Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide, with an estimated 110,500 men and 70,000 women diagnosed annually.1 While the majority of patients are diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are initially diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1
Radical cystectomy and trimodal therapy (i.e. maximal TURBT, chemotherapy, and radiotherapy) remain standard of care options for treatment of patients with clinically localized, muscle invasive disease.2,3 However, survival outcomes in this cohort of patients remain limited with five-year survival rates of 70% in patients with bladder-confined disease and 38% in those with extravesical extension and/or lymph node involvement.4
Early treatment intensification with neoadjuvant cisplatin-based chemotherapy has long been advocated as means to improve survival outcomes in patients with clinically localized, muscle invasive disease undergoing definitive local therapy. Theoretical advantages to administering early systemic therapy prior to surgical treatment, as opposed to adjuvant therapy, include:
- Early targeting of micrometastatic disease
- Early “litmus test” of in-vivo chemosensitivity
- Patient performance status and ability to tolerate chemotherapy expected to be better pre-operative, with potential delays to receiving systemic therapy in post-radical cystectomy patients
- Patients with favorable pathologic response (i.e. <ypT2 disease, ypN0) have favorable survival outcomes
In spite of these potential benefits, there are some (at least theoretical) downsides to a neoadjuvant chemotherapy approach including the potential to compromise outcomes by delaying surgical care among non-responders and to increase surgical morbidity. This is particularly pertinent among patients with variant histology in whom neoadjuvant chemotherapy may have variable efficacy. Regardless, on the balance of the evidence, current guidelines recommend the routine use of neoadjuvant chemotherapy prior to radical cystectomy in patients with clinically localized, muscle invasive bladder cancer given the documented survival benefits.2,3 In this Center of Excellence article, we review the current evidence for neoadjuvant chemotherapy prior to radical cystectomy for cisplatin eligible patients with clinically localized, muscle invasive bladder cancer.
Spanish Genitourinary Cooperative Group Trial: Cisplatin Alone
In 1984, the Spanish genitourinary cooperative group, Club Urologico Espanol de Tratamiento Oncologico, initiated a prospective trial of 122 patients with cT2-4aNx-2M0 urothelial carcinoma of the bladder who were randomized to radical cystectomy alone (n=60) or three cycles of neoadjuvant cisplatin (100 mg/m2) followed by radical cystectomy (n=62). After a median follow-up of 78.2 months, there were no significant differences in overall survival 37.3%). The proportion of patients with ypT0 disease in the neoadjuvant was 19.6% with a further 14.3% having <ypT2 disease. Neoadjuvant treatment with cisplatin did significantly prolong the time to relapse in patients with complete response (30.3 versus 13.1 months). However, based on these results, the authors concluded that use of three cycles of neoadjuvant cisplatin monotherapy does not significantly improve survival outcomes, and, as such, should not be standard of care treatment prior to radical cystectomy.5
Nordic Trial 1: Cisplatin + Doxorubicin
The Nordic Cystectomy Trial I was the first phase III randomized controlled trial to evaluate neoadjuvant cisplatin-based combination chemotherapy prior to radical cystectomy. This trial randomized 325 patients with stage T1, grade 3 or stages T2 to T4aNXM0 bladder cancer to either chemotherapy or no chemotherapy prior to planned low dose irradiation and radical cystectomy, between 1985 and 1989. Chemotherapy consisted of two cycles of cisplatin (70 mg/m2) and doxorubicin (30 mg/m2) given three weeks apart. Notably, all patients received pre-operative radiation, at a dose of 4 Gy daily for five consecutive days, to the bladder and iliac/obturator lymph nodes. Initial results of this trial were published in 1993,6 with updated five-year follow-up results published in The Journal of Urology in 1996.7 After five years, the overall (59% versus 51%, p=0.10) and cancer-specific survival rates (64% versus 54%, p=0.07) were numerically improved in the chemotherapy arm. The five-year overall survival benefit for chemotherapy was most pronounced for patients with pT3-T4a disease (59% versus 39%). On multivariable analysis, use of chemotherapy was shown to be a significant predictor of overall survival (relative death risk: 0.69; 95% CI: 0.49 to 0.98).
Nordic Trial 2: Cisplatin + Methotrexate
Building on these data, the Nordic Cystectomy Trial 2 assessed the combination of cisplatin and methotrexate prior to radical cystectomy only, as opposed to Nordic 1 which evaluated neoadjuvant chemotherapy prior to pre-operative radiation followed by radical cystectomy. In this trial, 317 patients with T2-T4aNxM0 urothelial bladder cancer were recruited between 1991 and 1997 and randomized to three cycles of cisplatin-methotrexate or no pretreatment before cystectomy. After a median follow-up of 5.3 years, there were no significant differences in 5-year overall survival rates (53% in experimental arm versus 46% in the control arm, p=0.24):
BA06 30894 Trial: Cisplatin + Methotrexate + Vinblastine
Published in The Lancet in 1999, the BA06 30894 trial enrolled 976 patients with T2 G3, T3, T4a, N0-NX, or M0 urothelial carcinoma of the bladder undergoing curative cystectomy or full-dose external-beam radiotherapy. Patients were randomly assigned to either three cycles of neoadjuvant chemotherapy (cisplatin, methotrexate, and vinblastine, with folinic acid rescue, n=491) or no chemotherapy (n=485). After a median follow-up of 4.0 years, three-year survival was improved by 5.5%: 55.5% for chemotherapy versus 50.0% for no chemotherapy (95% CI: -0.5 to 11.0, p=0.075). The median survival in the chemotherapy group was 44 months compared to 37.5 months for the no-chemotherapy group. The proportion of ypT0 disease in patients undergoing radical cystectomy was 32.5%.9 Updated results with a median follow-up of 8.0 years were published in The Journal of Clinical Oncology in 2011. This report demonstrated a statistically significant 16% reduction in the overall mortality hazard rate (HR: 0.84, 95% CI: 0.72 to 0.99, p=0.037). This corresponded to a 10-year survival improvement from 30% to 36% with neoadjuvant cisplatin, methotrexate, and vinblastine.10 The Kaplan-Meier survival curves for overall survival (A), metastasis free survival (B), locoregional disease free survival (C), and disease free survival (D) after extended follow-up are as follows:
Methotrexate + Vinblastine + Doxorubicin (Adriamycin) + Cisplatin (MVAC)
In 2003, Grossman et al. published the results of the SWOG-8710 trial evaluating the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Between 1987 and 1998, 307 patients with muscle-invasive bladder cancer (cT2 to T4a) planned for radical cystectomy were randomized to three cycles of MVAC + radical cystectomy (n=153) versus radical cystectomy alone (n=154). The median patient age was 63.0 years and radical cystectomy was performed in 82% and 81% of patients in the experimental and control arms, respectively. The median time to surgery in the cystectomy only arm was 17 days versus 113 days in the chemotherapy-cystectomy arm. After a median follow-up of 8.7 years, the median survival was 77 months in the chemotherapy-cystectomy arm versus 46 months in the cystectomy arm. The corresponding five-year overall survival rates were 57% and 43%, respectively (p=0.06):
Patients in the cystectomy alone arm had an increased hazard of cancer-specific mortality (HR: 1.66, 95% CI: 1.22 to 2.45, p=0.002). The proportion of patients with ypT0 disease in the neoadjuvant chemotherapy-cystectomy arm was 38%, compared to 15% of patients with pT0 disease in the cystectomy alone arm (p<0.001). Not surprisingly, ypT0 disease conferred improved survival regardless of whether the patient received neoadjuvant chemotherapy:
There were no deaths attributable to MVAC and no significant differences between the two groups in the rates or severity of postoperative complications.11
Given the inconsistent results of the published randomized controlled trials evaluating neoadjuvant chemotherapy, the Advanced Bladder Cancer Meta-Analysis Collaboration published their initial meta-analysis of ten randomized trials in The Lancet in 2003,12 with an updated report in 200513 following publication of the SWOG-8710 trial. The group found a significant survival benefit for platinum-based combination chemotherapy (HR: 0.86, 95% CI 0.77 to 0.95, p=0.003), irrespective of local treatment modality. This benefit corresponds to a 5% absolute improvement in five-year survival. There was also a significant disease-free survival benefit associated with platinum-based combination chemotherapy (HR: 0.78, 95% CI: 0.71 to 0.86, p < 0.001), corresponding to a 9% absolute improvement at five years.13
In 2014, Kitamura et al. published the results of a randomized trial of 130 patients with muscle invasive bladder cancer (cT2-4aN0M0) who were randomized to receive two cycles of neoadjuvant MVAC followed by radical cystectomy versus radical cystectomy alone. This trial terminated early due to slow patient accrual and, as such, was underpowered to evaluate the primary outcome of overall survival. Overall survival in the neoadjuvant MVAC arm was not significantly improved with a hazard ratio of 0.65 (multiplicity adjusted 99.99% CI: 0.19 to 2.18, one-sided p = 0.07). The proportion of patients with ypT0 disease was 34%.14
Gemcitabine + Cisplatin (GC)
While the majority of the evidence for the neoadjuvant combination of gemcitabine and cisplatin is based on retrospective evidence,15-17 an Egypt-based randomized controlled trial of 60 patients with cT2-4aN0M0 urothelial carcinoma of the bladder randomly allocated patients to three cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy versus radical cystectomy alone.18 This trial demonstrated that the neoadjuvant combination of gemcitabine and cisplatin improved:
- Three-year overall survival from 50% to 60%
- Median overall survival from 32.5 to 36.0 months
- Three-year progression-free survival from 43% to 57%
- Median progression-free survival from 28 to 36 months
On the basis of these data, neoadjuvant chemotherapy prior to surgery has become guideline recommended standard of care for patients undergoing radical cystectomy for MIBC. However, it is relatively under-utilized.19
GETUG-AFU V05 VESPER Trial: MVAC versus GC
To address the question of the preferred regimen for NAC prior to cystectomy, the GETUG-AFU V05 VESPER trial is a randomized phase III trial of 500 patients with cT2-4aN0M0 urothelial carcinoma of the bladder receiving neoadjuvant chemotherapy or pT3-4 or pTanyN+Many receiving adjuvant chemotherapy. Included patients were randomized to either six cycles of dose-dense MVAC (dd-MVAC) once every two weeks or four cycles of gemcitabine and cisplatin once every three weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). Patients with pure adenocarcinoma, squamous carcinoma, or small-cell neuroendocrine carcinoma were excluded. Results of the secondary endpoints of chemotherapy toxicity and pathologic response rate were initially published in European Urology in 2021,20 with results of the primary endpoint outcome of three-year progression-free survival subsequently published in The Journal of Clinical Oncology in 2022.21 Of the 493 patients in the intent-to-treat population, 88.6% received chemotherapy in the neoadjuvant setting, with the remaining 11.4% receiving adjuvant chemotherapy. Median patient age was 63.0 years. Of the patients in the neoadjuvant group, 60% received the full six cycles of dd-MVAC and 84% the full four cycles of GC; 91% and 90% of patients underwent a radical cystectomy, respectively.
A complete pathologic response (ypT0pN0) was observed in 42% of patients in the dd-MVAC arm compared to 36% in the GC arm (p=0.20). Patients in the dd-MVAC arm had higher local control rate, defined as pathologic complete response, tumor downstaging or presence of organ confined disease (p=0.021). Positive margins were found for 5.6% and 6.0% of radical cystectomies after neoadjuvant GC and dd-MVAC, respectively. Three-year progression-free survival in the overall cohort (neoadjuvant or adjuvant) was non-significantly superior in the dd-MVAC arm (64% versus 56%, HR: 0.77, 95% CI: 0.57 to 1.02, p=0.066). When analysis was restricted to patients receiving neoadjuvant chemotherapy, the three-year progression-free survival was significantly higher in the dd-MVAC arm (66% versus 56%; HR: 0.70, 95% CI: 0.51 to 0.96, p=0.025):
Compared to patients with ypT0 disease, those with ypTis, Ta or T1 disease had no significantly increased hazard of progression (HR: 1.13, 95% CI: 0.53 to 2.39). However, patients with ypT2N0 staging had an increased risk (HR: 2.61, 95% CI: 1.38 to 4.95), as did patients with ypT3+ or ypN1 staging (HR: 10.3, 95% CI: 6.37 to 16.8).
While overall survival data maturity was lacking at the time of the last report, overall survival following a 40-month median follow-up was in favor of dd-MVAC (HR: 0.66, 95% CI: 0.47 to 0.92):
Grade 3 or worse adverse events were reported for 52% and 55% of patients in the dd-MVAC and GC arms, respectively. Severe anemia was more frequently observed in the dd-
MVAC arm (p<0.001). Asthenia was reported for 14% of patients in the dd-MVAC arm compared to 4.1% of patients in the GC arm (p<0.001). Gastrointestinal (GI) grade ≥3 disorders were more frequently observed in the dd-MVAC arm (p=0.003). Four deaths occurred during chemotherapy, including three patients in the dd-MVAC arm: sudden death, pulmonary embolism, and septic shock.
Secondary analysis of the VESPER trial, presented at GU ASCO 2022, assessed outcomes in patients with histologic variants. Among 303 patients with available TURBT diagnostic specimens, urothelial carcinoma variants were present in 180 patients (59%), and 26 patients (8.6%) had two or more variants. Squamous divergence was the most common variant identified. In comparison with pure urothelial carcinoma, the presence of urothelial carcinoma variants was not associated with significant differences in complete pathological response (OR: 0.78, 95% CI: 0.48 to 1.27) or three-year progression-free survival (HR: 1.25, 95% CI: 0.83 to 1.86).
Neoadjuvant cisplatin-based combination chemotherapy regimens prior to radical cystectomy are associated with five-year overall survival improvements of at least 5% and remains guideline recommended therapy for those that are able to receive cisplatin. Future studies that evaluate chemotherapy alternatives, such as immunotherapy, in cisplatin-ineligible patients, both alone or in combination with chemotherapy are currently being evaluated to improve the efficacy and applicability of systemic therapy in patients with clinically localized, muscle invasive bladder cancer. Additionally, utilization of NAC is relatively poor; greater diffusion of this guideline-supported treatment in practice would be anticipated to improve population-level outcomes for patients with bladder cancer.
Published: March, 2023