European Urology

3.1.1. Rationale for perioperative therapy

Neoadjuvant or adjuvant chemotherapy has the potential to eradicate micrometastases and improve survival in patients with MIBC. This seems to be particularly true for patients with pathologic extravesical and lymph node-positive bladder cancer (BCa) [8]. While the majority of patients with pT2N0 BCa may be cured by surgery alone, only a minority of patients with pT3 or higher remain cancer free [3].

Chemotherapy prior to surgery offers potential advantages. Patients are able to tolerate full-dose chemotherapy better in the neoadjuvant setting, and the response of the primary tumor to chemotherapy can be assessed [9], [10], [11], [12], and [13], providing prognostic information. In a study of patients treated with neoadjuvant cisplatin-based therapy followed by surgery, 91% of patients who responded to chemotherapy (defined as pathologic stage ≤T1) were alive at a median follow-up of 25 mo, in contrast to 37% of nonresponders [10].

Downstaging of the tumor may provide an indication of the activity of neoadjuvant chemotherapy, especially in patients who have a pathologic complete response (pCR) or whose cancer is at stage pT1N0 after therapy. Patients with pT3+ and/or lymph node metastasis despite neoadjuvant chemotherapy may be offered clinical trials evaluating non–cross-resistant alternative agents due to their low probability of cure. The majority of patients who receive initial chemotherapy require cystectomy or radical radiotherapy (RT), even if they have an excellent clinical response to the initial transurethral resection of bladder tumor followed by chemotherapy. Performing a cystectomy after a cystoscopic complete response (CR) is especially important due to the discordance between clinical and pathologic staging. Scher et al. indicated that 57% of patients achieved a clinical and cystoscopic CR following neoadjuvant methotrexate, vinblastine, adriamycin, cisplatin (M-VAC); however, only 30% had a pCR at subsequent cystectomy [14]. Patients refusing cystectomy should be counseled about the high probability of local recurrence. A disadvantage of the neoadjuvant approach is the overtreatment of some patients. Some have developed a risk-stratified strategy with the hope of selecting patients at higher risk of locally extensive or metastatic urothelial carcinoma (UC) for neoadjuvant chemotherapy. In one series, the presence of high-risk features, including lymphovascular invasion, a mass on exam under anesthesia, and invasion of adjacent organs, predicted a 75% risk of locally advanced or lymph node involvement (pT3b or higher and/or N+) at cystectomy [15]. Another potential problem with induction chemotherapy is a delay in the cystectomy with disease progression if chemotherapy does not help [16].

The primary disadvantage of adjuvant chemotherapy is that it is not feasible in a third of patients within 90 d after RC due to postoperative complications, slow recovery of functional status, or patient refusal [17] and [18]. Also, approximately 40% of patients who would be candidates for neoadjuvant chemotherapy may not be candidates for postoperative cisplatin, the most effective drug, because of a decline in renal function [19].

Both approaches target microscopic disease. What is the best option for an individual patient: neoadjuvant or adjuvant chemotherapy? In the absence of an appropriately powered randomized trial that has compared optimal neoadjuvant and adjuvant chemotherapy in association with cystectomy, it is not possible to make a definitive recommendation. This will be further discussed in the section on adjuvant chemotherapy.

3.1.2. Data supporting neoadjuvant chemotherapy

In the United States, RC is the preferred treatment for patients with MIBC who have a good performance status. RT is generally reserved for patients with comorbid medical conditions or who meet very selective criteria for bladder preservation. In most of Europe, RC is also the preferred option, although some institutions consider RT a reasonable alternative.

Several randomized trials have explored whether neoadjuvant chemotherapy improves survival in BCa [20] and [21]. Some studies suffered from small sample size, suboptimal chemotherapy, premature closure, or inadequate follow-up [22]. Among these trials, single-agent regimens failed to show a survival benefit from neoadjuvant therapy [23]. However, well-designed, multiagent, chemotherapy trials using effective chemotherapeutic regimens have demonstrated a small, but statistically significant, improvement in survival. These trials have shifted the treatment paradigm in MIBC, favoring the use of neoadjuvant chemotherapy [24], [25], and [26].

The Southwest Oncology Group (SWOG) Intergroup trial 0080 randomized patients with T2-T4a UC of the bladder to RC alone (n = 154) versus three cycles of M-VAC followed by RC (n = 153) [26]. Patients who received neoadjuvant chemotherapy had a higher rate of pCR (38% vs 15%, p < 0.001). At a median follow-up of 8.7 yr, improvements in median survival (77 vs 46 mo; p = 0.06) and 5-yr survival (57% vs 43%; p = 0.06) favored the neoadjuvant M-VAC arm. Because of the sample size, this trial had limited potential to discern a clinically meaningful difference. This trend toward improved survival favoring M-VAC-treated patients with an estimated reduction in the risk of death by 25% (hazard ratio [HR]: 1.33) provides some evidence of benefit (LE: 1) [26]. There were no treatment-related deaths and neoadjuvant chemotherapy did not adversely affect the ability to perform RC or increase adverse events related to surgery.

Several surgical variables in this trial were evaluated in a retrospective review. Surgical variables associated with longer postcystectomy survival were negative margins (HR: 0.37; p = 0.0007) and removal of ≥10 nodes (HR: 0.51; p = 0.0001). These associations did not depend upon whether M-VAC was administered (p = 0.21 for all tests of interactions between treatment and surgical variables). Predictors of local recurrence were a positive margin (odds ratio [OR]: 11.2; p = 0.0001) and removal of <10 nodes (OR: 5.1; p = 0.002). The quality of surgery was an independent prognostic factor for outcome after adjustments were made for pathologic factors and neoadjuvant chemotherapy (LE: 2) [27].

Another recent analysis of the same trial evaluated the impact of histology when neoadjuvant M-VAC was given. There was a survival benefit from chemotherapy in patients with mixed tumors [28]. The presence of squamous or glandular differentiation in locally advanced UC of the bladder does not seem to confer resistance to M-VAC and in fact, based upon this study, may even be an indication for the use of neoadjuvant chemotherapy before cystectomy.

A trial that was almost identical to the SWOG study was performed by the Gruppo Uro-Oncologico Nord Est cooperative group in Italy [29]. Over a 6.5-yr period, 206 patients were randomly assigned to neoadjuvant M-VAC before cystectomy or to cystectomy alone. No clear differences in survival were demonstrated; 3-yr survival was 62% for the M-VAC-treated patients and 68% for patients who had a cystectomy alone (LE: 2).

The International Collaboration of Trialists performed the largest neoadjuvant chemotherapy trial (n = 976). Patients with cT2 -T4N0 UC were randomized to receive three cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) (n = 491) or no neoadjuvant chemotherapy (ie, local therapy alone [cystectomy or radiation]) (n = 485) over 5.5-yr in 106 institutions. This trial was performed during the same time as the SWOG trial. The results were updated at a median follow-up of approximately 7 yr [25]. An 8% improvement in time to progression and a 5.5% difference in absolute 3-yr survival (HR: 0.85; 95% confidence interval [CI], 0.71–1.02) favoring the neoadjuvant chemotherapy arm was reported.

At 5 yr, the OS benefit was 56% in the neoadjuvant chemotherapy group compared to 50% in the group receiving only local therapy, and the 10-yr OS benefit for patients in the former group was 36% versus 30% for the latter group (HR: 0.84; p = 0.037 and p = 0.03, respectively) [24]. There was no evidence that neoadjuvant CMV was less effective when preceding RT, with a 20% reduction in the risk of death compared to an impressive 26% reduction with RC. Following neoadjuvant chemotherapy, a pCR was attained in 32.5% of patients. While this study is generally considered evidence of the benefit of neoadjuvant chemotherapy (LE: 1), the investigators used a regimen that is not considered the current standard and did not achieve the planned goal of a 10% absolute survival benefit. Nonetheless, the OS improvement was clearly significant and of a similar magnitude to the benefit achieved with adjuvant chemotherapy in breast and colon cancers.

The Nordic Cystectomy Trial I evaluated neoadjuvant doxorubicin, cisplatin, and preoperative RT before cystectomy versus preoperative RT and cystectomy alone [30]. A 15% survival difference in favor of patients treated with chemoradiotherapy was seen only in a subset analysis of patients with T3 or T4 disease. Investigators were unable to confirm this survival advantage in the subsequent Nordic Cystectomy Trial II, in which 317 patients were randomly assigned to cystectomy or cystectomy preceded by methotrexate and cisplatin (without RT) [31]. However, combining the two trials provided positive results in favor of neoadjuvant chemotherapy (LE: 2) [32].

3.1.3. Meta-analysis

Because of uncertainties of the value of neoadjuvant chemotherapy, a meta-analysis was performed [33]. Data from 2688 patients treated in 10 randomized trials evaluating neoadjuvant chemotherapy for invasive UC were reviewed. Of note, this analysis did not include data from the SWOG Intergroup trial. Compared to local treatment alone, neoadjuvant, platinum-based, combination chemotherapy was associated with a significant benefit in OS (HR: 0.87; 95% CI, 0.78–0.98; p = 0.016), a 13% decrease in the risk of death, and a 5% absolute survival benefit at 5 yr (OS increased from 45% to 50%). When trials using single-agent cisplatin were included, the survival benefit did not achieve statistical significance (HR: 0.91; 95% CI, 0.83–1.01; p = 0.084) (LE: 2). Single-agent cisplatin did not show an improvement in survival (p = 0.26) compared with no neoadjuvant therapy. All platinum-based combination trials were analyzed as a group, so it is not possible to discern the best combination for use in neoadjuvant therapy.

A subsequent meta-analysis that included individual data from 3005 individuals enrolled in 11 randomized trials, including the SWOG data extrapolated from the published report [26], confirmed the survival benefit for neoadjuvant cisplatin-based therapy compared to local therapy alone [34]. A very similar meta-analysis of neoadjuvant, randomized, controlled trials was conducted in Canada [35]. A total of 16 eligible trials that included 3315 patients were identified, and 2605 patients provided data suitable for a meta-analysis of OS. The pooled HR was 0.90 (95% CI, 82–99%; p = 0.02). According to the published report, Eight trials used cisplatin-based combination chemotherapy, and the pooled HR was 0.87 (95% CI, 0.78–0.96; p = 0.006). The data correspond to an absolute OS benefit of 6.5% (95% CI, 2–11%) from 50% to 56.5%. Of note, a major pathologic response was associated with improved overall survival in four of the trials [35]. Neoadjuvant cisplatin-based chemotherapy was associated with improved overall survival with a modest benefit (LE: 2).

The use of perioperative chemotherapy was limited until 2003–2005, when these meta-analyses were published. Among 7161 analyzable patients in the National Cancer Data Base (NCDB) with stage III BCa diagnosed between 1998 and 2003, perioperative chemotherapy was administered to 11.6% of patients, with 10.4% receiving adjuvant chemotherapy and only 1.2% receiving neoadjuvant chemotherapy [36]. In a more recent report from the NCDB on 40 388 patients diagnosed with MIBC in 2003 to 2007, those who received chemotherapy increased from 27.0% in 2003 to 34.5% in 2007 due to an increase in neoadjuvant chemotherapy and chemotherapy without surgery [37]. Clinical practice guidelines can help increase the implementation of neoadjuvant chemotherapy. A Canadian study [38] has shown that neoadjuvant referral and treatment rates increased after publication of the clinical practice guidelines. Despite level 1 evidence, neoadjuvant cisplatin-based chemotherapy continues to be underused in the management of MIBC, even at high-volume tertiary centers [29] and [39].

3.1.4. Novel combinations as neoadjuvant therapy for bladder cancer

The promising results from newer combinations, such as gemcitabine and cisplatin/carboplatin with or without paclitaxel in patients with metastatic disease, have led to their investigation in the neoadjuvant and adjuvant setting. Although these newer regimens are promising, there are no data from randomized trials supporting their use in the neoadjuvant setting [40] and limited data from phase 2 trials.

The SWOG conducted a phase 2 trial of three cycles of neoadjuvant paclitaxel, gemcitabine, and carboplatin followed by cystoscopic surveillance or immediate RC for patients with cT0 status after chemotherapy [41]. Patients with cT0 status could elect immediate RC or cystoscopic surveillance, and those with greater than cT0 status underwent immediate RC. There was an unacceptably high rate (60%) of persistent cancer at RC in patients presumed to have pT0 status, which suggests that RC is a critical component of therapy.

While some potential benefits have been reported with the use of the triple regimen in the adjuvant setting [42], only the M-VAC regimen has been extensively evaluated. Similarly, M-VAC is the standard regimen when neoadjuvant chemotherapy is used. While the gemcitabine/cisplatin (GC) doublet has not been validated in the perioperative setting, retrospective data from the Memorial Sloan-Kettering Cancer Center (MSKCC) show that the GC regimen produces a pCR rate of 35% [43]. However, this review only included patients who had a cystectomy. Patients treated with this chemotherapy but who did not go to surgery, either due to lack of response or toxicity, were not included, limiting direct comparison with prospective clinical trials. In contrast to the above MSKCC study, data from the Cleveland Clinic showed that only 7% of patients achieved a pCR with mostly GC and other non–M-VAC-based regimens mainly administered in community oncology practices [40]. Therefore, in the absence of supportive data for GC in the neoadjuvant setting, M-VAC remains the regimen with the best supportive data.

3.2.1. Introduction

Despite the high rate of downstaging and response in the neoadjuvant and metastatic setting, cisplatin-based chemotherapy is underused in the treatment of UC. As a consequence, >50% of patients with MIBC die of disseminated disease. Patients with pT3-pT4 N0 BCa have ≤5-yr OS of 47% after cystectomy; patients with lymph node metastases have an overall 5-yr survival rate of ≤31% after RC [3] and [44]. Despite a high risk of relapse, translating the high initial response seen in metastatic UC with the use of chemotherapy into long-term survival in the locally advanced setting has proved difficult [45] and [46]. The chemotherapy agents used in UC have been reviewed extensively and will not be discussed in detail here [47].

Adjuvant chemotherapy for BCa is controversial. This controversy is fueled by a small potential benefit of chemotherapy and a sequence of trials that have been underpowered and/or closed early due to poor accrual, as well as the presence of evidence supporting neoadjuvant chemotherapy.

Slow adoption of neoadjuvant treatment has resulted in clinicians being confronted with patients who have not had the potential benefit of chemotherapy in combination with surgery but who have pathologic staging that portends a ≤70% risk of relapse. This scenario begs the question as to whether patients would be better treated with immediate postoperative chemotherapy or observed for possible relapse and treated at that time. This question is currently the subject of ongoing studies. However, one clinical trial comparing adjuvant chemotherapy with neoadjuvant chemotherapy suggests similar long-term outcomes regardless of whether M-VAC was given pre- or postoperatively [15].

Unfortunately, there have been methodological issues with many of the studies undertaken in the postoperative chemotherapy setting and we are left with meta-analyses for our best evidence. A pooled analysis supported adjuvant chemotherapy, with a more extensive meta-analysis demonstrating a benefit to adjuvant cisplatin-combination chemotherapy [48] and [49]. Since these analyses were undertaken, four major phase 3 studies were commenced and closed: Spanish Oncology Genitourinary Group (SOGUG) 99/01 [42], Cancer and Leukemia Group B (CALGB) 90104 [50], an Italian multicenter trial [51] and [52], and European Organization for Research and Treatment of Cancer (EORTC) 30994 [53]. These trials continue the pattern of premature closure for poor accrual seen in earlier studies, but may contribute in composite to the field. Recently, a large cohort analysis assessing the effect of adjuvant chemotherapy from several large centers has been published [54] and suggests the greatest impact of adjuvant chemotherapy is seen in patients with extravesical extension or N+ disease.

3.2.2. A short history of early clinical trials of adjuvant chemotherapy in bladder cancer

Multiple cisplatin-based combinations have been evaluated in the adjuvant setting [55]. Logothetis et al. administered cisplatin, cyclophosphamide, and adriamycin (CISCA) to a group of 71 postcystectomy patients with resected nodal metastases, extravesicular extension, lymphovascular invasion, or pelvic visceral invasion [56]. These patients were compared in a nonrandomized fashion to 62 high-risk patients and 206 low-risk patients who did not receive adjuvant chemotherapy. They concluded that adjuvant CISCA conferred a 2-yr disease-free survival (DFS) advantage to patients with unfavorable pathologic findings (70% vs 30%; p = 0.00012).

Given the superiority of the M-VAC combination over single-agent cisplatin in the metastatic setting [57], it became important to evaluate M-VAC or M-VEC (which uses epirubicin rather than Adriamycin [doxorubicin]) combinations in the adjuvant setting. Stockle et al. randomized patients with pT3, pT4, and/or pelvic lymph nodes to three cycles of M-VAC or M-VEC versus observation [58] and [59]. Although planned to accrue 100 patients, the study was closed after an interim analysis of 49 randomized patients revealed a significant advantage in relapse-free survival with chemotherapy (p = 0.0015). This trial has been interpreted with caution, given its early closure and the fact that only 62% of patients randomized to chemotherapy completed the three cycles of treatment. Furthermore, patients in the observation arm were not offered chemotherapy at relapse. After 2 to 3 yr, the same authors reported their longer experience with adjuvant M-VAC/M-VEC in 83 patients. Forty-nine of the patients had been enrolled in the prospective trial before it was closed, while the remaining 38 had received M-VAC/M-VEC as routinely recommended therapy based on the interim results of the prior trial. Longer follow-up of the patients (38–78 mo) confirmed significant improvement in progression-free survival in the adjuvant chemotherapy group (p = 0.0005). The continued advantage in progression-free survival with more mature data offered support to the beneficial role of chemotherapy.

3.2.3. Meta-analysis and composite analysis

In 2006, a composite trial analysis and an individual meta-analysis was published of patients accrued to adjuvant trials in which chemotherapy was compared to observation. The meta-analysis was limited because only 491 patients from six randomized controlled trials were included [49]. The overall HR for survival of 0.75 (95% CI, 0.60–0.96; p = 0.019) suggested a 25% relative reduction in the risk of death for chemotherapy compared to controls. The authors commented on the small number of patients and relative poor quality of data in the meta-analysis, and highlighted the need for accrual to ongoing phase 3 trials examining adjuvant therapy.

Contemporaneously, Ruggeri and colleagues performed a composite analysis based upon published data from all phase 3 published studies of adjuvant chemotherapy [48]. Much less stringent criteria than the Cochrane review were used. The conclusions, however, were similar, with a benefit in favor of adjuvant chemotherapy for OS (relative risk [RR]: 0.74; 95% CI, 0.62–0.88; p = 0.001) and DFS (RR: 0.65; CI 0.54–0.78; p < 0.001) (LE: 3).

Concurrently, investigators have begun to compare different adjuvant regimens. Investigators at the MD Anderson Cancer Center presented data comparing two cycles of preoperative chemotherapy with M-VAC and three cycles afterwards with the same chemotherapy given only postoperatively in a group of patients at high risk for extravesical extension or nodal involvement at surgery [15]. This study demonstrated a high likelihood of extravesical extension or nodal involvement in nearly 80% of patients treated with initial surgery, and no difference in survival whether the chemotherapy was given in the neoadjuvant or adjuvant setting. While there was no difference between the two approaches in terms of outcome, it demonstrated the feasibility of preoperative chemotherapy and, in particular, that such therapy did not result in toxicity that caused the patient to have delayed or no surgery. The German Urologic Oncology Group ran a phase 3 trial for patients with stage pT3a-4a and/or pathologic node-positive UC of the bladder after cystectomy, randomizing 327 patients to either cisplatin and methotrexate (CM) or M-VEC [60]. The 5-yr progression-free, tumor-specific, and OS rates were not significantly different between the two arms, although patients given M-VEC had higher rates of grade 3 or 4 leukopenia (22%) than those given CM (7%; p = 0.0001).

The meta-analysis and composite analysis represent a watershed in perioperative chemotherapy for BCa in part because they suggested benefit from chemotherapy, but highlighted the relative poor quality of the trials. The advent of phase 3 evidence for neoadjuvant M-VAC at around this time also shaped thinking, with neoadjuvant therapy becoming a standard of care. Despite this, most patients are not being offered chemotherapy before surgery.

3.2.4. More recent phase 3 trials

The four major phase 3 trials mentioned earlier—SOGUG 99/01 [42], CALGB 90104 [50], Italian Multicenter [51] and [52], and EORTC 30994 [53]—share a common theme: adjuvant chemotherapy for transitional cell-predominant UC coupled with the acrimony of early closure for slow accrual.

In the Italian multicenter trial, 194 patients with pT2G3, pT3-4, N0-2 UC who had been treated with RC were then randomized to immediate chemotherapy or a control arm of observation and chemotherapy at relapse [51] and [52]. Patients were stratified by center and lymph node metastases. Those patients given adjuvant chemotherapy were randomized to two slightly different schedules of GC over a 4-wk cycle for four cycles. The primary end point was OS. Only 62% of patients received the planned cycles of chemotherapy. The 5-yr OS was 48.5% with no difference between the arms (p = 0.24) and there was no difference between arms for DFS. The authors concluded that the study was underpowered to demonstrate that adjuvant chemotherapy with GC improves OS and DFS in patients with muscle-invasive BCa.

The SOGUG opened the 99/01 trial comparing four cycles of paclitaxel, cisplatin, and gemcitabine (PCG) compared to observation [42]. This regimen was based on the results of a phase 1/2 trial in advanced disease [61]. In advanced UC, the addition of paclitaxel increased the efficacy in terms of RR when compared to GC, with a benefit in OS seen only in patients having the bladder as primary (post hoc analysis). In the intention-to-treat population, only a trend was observed (p = 0.07) [62]. The adjuvant 99/01 trial accrued patients with pT3-4 and/or lymph node-positive BCa with a creatinine clearance >50 ml/min and mandated chemotherapy commencement within 8 wk of cystectomy, whereas prior studies had allowed up to 12 wk after surgery. The trial enrolled 142 patients between July 2000 and July 2007, when it was closed prematurely due to poor accrual. Toxicity in the triple-drug chemotherapy arm was acceptable with a single treatment-related death due to sepsis. At a median follow-up of 30 mo, OS was significantly prolonged in the PCG arm (median not reached; 5-yr OS: 60%) compared to observation (median: 26 mo; 5-yr OS: 31%; p < 0.0009). DFS (p < 0.0001) and disease-specific survival (p < 0.0002) were also superior in the PCG arm.

The results from this trial raise several questions. Does the addition of paclitaxel increase the efficacy of PCG in this setting compared to GC or M-VAC, when data for the addition of paclitaxel to GC in the advanced setting are lacking [62]? Did the earlier time to commencement of chemotherapy contribute to the difference seen in OS? Given data from several centers suggesting diminished survival outcomes in patients with later commencement of chemotherapy compared to those starting earlier [15], should clinical trials and clinical practice outside trials mandate commencement within 8 wk of surgery?

3.2.5. Data from larger cohort studies

A recent collaborative effort among 11 major centers has yielded an international cohort analysis of off-trial adjuvant chemotherapy [54]. Patients were grouped into quintiles based on risk characteristics for relapse and death and chemotherapy impact assessed across the cohort as a whole, but also within each risk segment. The cohort consisted of 3947 patients undergoing cystectomy and lymph node dissection between 1979 and 2008. Of these, 932 (23.6%) received adjuvant chemotherapy—the largest analysis of an adjuvant chemotherapy cohort to date. Adjuvant chemotherapy was independently associated with improved survival (HR: 0.83; 95% CI, 0.72–0.97; p = 0.017). The risk group significantly predicated the survival impact of chemotherapy on outcome. Increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (p < 0.001), especially in those with extravesical extension or nodal involvement. There was a significant improvement in survival between the treated and nontreated patients in the highest-risk quintile (HR: 0.75; 95% CI, 0.62–0.90; p = 0.002). This group was characterized by an estimated 32.8% 5-yr probability of cancer-specific survival, with 86.6% of patients having both stage T3 or greater and node metastasis. These data may be useful in stratifying and selecting patients for future studies. Analysis from the same group of investigators suggests that 2- and 3-yr DFS after cystectomy is a strong surrogate for 5-yr OS [63].