Review

Neoadjuvant chemotherapy preceding cystectomy for bladder cancer

1. 2. Introduction Efcacy of systemic chemotherapy for metastatic transitional cell cancer 3. 4. 5. 6. Adjuvant chemotherapy for bladder cancer Neoadjuvant chemotherapy for bladder cancer Conclusions Expert opinion

Guru Sonpavde, Gilad E Amiel, Martha P Mims, Teresa G Hayes & Seth P Lerner
Texas

Oncology, P.A. and US Oncology Research, Webster, TX 77598, USA

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Background: Occult 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. Objectives: Data supporting neoadjuvant chemotherapy for locally advanced bladder cancer are reviewed. Results: 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. Trials employing neoadjuvant therapy are particularly valuable in the development of novel systemic therapy regimens, since pathological complete remission appears to be a powerful prognostic factor for long-term survival. Conclusion: Neoadjuvant chemotherapy is a standard for the therapy of locally advanced bladder cancer, and the neoadjuvant paradigm may assist in accelerating novel agent development.
Keywords: adjuvant chemotherapy, bladder cancer, neoadjuvant chemotherapy Expert Opin. Pharmacother. (2008) 9(11):1885-1893

1.

Introduction

In 2008, approximately 68,810 cases of bladder cancer will be reported in the United States, and 14,100 patients will die [1]. Radical cystectomy has yielded excellent outcomes for muscle-invasive transitional cell carcinoma (TCC) of the bladder, with higher pathologic stage correlating with a poorer baseline prognosis [2-7]. The overall long-term progression-free survival (PFS) was 60 70% in large retrospective reports of outcomes following radical cystectomy, where the vast majority of patients did not receive perioperative chemotherapy [2-7]. Extravesical disease; however, confers a relatively poor PFS of 40 60%, while lymph node involvement is associated with a PFS of 15 35%. Recently, two consortia developed a postoperative nomogram with better predictive accuracy than standard TNM staging. These nomograms examined multiple variables including age, gender, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status [8]. Other studies have revealed that the quality of radical cystectomy has a major impact on survival. Extended pelvic lymph node dissection (regardless of pathologic tumor involvement) to the aortic bifurcation as compared with dissection to the common iliac bifurcation, lymph node density (number of pathologically positive lymph nodes/total number of lymph nodes removed) and margin status all appear to significantly impact outcome [9-11]. Administration of adjuvant chemotherapy also appears to play a role in prognosis. This is not surprising since the incidence of distant recurrence (20 50%) is greater than that of locoregional recurrence (5 15%), and implies that perioperative systemic therapy, particularly in patients with pathological extravesical and lymph node positive disease, may eradicate
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distant micrometastases and improve survival. This review will discuss the role of neoadjuvant chemotherapy preceding radical cystectomy for locally advanced muscle-invasive bladder cancer.

Efcacy of systemic chemotherapy for metastatic transitional cell cancer

2.

In metastatic disease, MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy improves outcomes compared with single-agent cisplatin, CISCA (cisplatin, cyclophosphamide and doxorubicin) or cisplatindocetaxel [12-14]. The median PFS and overall survival (OS) with the MVAC regimen are approximately 8 and 14 months, respectively. Dose-dense (DD)-MVAC given every 2 weeks with growth factor support demonstrated nearly identical median survival as conventional MVAC (15.1 versus 14.9 months), while the 5-year survival was superior for DD-MVAC (21.8 versus 13.5%, p = 0.042) [15]. A regimen of gemcitabine and cisplatin (GC) appeared to have efficacy similar to MVAC but was less toxic [16]. The median survival (13.8 months for GC versus 14.8 months for MVAC), response rate (49% for GC versus 46% for MVAC) and time to progression (7.4 months for both GC and MVAC) were similar but the study was underpowered for equivalence. The toxicity profile favored GC with a significant reduction in the incidence of grades 3 4 mucositis (1 versus 22%), neutropenic sepsis (1 versus 12%), neutropenic fever (2 versus 14%) and alopecia (11 versus 55%). As a result of the better toxicity profile for GC and the superimposed survival curves, most oncologists have adopted GC as frontline therapy for metastatic TCC. Attempts to improve outcomes with GC by the addition of a third agent have thus far been unsuccessful as demonstrated by a recent large randomized trial of 627 patients examining the addition of paclitaxel to GC [17]. This trial demonstrated no statistical improvement in median survival (12.8 versus 15.7 months, p = 0.1) or PFS (7.7 versus 8.8 months, p = 0.109) for GC compared with PCG (paclitaxel cisplatingemcitabine). While the response rate was superior for PCG (57 versus 46%, p = 0.02), PCG was more toxic with more neutropenic fever (12.5 versus 3.8%), diarrhea (18.9 versus 8.9%) and alopecia (50.6 versus 15.6%). Of note, thrombocytopenic hemorrhage was less common with PCG (6.8 versus 11.4%). Thus, reasonable choices for initial treatment of metastatic urothelial cancer include MVAC, DD-MVAC and GC but should be considered palliative with suboptimal long-term survival, particularly for visceral metastases. Patients with good performance status and node only metastasis may achieve durable complete response compatible with long-term survival. Salvage chemotherapy for refractory or relapsed disease yields median PFS and OS of 2 3 and 6 9 months, respectively, with currently available agents [18]. As a result of the poor outcomes for these patients, significant effort is being directed toward

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initiating clinical trials, including a Phase III trial planned by the CALGB (Cancer and Leukemia Group B), which will examine the benefit of combining GC with bevacizumab. Ongoing early Phase I/II trials are evaluating novel chemotherapeutic (vinflunine, nab-paclitaxel, E7389) and biologic agents (sunitinib, sorafenib, vandetanib, pazopanib, lapatinib, cetuximab, trastuzumab, VEGF-trap), alone or in combination with conventional cytotoxic agents. Renal dysfunction, usually defined as a calculated creatinine clearance (CrCl) of less than 60 ml/min by the Cockroft-Gault equation, is quite common in patients with urothelial carcinoma and frequently renders patients ineligible for cisplatin. Renal dysfunction may be attributable to advanced age, comorbidities or ureteric obstruction. In fact, more than 40% of postoperative patients greater than 70 years of age are ineligible for cisplatin [19]. Additionally, advanced age, comorbidities and poor performance status may also contraindicate cisplatin-based systemic chemotherapy. Carboplatin-based and nonplatinum regimens (carboplatintaxanegemcitabine, carboplatin gemcitabine, carboplatinmethotrexatevinblastine, carboplatin paclitaxel, taxanegemcitabine, single agent gemcitabine) have been employed in patients with advanced urothelial cancer and renal dysfunction or poor performance status [20-25]. However, small randomized trials suggest that carboplatin-based regimens are inferior to cisplatin-based regimens [26-28]. Therefore, this population requires a special focus employing tolerable regimens.
3.

Adjuvant chemotherapy for bladder cancer

Interpretation of adjuvant chemotherapy trial results is plagued by the lack of statistical power as well as early trial termination. The single largest published randomized clinical trial enrolled 91 patients at University of Southern California (USC) [29]. Patients with deeply muscle-invasive (T3, T4) and/or node-positive disease were randomized to observation or chemotherapy including a CISCA-like regimen (cisplatin, cyclophosphamide, doxorubicin), single agent cisplatin, and regimens selected by clonality assays. Median survival was significantly improved in the chemotherapy arm (4.3 versus 2.4 years, p = 0.0062) but 3-year survival was not statistically superior to observation (66 versus 50%, p = 0.09). Of the 44 patients randomized to chemotherapy, 11 refused treatment and accrual was extremely slow, requiring 8 years to accrue 91 patients. In addition, the Wilcoxon method employed for statistical analysis emphasizes early but often nonsustained, differences. A German randomized trial of 49 patients included those with extravesical and/or nodepositive disease [30]. Patients were randomized to observation versus adjuvant MVAC or MVEC (methotrexate, vinblastine, epirubicin and cisplatin). A significant improvement in relapse-free survival (p = 0.0012) was observed in the chemotherapy arm without a difference in OS. The

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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 at the time of progression. Of the 26 patients in the chemotherapy group, eight 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 [31,32]. The German multicenter trial AUO-AB 5/95 randomized 327 patients with extravesical and/or lymph node positive disease to adjuvant CM (cisplatin and methotrexate) or MVEC, with the goal of proving noninferiority of CM [33]. The hazard ratio (HR) for PFS (1.13) supported the noninferiority of CM. The 5-year PFS, disease-specific survival and OS rates were similar for the two regimens. Grade 3/4 leukopenia occurred in 7% of patients treated with CM and 22.2% of patients treated with MVEC (p < 0.0001). In the absence of definitive data demonstrating a survival benefit with adjuvant chemotherapy, inclusion of an arm receiving no adjuvant therapy may have been a better 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 [34]. The overall HR for survival of 0.75 suggests a 25% relative reduction in the risk of death for treatment with chemotherapy compared with no adjuvant therapy. However, the findings of this meta-analysis may be limited by the inclusion of poorly conducted small trials. Therefore, all of the available data for adjuvant chemotherapy are underpowered and do not provide adequate evidence for clinical decision-making. The advantage of adjuvant therapy, however, is that it treats a population of patients whose risk of relapse is clearly defined by pathologic stage at cystectomy. An adequately powered and well-designed study is needed to prove definitively the efficacy of adjuvant chemotherapy. The EORTC (European Organization for Research and Treatment of Cancer) 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. Selection of candidates for adjuvant chemotherapy based on molecular factors is being explored based on published data, suggesting that overexpression of p53 is correlated with increased risk of progression as well as chemosensitivity [35,36]. Further light may be shed on this issue when data are available from a recently closed trial led by USC and supported by the Southwest Oncology Group designed to assess three cycles of adjuvant MVAC in patients with p53 overexpressing pathologic T1 and T2 (invasion of the lamina propria or muscle layer) bladder cancer.

Neoadjuvant chemotherapy for bladder cancer

4.
4.1 Memorial Sloan-Kettering Cancer Center retrospective experience

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A total of 111 patients at Memorial Sloan-Kettering Cancer Center (MSKCC) with clinical T2 T4N0M0 (muscleinvasive and extravesical) operable bladder cancer treated with neoadjuvant MVAC were assessed [37]. Postchemotherapy surgery was administered in 81 patients. Prechemotherapy T stage and postchemotherapy pathologic stage were the only factors with independent prognostic value for survival. An association between pathologic downstaging and survival was found in patients with initial extravesical disease (5-year survival was 54% with downstaging versus 12% without downstaging) but not for bladder-confined disease. In a separate report, p53 overexpression was a negative prognostic factor for survival (p = 0.001) [38].
4.2

Nordic cystectomy trials

The Nordic Cooperative Bladder Cancer Study Group conducted a randomized Phase III study (Nordic Cystectomy trial I) to assess the benefit of neoadjuvant chemotherapy in patients with bladder cancer scheduled to undergo brief radiation (4 Gy daily for 5 consecutive days) followed in sequence by radical cystectomy (Table 1) [39]. A total of 325 patients with T1 grade 3 and T2 T4aNxM0 bladder cancer were randomized to local therapy with or without two cycles of neoadjuvant cisplatin plus doxorubicin. The 5-year OS was similar in both groups (59 versus 51%, p = 0.1). In the subset of patients with extravesical disease, the 5-year survival was significantly better for the neoadjuvant chemotherapy arm (52 versus 37%, p = 0.03), although the trial was not designed to address this issue. As a follow-up to this trial, the Nordic Cystectomy Trial II evaluated neoadjuvant chemotherapy alone (without preoperative radiation) [40]. A total of 317 patients with clinical stages T2 T4aNxM0 disease underwent radical cystectomy with or without three cycles of neoadjuvant CM. Chemotherapy was administered according to protocol in only 74% of patients. Five-year survivals were similar in the two arms (53% with chemotherapy and 46% in the control group, p = 0.2375) with pathologic complete remission (pCR) observed in 26.4% of the chemotherapy group compared with 11.5% of the control group (p = 0.001). Thus, despite substantial pathologic downstaging, no improvement in survival was demonstrated with neoadjuvant chemotherapy.
4.3 MD Anderson Cancer Center perioperative chemotherapy trial

One hundred and forty patients were randomized to receive two cycles of MVAC before and three cycles after radical cystectomy or five cycles of MVAC after radical cystectomy (Table 1) [41]. Eligible patients had TCC with extravesical

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Table 1. Reported randomized trials of neoadjuvant chemotherapy.

Trial (Ref.) Nordic Cystectomy I [39] Nordic Cystectomy II [40] MDACC [41] International Collaboration
[42,43]

n 325 317 976 317

Standard regimen Observation Observation Adjuvant MVAC 5 Observation Observation

Chemotherapy regimen Cisplatin + doxorubicin Cisplatin + methotrexate MVAC 2 cystectomy MVAC 3 CMV 3 MVAC 3

Survival benet No No No Yes Yes

US Intergroup [44]

CMV: Cisplatin, methotrexate, vinblastine; MDACC: MD Anderson cancer center; MVAC: Methotrexate, vinblastine, doxorubicin, cisplatin.

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disease or muscle-invasive disease with vascular invasion. Survival was similar at approximately 60% at 31.7 months for both groups. Neoadjuvant chemotherapy achieved pCR in 37% of patients compared with 4% for radical cystectomy before chemotherapy (p = 0.00006). Neoadjuvant MVAC was feasible, lowered the positive surgical margin rate (2 versus 11%) and was not accompanied by increased postoperative morbidities. However, this trial was designed to detect a 20% difference in outcomes, and was not powered to confirm equivalence of the two approaches.
4.4

International Collaboration of Trialists study

This is the single largest trial of neoadjuvant chemotherapy for bladder cancer with accrual of 976 patients (Table 1) [42]. Eligible patients included those with T2 grade 3, T3 or T4a disease who were candidates for local therapy with radical cystectomy or external-beam radiation. Patients were randomized to local therapy with or without three cycles of neoadjuvant CMV. The study aimed to detect an absolute improvement in survival of 10% (from 50 to 60%). During the initial report, the difference between the 3-year survivals with neoadjuvant chemotherapy and local therapy alone approached but did not reach statistical significance (55.5 versus 50%, p = 0.075). The median survival for chemotherapy was 44 months versus 37.5 months for the local therapy alone group. After a longer median follow-up of 7 years, the difference achieved statistical significance (p < 0.05) [43]. The 3-year disease-free survival was significantly longer with neoadjuvant chemotherapy (46 versus 39%, p = 0.019). Following neoadjuvant chemotherapy, pCR was found in 32.5%. Chemotherapy-related mortality was 1% and postoperative complications did not increase. The chemotherapeutic regimen used in this study is not considered standard, albeit CMV has never been compared with MVAC. Although the improvement in survival was less than the magnitude originally sought, this trial is considered a positive trial in favor of neoadjuvant CMV.
4.5

Intergroup trial

A total of 317 patients with operable T2N0M0 to T4aN0M0 disease were enrolled on the Intergroup trial (Table 1) [44].
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The patients were stratified for age and stage and randomized to radical cystectomy alone or three cycles of MVAC before radical cystectomy. At 5 years, 57% of patients in the neoadjuvant chemotherapy group were alive compared with 43% of those in the radical cystectomy alone group (two-sided p = 0.06). The median survival was 77 months for the neoadjuvant chemotherapy group and 46 months for the radical cystectomy alone group. However, it is unclear if most of the radical cystectomy alone group of patients received prompt cisplatin-based combination chemotherapy at recurrence of malignancy. Improved survival was associated with pCR defined as absence of all residual tumor. The 5-year survival for all patients with pCR was an impressive 85%. The neoadjuvant chemotherapy group displayed a significantly higher pCR rate (38 versus 15%, p < 0.001). The planned radical cystectomy was performed in 82% of patients in the neoadjuvant chemotherapy group compared with 81% of patients in the radical cystectomy alone group. Reasons for not performing radical cystectomy (n = 39) in all patients enrolled were aborted surgery at time of exploration due to unresectability or positive nodes, patient refusal and progression of malignancy. Eighty-seven per cent of patients in the chemotherapy group received at least one cycle of MVAC. Chemotherapy induced grade 4 neutropenia in 33% and grade 3 gastrointestinal toxicities occurred in 17%. However, no life-threatening toxicities or deaths occurred from chemotherapy, and no increase in postoperative complications was observed. Although the two-sided p value was 0.06, the original goal of a statistically significant difference defined as a one-sided p < 0.05 was achieved. Survival was associated with neoadjuvant chemotherapy (HR 1.39, p = 0.06), completion of radical cystectomy (HR 2.88, p < 0.001) and removal of 10 pelvic lymph nodes (HR 2.38, p < 0.001) [45]. Five-year survival and freedom from local relapse were 81 and 91%, respectively, in patients who had neoadjuvant chemotherapy/radical cystectomy and 10 lymph nodes removed (n = 66), 66 and 90% in patients with radical cystectomy alone and 10 lymph nodes removed (n = 60), 55 and 73% in chemotherapy/radical cystectomy and < 10 lymph nodes removed (n = 49), and 39 and 66%

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in radical cystectomy alone with < 10 lymph nodes removed (n = 44). Five-year survival of patients with positive surgical margins (n = 25) and those who did not undergo radical cystectomy (n = 39) was dismal at 0 and 11%, respectively. Therefore, both the quality of surgery and neoadjuvant chemotherapy appear to have favorable and independent impact on outcomes.
4.6 Meta-analysis by the Advanced Bladder Cancer Meta-analysis Collaboration

4.8 Neoadjuvant therapy with combination gemcitabine and cisplatin

While not tested in a prospective fashion, recent retrospective data from MSKCC reveal that the GC regimen produces a pCR rate of 35%, similar to MVAC [49]. The caveat is that Phase III trials have not compared neoadjuvant MVAC with GC. However, given the similar activity of both regimens in the advanced setting, and the superior tolerability of GC, it may be reasonable to administer GC as neoadjuvant therapy.
4.9

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A meta-analysis was initiated by the Medical Research Council (UK) Clinical Trials Unit and reported by the Advanced Bladder Cancer Meta-analysis Collaboration [46,47]. A total of 2688 patients were analyzed from 10 trials and information for individual patients was updated. Groups were defined according to the type of chemotherapy regimen (cisplatin-alone or platinum-based combination) and local therapy (cystectomy, radiation or preoperative radiation followed by cystectomy). Platinum-based combination chemotherapy (the vast majority received cisplatin) significantly improved 5-year OS compared with local therapy alone (50 versus 45%, p = 0.016, HR 0.87). Combination chemotherapy also displayed an improvement in disease-free survival (p = 0.0001), locoregional disease-free survival (p = 0.012) and metastasisfree survival (p = 0.001). While single agent cisplatin chemotherapy did not demonstrate an improvement in survival (p = 0.26) or any other end point, combination chemotherapy yielded significantly improved survival (p = 0.044) and disease-free survival (p = 0.046) compared with cisplatin alone. Therefore, the meta-analysis supports platinum-based combination neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer. Since all platinum-based combination trials were analyzed as a group, it is not possible to discern the best combination for use in neoadjuvant therapy. Additionally new regimens (e.g., GC) were not evaluated in the included trials.
Meta-analysis by the Canadian cancer care Ontario Program
4.7

Carboplatin-based neoadjuvant therapy

In a Phase II trial of 68 patients with adequate renal function and clinical T3 or T2 with hydronephrosis, N0, M0 bladder cancer received 3 cycles of neoadjuvant PCaG (paclitaxel, carboplatin, gemcitabine) with a primary end point of pCR. Patients with T4 or node-positive patients received six cycles of PCaG with an end point of respectability [50]. pCR was observed in 32% of evaluable patients in the T2 T3 group and 17% in the T4/node-positive group. The resection rate for the T4/node-positive group was 67%. Unfortunately, toxicities were unexpectedly common and 79% of all patients had grade 3/4 hematologic toxicity. Six patients died during chemotherapy or postoperatively (only one death clearly attributable to chemotherapy), which led to premature closure of the trial. The pCR rate appeared comparable to that observed for platinum-containing regimens, with the limitation that this was a Phase II trial. Thus, in selected cisplatin ineligible patients with good performance status, neoadjuvant PCaG may be considered based on these data. The caveat is that this regimen was fairly toxic in a population with adequate baseline renal function and may often warrant prophylactic granulocyte growth factors in accordance with guidelines [51]. PCaG has also not been compared with a cisplatin-based regimen in the perioperative setting.
5.

Conclusions

A systematic review and meta-analysis were performed from 11 suitable randomized controlled trials (totaling 2605 patients) of neoadjuvant chemotherapy by the Cancer Care Ontario Program in Canada. The pooled HR was 0.90 (p = 0.02). Eight trials used cisplatin based combination chemotherapy and the pooled HR was 0.87 (p = 0.006), consistent with an absolute overall survival benefit of 6.5% (from 50 to 56.5%). Reported progression-free survival data were insufficient for meta-analysis but they appeared concordant with overall survival results. Mortality due to combination chemotherapy was 1.1% but combination chemotherapy could generally be administered safely without adverse outcomes. An optimal chemotherapy regimen was not identified and newer regimens (e.g., GC) were not tested in these trials [48].

Based on the above studies, neoadjuvant cisplatin-based combination chemotherapy preceding radical cystectomy is now accepted as a standard of care for muscle-invasive bladder cancer, while definitive data are not available for adjuvant chemotherapy. While randomized trials have evaluated and support neoadjuvant therapy with MVAC or CMV, many treating physicians have recently adopted GC due to a favorable toxicity profile and similar efficacy in the advanced disease setting. Additionally, most ongoing and planned trials in the advanced disease setting employ GC as the backbone of frontline therapy in combination with biologic agents. Trials have not addressed perioperative chemotherapy specifically targeting patients ineligible for cisplatin (due to renal dysfunction and/or poor performance status), and these patients require a special investigational focus. At present, patients that are not candidates for cisplatin should probably not be considered candidates for perioperative chemotherapy in the absence of clinical trials
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Neoadjuvant chemotherapy preceding cystectomy for bladder cancer

Table 2. Ongoing and planned nonrandomized neoadjuvant trials for bladder cancer.
Regimen Ifosfamidecisplatin Nab paclitaxel CaGNab paclitaxel GCbevacizumab DD-MVAC DD-MVAC bevacizumab Erlotinib Sunitinib GCsunitinib Dasatinib Ipilimumab (CTLA-4 antibody) Primary end point pCR pCR pCR pCR pCR Correlative pCR pCR Correlative Correlative Institution MSKCC U Minnesota MUSC DFCI MDACC UNC Cleveland Clinic Baylor-HOG Baylor-HOG MDACC

CaG: Carboplatin-gemcitabine; DD-MVAC: Dose dense MVAC; DFCI: Dana farber cancer Institute; GC: Gemcitabine, cisplatin; HOG: Hoosier oncology group; MDACC: MD Anderson cancer center; MSKCC: Memorial sloan kettering cancer center; MUSC: Medical university of south carolina; Nab paclitaxel: Nanoparticle albumin bound paclitaxel; pCR: pathologic complete response; UNC: University of North Carolina.

available for this population. Further advances will require close collaboration between oncologists, urologists and basic researchers.
6.

Expert opinion

Several novel agents and regimens are being evaluated in patients with invasive bladder cancer in the neoadjuvant setting with both pathologic and correlative pharmacodynamic end points (Table 2). Trials are building upon gemcitabineplatinum as well as DD-MVAC in the neoadjuvant setting. Neoadjuvant chemotherapy for muscle-invasive bladder cancer has several advantages compared with adjuvant therapy in that it permits in vivo assessment of tumor response and pathologic downstaging and provides powerful prognostic assessment, since pCR correlates with prolonged survival. pCR needs to be further defined; that is, whether lack of all tumor or lack of nonmuscle-invasive tumor is a better predictor of outcomes. Additionally, the prognostic impact of residual carcinoma in situ needs to be studied. Similar to breast cancer, it is possible that residual nonmuscle-invasive cancer will not adversely impact prognosis [52]. Outcomes may vary as a continuous variable in relation to residual tumor burden as has been demonstrated in breast cancer [53]. Additionally, a near-pCR in patients with breast cancer appeared to confer a prognosis similar to true pCR. Additionally, baseline tumor genomics and proteomics appear promising preliminarily as predictors of pathologic response [54,55]. Fourteen predictive genes separated the
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responder group (no muscle-invasive disease) from the nonresponder group in a retrospective study of patients with invasive bladder cancer who received neoadjuvant MVAC chemotherapy [54]. This system accurately predicted the drug responses of eight of nine test cases. Among those genes, topoisomerase IIa, a target of doxorubicin, was downregulated in the nonresponder group. Because real-time reverse transcription polymerase chain reaction data were highly concordant with the cDNA microarray data for those 14 genes, a quantitative reverse transcription polymerase chain reaction-based prediction system was developed. To further validate the clinical significance of the system, the investigators applied it to 22 additional cases of bladder cancer patients and found that the scoring system correctly predicted clinical response for 19 of the 22 test cases [55]. These data suggest that the goal of personalized medicine may be achievable. Other potential but, unproven benefits, include earlier therapy for micrometastases before development of drug resistance, and superior efficacy compared with adjuvant chemotherapy. Besides the lack of definitive data from prospective trials, the primary disadvantage of the adjuvant chemotherapy paradigm may be that it is less feasible in a proportion of patients after radical cystectomy due to slow postoperative recovery, although there are no data to definitively support this assertion. A recent retrospective study from the MSKCC demonstrated that 30% of 1142 patients that underwent radical cystectomy suffered from grade 2 5 adverse events within 90 days that could potentially contraindicate adjuvant chemotherapy [56]. A disadvantage of the neoadjuvant approach is the possibility that some low-stage low-risk patients may unnecessarily receive neoadjuvant chemotherapy. For example, patients with small muscle-invasive T2 tumors who bear no residual disease in the cystectomy specimen (owing to complete resection during the preceding cystoscopic biopsy) and have no accompanying hydronephrosis or carcinoma in situ have an excellent long-term disease-free survival with radical cystectomy alone and may not warrant perioperative chemotherapy. However, the adjuvant chemotherapy model provides precise pathological data that can be utilized to determine prognosis and need for additional therapy. Prompt surgical resection may allay patient anxiety, while in the neoadjuvant model, the patient bears the tumor for several weeks or months until surgery. The delay in cystectomy in nonresponders may be adversely impacting their long-term outcomes since delay of cystectomy has been demonstrated in some but not all studies, to negatively impact outcomes [57,58]. For these reasons, many urologists have not embraced neoadjuvant chemotherapy [59]. Among 7161 analysable patients in the National Cancer Database with stage III bladder transitional cell carcinoma diagnosed between 1998 and 2003, perioperative chemotherapy was administered to 11.6% of patients with 10.4% receiving adjuvant chemotherapy and 1.2% receiving neoadjuvant

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chemotherapy. Whether these patterns are changing more recently needs further study. In addition to enhancing outcomes, the neoadjuvant paradigm may accelerate the pace of development of novel systemic agents. Employing the operable muscle-invasive disease population to develop novel agents represents an efficient use of resources. Regimens yielding higher than currently attained pCR rates may deserve further evaluation and development. Given the proliferation of novel biologic agents, it is imperative that the signal of pathologic and biologic activity is determined rapidly. The neoadjuvant paradigm also affords the rapid determination of a signal of pharmacodynamic activity due to availability of pathologic data immediately after completion of therapy. The caveat is that activity in the neoadjuvant setting should probably be complemented by a signal of activity in the advanced disease setting before launching a large Phase III trial in the advanced setting. In the setting of breast cancer, tumor pharmacodynamic response (altered proliferation or apoptosis) to a short (1 3 weeks) preoperative course of a hormonal or biologic agent may be predictive of outcome following chronic administration of the same agent [60,61]. A similar Bibliography
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96 Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19(3):666-75 Quek ML, Stein JP, Clark PE, et al. Natural history of surgically treated bladder carcinoma with extravesical tumor extension. Cancer 2003;98(5):955-61 Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35-41 Hautmann RE, Gschwend JE, de Petriconi RC, et al. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006;176(2):486-92 Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21(4):690-6 9. 7.

window-of-opportunity trial paradigm may apply to bladder cancer but a correlation between pharmacodynamic response and long-term outcomes would need to be defined. Owing to the availability of tissue before and after chemotherapy, it may be possible to determine molecular and biologic characteristics that predict for chemosensitivity. A greater acceptance and institution of neoadjuvant therapy for bladder cancer by the urologic oncology community is critically important to make further advances in a timely manner.

Declaration of interest
Guru Sonpavde is on the Speakers bureau for sanofiaventis, Pfizer and Novartis; and has received research support from Pfizer, Eli Lilly, BMS, Astrazeneca and Cytogen. Seth P Lerner has received research support form Pfizer, Eli Lilly, BMS, Cytogen, Photocure and Cell Genesys. Martha P Mims has received research support from The Diana Henry Helis Foundation and Keryx. Teresa G Hayes has received research support from Agennix, Inc., Endo Pharmaceuticals and Genentech. Gilad E Amiel has no conflicts of interest.
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Afliation
Guru Sonpavde1,2,3 MD, Gilad E Amiel3 MD, Martha P Mims1 MD PhD, Teresa G Hayes2,4 MD PhD & Seth P Lerner3 MD FACS Author for correspondence 1Texas Oncology, P.A. and US Oncology Research, 501 Medical Center Blvd, Webster, TX 77598, USA Tel: +1 281 332 7505; Fax: +1 281 332 8429; E-mail: gurUSonpavde@usoncology.com 2Baylor College of Medicine, Department of Medicine, Section of Medical Oncology, One Baylor Plaza, Houston, TX 77030, USA 3Baylor College of Medicine, Scott Department of Urology, 6560 Fannin Suite 2100, Houston, TX 77030, USA 4Veterans Affairs Medical Center, 2002 Holcombe Blvd, Houston, TX 77030, USA

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