment and allowing the identification of patients at high risk for micrometastatic disease, and (b) the minimization of potential delays in definitive local therapy, especially in patients whose cancer may not be chemosensitive and may progress during treatment. This approach does, however, suffer from two major disadvantages: (a) the inability to assess pathological response of primary tumors, and, most important, (b) delays in or intolerance of systemic treatment as a result of postoperative morbidity. The benefit of adjuvant chemotherapy was first demonstrated by Logothetis et al. [42] in a retrospective analysis of postoperative cyclophosphamide, doxorubicin, and cisplatin (CISCA) in patients with pathological findings associated with a high risk for recurrence, including the presence of nodal metastasis, extravesicular involvement, or lymphovascular or pelvic visceral invasion. At a median follow-up of 118 weeks, the disease-free survival rates were 70% versus 37% (p =.00012), favoring patients who received adjuvant chemotherapy. Despite the inherent selection bias in this study, the provocative results ultimately led to clinical trials evaluating the role of adjuvant chemotherapy in a prospective fashion. Review of existing literature reveals five such trials, all suboptimal in that they were underpowered [43], often enrolling patients with good prognoses [33, 44], not fully analyzed in an intention-to-treat fashion [45], not randomized [46], or employed substandard chemotherapy regimens (Table 4) [45, 47]. Freiha and colleagues at Stanford University randomized 55 patients with pt3 4 or node-positive disease to observation or adjuvant chemotherapy with CMV [43]. With a median follow-up of more than 5 years, CMV resulted in a longer freedom from progression time, a median of 37 months versus 12 months (p =.01), but no difference in overall survival was seen (p =.32). Of note, 20% of the patients in the observation arm were salvaged with CMV at the time of recurrence. The Italian Uro-Oncologic Cooperative group treated 125 patients, with a clinical tumor deemed stage T2, >3 cm, T3, or T4, on a protocol that randomized node-negative patients after radical cystectomy to adjuvant treatment with methotrexate and cisplatin or observation, while all node-positive patients received methotrexate and cisplatin [46]. survival benefit was seen for treated patients The Oncologist

6 Cohen, Goel, Phillips et al. 635 Table 4. Randomized clinical trials of adjuvant cisplatin-based chemotherapy versus observation Trial n Pathologic TNM stage Schema Survival benefit p-value Skinner et al. [45] Stockle et al. [33, 44] Studer et al. [47] Freiha et al. [43] Bono et al. [46] T3 4 N+ M0 T3b 4a and/or N+ T3 4 Nx M0 T3b 4 Nx M0 T2 (>2 cm) or T3 4a N0 M0 +/ CACyc +/ MVA(E)C +/ C +/ CMV +/ CM Yes Yes.056 a.0012 b NS a Median survival improved from 2.4 years to 4.3 years (p =.0062). b Relapse-free survival. Abbreviations: A, doxorubicin; C, cisplatin; Cyc, cyclophosphamide;, cystectomy; E, epirubicin; M, methotrexate;, not available; V, vinblastine. relative to observed patients in either the whole study population or in the randomized node-negative subgroup. Studer et al. [47] randomized 77 patients with invasive, nonmetastatic bladder cancer, without clinical N2 or N3 disease, to adjuvant cisplatin alone or observation. After a median follow-up of almost 6 years, no statistically significant difference in the 5-year overall survival rate was noted (57% vs. 54%; p =.65). In contrast, Skinner et al. [45], randomized 91 patients with pathological T3, T4, or node-positive disease to either four cycles of chemotherapy or observation following radical cystectomy. A greater 3-year disease-free survival rate (70% vs. 46%; p =.0010) and median survival time (4.3 years vs. 2.4 years; p =.0062) were observed. In an update published at a later date, a strong trend toward an overall survival benefit for chemotherapy became apparent (p =.056) with an additional 15 months of follow-up. Several criticisms of that trial exist. First, the 91 enrolled patients fell short of the initially planned goal (75 patients per arm). Second, a heterogeneous group of chemotherapy agents was used early in the course of the study, based on an unproven clonogenic assay meant to assess tumor chemosensitivity. In fact, only 5 of the first 17 patients in the treatment arm received the defined chemotherapeutic intervention, CISCA. Third, Kaplan-Meier survival curves were evaluated using the Wilcoxon test, which is more sensitive for early differences, perhaps artificially assigning a difference that may not exist with extended follow-up. Although no data are provided, the authors do note that the use of the log-rank test made no difference. A similar study was conducted by Stockle et al. [33, 44] at the University of Mainz in Germany. Forty-nine of an originally planned 100 pt3b, pt4a, or pn+ patients were randomized to either three cycles of M-VAC or M-VEC (methotrexate, vinblastine, epirubicin, and cyclophosphamide), depending on treatment site, or observation, after radical cystectomy. In an interim analysis, a significantly higher 3-year relapse-free survival rate (p =.0012) in favor of adjuvant treatment necessitated closure to accrual. tably, patients with lymph node involvement seemed to benefit the most. analysis of overall survival by the intention-to-treat principle has been presented to date. This body of evidence is significantly less convincing than that for neoadjuvant chemotherapy and remains controversial. Nevertheless, efforts to optimize adjuvant treatments are ongoing. A German phase III trial comparing two adjuvant chemotherapy regimens was recently reported. Patients with pt3a 4a and/or N+ TCC of the bladder were randomized to either three cycles of cisplatin and methotrexate (CM) or three cycles of a standard regimen, M-VEC, after radical cystectomy [48]. Although the 5-year progression-free survival rates were similar (46.3% vs. 48.8%) in this noninferiority trial, the degree of efficacy a clinician must be willing to concede (represented by the upper limit of the 95% CI of the HR for survival) in exchange for reduced toxicity, was 48%. While patients receiving CM experienced less grade 3 and 4 leukopenia (7% vs. 22.2%; p <.0001), there was no difference in the incidence of clinically significant toxicities, including neutropenic fever, infection, and treatment-related death, calling into question the reason for accepting such reduced efficacy. Neoadjuvant Versus Adjuvant Therapy Although each of these potentially curative strategies has advantages and disadvantages, no randomized comparison has been undertaken to date (Table 5). The group from M.D Anderson Cancer Center has, however, compared pre- and postoperative treatment with postoperative treatment alone in patients with high-risk, resectable urothelial cancer (clinical T2 with lymphovascular invasion, T3, or T4a, N0, M0) [49]. One hundred forty patients were randomly assigned to either cystectomy followed by five cycles of adjuvant M- VAC or to two preoperative and three postoperative cycles of M-VAC. The study was powered to detect a 20% difference in survival between the arms (60% to 80%). In the final analysis, there was no significant difference between the groups with respect to overall survival, time to progression, or cause-specific survival. Further studies, directly comparing patients treated with neoadjuvant or adjuvant chemotherapy, are needed to clarify the optimal timing of such treatment.

7 636 Perioperative Chemotherapy for Urothelial Cancer Barriers to the Incorporation of Chemotherapy into the Management of Localized Disease Despite the cited large-scale randomized trials and metaanalyses showing evidence of a survival benefit for neoadjuvant chemotherapy, it is not widely practiced. Clearly, oncologic urologic surgeons are more concerned by the potential delays in surgery [50] and lack of pathologic staging mandated by the use of neoadjuvant chemotherapy than they are impressed by its efficacy. The 11 years required to accrue patients to the U.S. intergroup trial is evidence to this fact. In that vein, efforts to confirm the benefit of postoperative therapy are ongoing (Table 6). Another barrier to the standard incorporation of perioperative chemotherapy in the management of bladder cancer is the perceived toxicity of cisplatin-based combination regimens. The widespread adoption of GC in the treatment of metastatic disease based on a lower incidence of toxicity has prompted practicing oncologists to apply this regimen in the perioperative setting as a result. In order to confirm the efficacy of GC in this setting, investigators have shown its tolerability in the phase II setting [51] and, in Italy, have initiated a randomized, controlled, postoperative trial with observation as the reference arm [52]. Firm evidence of the efficacy of GC when used with curative intent is preferable to extrapolation. Other efforts have focused on developing the combination of carboplatin and paclitaxel as adjuvant therapy [25]. Both carboplatin and paclitaxel have shown single-agent activity in phase II studies [53, 54] but as a combination have not been proven to be superior to M-VAC [23]. Alternatively, high-dose M-VAC with growth factor support has been postulated to be a reasonable area of investigation in the neoadjuvant setting in light of a shorter cycle length (14 days), less toxicity, and higher response rates relative to M-VAC, although no difference in survival was seen in patients with advanced disease [21]. The EORTC is conducting a well-designed, large-scale study of the value of adjuvant modern chemotherapy, relative to treatment with that same chemotherapy at the time of relapse (Table 6). At least one rth American cooperative group (the Cancer and Leukemia Group B), already convinced of the value of adjuvant therapy, abandoned observation as the control arm in a prospective study in an attempt to optimize postoperative treatment. Unfortunately, that trial recently closed as a result of slow accrual, calling into question the ability to study perioperative chemotherapy in the treatment of urothelial cancer in U.S. Table 5. Comparison of adjuvant and neoadjuvant strategies Neoadjuvant Adjuvant Advantages Disadvantages Advantages Disadvantages Administration of chemotherapy easier in preoperative setting Ability to assess sensitivity of primary to chemotherapy, aiding in prognostication Clinical stage correlates poorly with pathologic stage, leading to overtreatment Potential delay in or noncompliance with local therapy Pathologic staging aids in prognostication and avoids over- and undertreatment delays prior to or noncompliance with local therapy Chemotherapy may be delayed or abandoned as a result of postoperative morbidity Inability to assess response of primary to chemotherapy Table 6. Phase III trials of perioperative chemotherapy currently open to accrual Sponsor Phase Patient/tumor characteristics Schema Chemotherapy Open in the U.S.? EORTC III Stage 3 or 4 4 cycles of postoperative chemotherapy vs. 6 cycles of chemotherapy at the time of relapse ITNRC III T2 (G3 only) or T3 4 (any G), N0 2 or any T, N1 2, M0 AUO III T3, T4a, and/or N1 or N2 (<6 LN), and inappropriate for cisplatin 4 cycles of postoperative chemotherapy vs. observation Up to 6 cycles of chemotherapy vs. observation Classical M-VAC, high-dose M-VAC, or gemcitabine and cisplatin Gemcitabine and cisplatin Gemcitabine INT III T1 or T2, N0 p53-directed chemotherapy M-VAC Yes (temporarily vs. observation closed 1/18/06) Abbreviations: A, doxorubicin; AUO, Association of Urogenital Oncology; C, cisplatin; EORTC, European Organization for the Research and Treatment of Cancer; INT, Intergroup; ITNRC, Italian National Research Council; M, methotrexate; V, vinblastine. The Oncologist

8 Cohen, Goel, Phillips et al. 637 Prognostic Markers Prognostic markers in the premolecular era were based solely on clinical and pathological parameters. A retrospective analysis of the long-term outcomes of >1,000 patients at the University of Southern California between 1971 and 1997 found pathologic determinants of survival, stratifying patients into prognostic categories [2]. Patients with organconfined (pt2 and pt3a), node-negative lesions had 89% and 78% 5-year recurrence-free survival rates, respectively. Patients with extravesical (pt3b and pt4), node-negative lesions had a statistically significant higher risk for recurrence (p <.001), with 5-year recurrence-free survival rates of 62% and 50%, respectively. Patients could also be stratified by the presence of lymph node involvement. The 5-year recurrence-free survival rate for patients with lymph node metastasis was 35%, significantly lower than that for patients without node involvement (p <.001). These prognostic factors have been corroborated in a number of studies [55 57]. The presence of either perineural or angiolymphatic invasion are independent predictors of prognosis in some studies [57 60] but not in others [55, 61]. Extracapsular extension of pelvic lymph node metastasis was recently shown to be a marker of a group with a particularly poor prognosis [62]. Unlike for superficial tumors [63], tumor grade has never been shown to predict outcome in the invasive setting [55]. Surgical factors, including the extent and quality of lymph node dissection, have also been shown to influence survival. In single-institution studies, the number of examined lymph nodes has consistently been correlated with outcomes [64, 65]. Importantly, in the context of a large, multi-institutional trial of neoadjuvant chemotherapy, survival varied both with the extent of lymph node dissection and with the presence or absence of positive margins [66]. Future Directions It is important that future multimodality trials incorporate these known surgical and pathologic prognostic factors as stratification variables, to ensure adequate randomization, and by mandating high-quality and extensive lymph node dissections. Studies incorporating biological markers of prognosis as stratification and randomization variables have already been initiated. TP53 mutation and resultant p53 nuclear overexpression correlate with progression of superficial TCC to invasive stages [67, 68]. Although the data are somewhat variable, p53 overexpression is also thought to confer a negative prognosis in patients treated with M-VAC chemotherapy in the neoadjuvant and advanced settings, possibly related to resistance [69, 70]. The Southwest Oncology Group and the National Cancer Institute of Canada currently are enrolling patients with organ-confined TCC of the bladder in a marker-dependent, risk-directed trial, randomizing patients with TP53 mutations to M-VAC versus observation; those patients without mutations are observed [71]. Other biologic predictors of resistance or sensitivity to TCC-directed therapy include P-glycoprotein, glutathione, metalloproteinase, the nucleotide excision-repair (NER) system, BRCA-1, and RRM-1, and their clinical utility is being evaluated [72]. DNA microarray and proteomic analyses are active areas of research. In addition to improving our understanding of urothelial cancer development and progression, it is hoped that they might illuminate new therapeutic targets. Conclusions The outcome of local therapy in muscle-invasive, extravesical, or lymph node-involved urothelial cancer is poor. Attempts to improve the cure fraction have included neoadjuvant and adjuvant chemotherapy strategies. Preoperatively, cisplatin-based combinations were proven to be effective in two large, randomized clinical trials of M-VAC and CMV. Additional validation for this approach derives from a meta-analysis including these and other trials. Still, today the neoadjuvant approach is not practiced as commonly as one might expect. Obstacles to the employment of neoadjuvant chemotherapy include the inaccuracy of clinical staging techniques, the necessary delay in definitive local therapy, and concerns regarding the generalizability of existing data [73]. Data for the use of adjuvant chemotherapy are significantly less compelling, and it remains controversial, although most medical oncologists feel it is reasonable to offer such treatment to patients found to have pathologic evidence of extravesical invasion or lymph node involvement. Certainly, one might extrapolate from other tumors for which neoadjuvant and adjuvant chemotherapy were equally effective [32], but in the attempt to cure, explicit data in urothelial cancer are desirable. The ongoing EORTC study of early versus delayed chemotherapy in pt3 4 and/ or lymph node-positive disease may confirm the value of adjuvant chemotherapy. Investigation of the clinical utility of biologic markers is expanding as new markers are discovered, and exciting techniques, including quantitative real-time polymerase chain reaction and DNA microarray and proteomic analysis, are applied. It is important to continue to support the clinical trials that will clarify the efficacy of adjuvant chemotherapy, perhaps elucidate the optimal timing of chemotherapy (i.e., neoadjuvant vs. adjuvant), and incorporate these new biologic markers. Finally, it is important to

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