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Future Directions of Neoadjuvant Therapy in Muscle-Invasive Bladder Cancer

Vadim S. Koshkin, MD, and Petros Grivas, MD, PhD
Published Online: Apr 20,2018

Vadim S. Koshkin, MD
ABSTRACT

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care in muscle-invasive bladder cancer (MIBC) for almost 2 decades. However, the rates of NAC utilization remain low and many patients are ineligible to receive cisplatin due to diminished renal function or other factors. Additionally, there are no reliable biomarkers routinely used in clinical practice that identify patients most likely to benefit from NAC, and limited prospective comparisons of the NAC regimens. This paper begins by summarizing existing evidence to support the use of cisplatin-based neoadjuvant chemotherapy in patients with MIBC. It then discusses the likely challenges and issues that will shape neoadjuvant treatments for bladder cancer in the near future, and reviews emerging data regarding tumor biomarkers and molecular subtypes of MIBC that may help identify patients most likely to benefit from neoadjuvant treatment. The paper concludes by describing emerging novel neoadjuvant clinical trial designs in MIBC; such designs incorporate biomarker-driven and bladder-sparing approaches as well as novel immunotherapy regimens that include, but are not limited to, patients who are ineligible for cisplatin-based chemotherapy. The ongoing rapid expansion of knowledge about the underlying biology of bladder cancer and newly generated data regarding the efficacy of immunotherapy agents in this disease herald significant changes in the future direction of its neoadjuvant therapies.

Introduction

The established standard of care in muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy with bilateral pelvic lymph node dissection. There is well-established level I evidence for the benefit of NAC in this setting based on an overall survival (OS) advantage that was demonstrated in several randomized clinical trials. Unfortunately, many patients are ineligible for cisplatin-based therapy, most commonly due to diminished renal function but also as result of a number of other factors that may make a patient “unfit” for cisplatin. Consequently, many patients with MIBC have to forgo this potentially life-prolonging treatment. Given the established OS benefit of neoadjuvant systemic therapy with cisplatin-based combinations, there is considerable interest in identifying patients most likely to benefit from this approach and also in novel neoadjuvant therapies to address an unmet clinical need, including in cisplatin-ineligible patients. In particular, several trials of immunotherapy agents in the neoadjuvant setting are currently enrolling patients or will begin accrual in the coming months. For patients eligible to receive cisplatin, there are no prospectively validated molecular biomarkers to provide guidance on which patients are most likely to respond to treatment, although new data in genomics and molecular subtyping are beginning to shift this paradigm.

Evidence for Cisplatin-Based Neoadjuvant Chemotherapy

Cisplatin-based NAC has been the standard of care in MIBC for almost 2 decades, as established by evidence from several randomized clinical trials and a large meta-analysis. The meta-analysis, initially published by the Advanced Bladder Cancer Meta-analysis Collaboration in 20031 and updated in 2005,2 included in its final version 11 randomized clinical trials and 3005 patients; it compared platinum-based NAC (1 trial included carboplatin, the rest cisplatin) plus definitive local therapy (cystectomy or radiation) with definitive local therapy alone. The results showed significant benefit for patients who received cisplatin-based NAC combination with a 14% reduction in risk of death (hazard ratio [HR], 0.86; 95% CI, 0.77-0.95; P = .003), which translated into a 5% improvement in OS and a 9% improvement in DFS at 5 years.2 The 5-year OS was 50% for patients who received cisplatin-based NAC compared with 45% for patients who received definitive local therapy alone. It is notable that a survival benefit was observed only for patients who received cisplatin-based chemotherapy combinations; the same benefit has not been shown for patients who received carboplatin-based combinations.

An illustrative trial included in this meta-analysis was SWOG 8710, which used MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) given every 28 days for a total of 3 cycles as the NAC regimen prior to radical cystectomy.3 This trial included 317 patients enrolled from 1987 to 1998 with stage cT2-T4a MIBC who were intended to undergo radical cystectomy, and were randomized 1:1 to receive either 3 cycles of MVAC (28-day cycle) followed by radical cystectomy or radical cystectomy alone. Intention-to-treat analysis revealed median OS in the MVAC-and-cystectomy group to be 77 months compared with 46 months in the cystectomy group (P =.06). Patients who received MVAC had higher rates of pathologic complete response (pCR) at cystectomy (38% vs 15%; P <.001). In both groups, patients with pCR had improved survival, with 85% of patients with pCR remaining disease-free at 5 years.

Another large neoadjuvant study with long-term follow-up randomized 976 patients with high-grade cT2-T4a N0-NX MIBC to receive either CMV (cisplatin, methotrexate, vinblastine) chemotherapy for 3 cycles followed by local therapy (cystectomy or radiotherapy) or local therapy alone.4 Long-term follow-up revealed an OS advantage at the 10-year time point for patients receiving CMV (36% vs 30%) with a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.72-0.99; P = .037).

More recently, additional neoadjuvant regimens have been studied with the aim of improving patient tolerance and shortening treatment duration. These have included accelerated or dose-dense MVAC (ddMVAC) regimens administered in 2-week cycles with granulocyte colony stimulating factor (G-CSF) support (total of 3 to 4 cycles over 6 to 8 weeks), which have shown comparable pathologic response rates (pRRs) and a favorable profile of treatment-related adverse events compared with historical classic MVAC data.5-7 In general, about 30% of patients achieved pCR and 40% to 50% had pathologic downstaging with ddMVAC. Another frequently used NAC regimen is the combination of gemcitabine and cisplatin (GC) administered in 21-day cycles for a total of 3 to 4 cycles (4 cycles corresponding to the 12-week duration of NAC in the SWOG 8710 trial). Retrospective comparisons of GC with MVAC in the neoadjuvant setting showed a similar rates of pCR in the 2 regimens, at around 30%.8,9 Dose-dense GC (ddGC) administered in 14-day cycles with G-CSF support (total of 3 cycles over 6 weeks) has also been investigated, with initial results showing pRRs comparable with MVAC and ddMVAC.10 A retrospective comparison of MVAC, GC, and ddMVAC has shown the regimens to be comparable in terms of pCR and partial (pPR) response rates, but with superior patient tolerance of the ddMVAC and GC regimens compared with classic MVAC.11

Currently, no approved biomarkers exist to assist in individualized treatment decisions of whether to pursue NAC for a particular patient, or to choose among the different NAC regimens. This may change following completion of the currently ongoing SWOG 1314 study, which randomizes MIBC patients to receive either ddMVAC or GC as NAC prior to cystectomy. The primary endpoint of this study is to prospectively validate the coexpression extrapolation (COXEN) score, which assesses tumor sensitivity to chemotherapy based on gene expression. This is a novel trial design in which the COXEN score generated based on gene expression in the transurethral resection of bladder tumor (TURBT) specimen will be assessed in its ability to predict the patient’s pathologic response at the time of cystectomy to either ddMVAC or GC NAC regimen.12 Although not definitively powered to compare the efficacy of ddMVAC versus GC, this trial will provide insights by comparing the 2 regimens in a randomized prospective fashion.

The use of adjuvant chemotherapy following cystectomy in bladder cancer has also been investigated in several trials. The European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial randomized patients with pT3-pT4 or N+ disease at cystectomy and no evidence of distant metastases to receive adjuvant chemotherapy with GC or MVAC within 90 days of treatment start or at the time of relapse. The trial was underpowered, enrolling only 284 of the intended 660 patients, and the 5-year OS had a trend favoring adjuvant chemotherapy but was not statistically different between the 2 groups. It did, however show an advantage, 48% versus 32% after 5 years, in progresson-free survival (PFS) for patients who received immediate adjuvant therapy (HR, 0.5; 95% CI, 0.40-0.73; P <.001).13 A meta-analysis of 9 randomized adjuvant trials that included 945 patients did show an OS advantage for patients receiving adjuvant therapy, with a pooled HR at 0.77 (95% CI, 0.59-0.99; P = .049) and a DFS advantage with HR at 0.66 (95% CI, 0.45-0.91; P = .014) and a more apparent DFS benefit in patients with nodal metastases.14 However, concerns have been raised regarding significant variability among individual trials included in the meta-analysis, such as variations in eligibility criteria, statistical designs, treatment in the control arm, and definitions of DFS. Benefit of adjuvant chemotherapy was also supported by a large retrospective study of more than 5600 patients with locally advanced bladder cancer (pT3-T4 or N+), in which adjuvant therapy was associated with improved OS in comparison with post cystectomy observation (HR, 0.70; 95% CI, 0.64-0.76; P <0.001).15 In general, although a degree of benefit with adjuvant treatment has been suggested, the data have been mixed and not as consistent as those data supporting cisplatin-based NAC. Right now, adjuvant cisplatin-based chemotherapy following radical cystectomy is generally considered for higher-risk patients (pT3-pT4 or N+) if they have not received prior cisplatin-based neoadjuvant therapy.

Molecular Subtypes, Mutations, and Other Putative Predictive Biomarkers

Current treatment recommendations for cisplatin-based NAC in MIBC follow a “one size fits all” approach, but new data on predictive biomarkers are emerging. Presence of genomic alterations in genes such as ERBB2, ERCC2, and RB1, as well as other genes involved in DNA-repair pathways (eg, ATM, FANCC), has been shown to be potentially predictive of response to cisplatin-based NAC.16-20 Additionally, the recent discovery of several distinct molecular subtypes in urothelial carcinoma has considerably advanced our understanding of the underlying biology of this disease, yielding information that may impact treatment decisions in the near future. The results of 4 distinct molecular classification methods have been published,18,21-23 all of which broadly divide urothelial carcinomas into basal and luminal tumors and then into more narrow subtypes specific to each method. The most comprehensive integrative molecular analysis was undertaken by The Cancer Genome Atlas (TCGA), initially on 131 tumors in 201421 and updated with 412 samples in 2017.24,25 The updated analysis identified 5 distinct molecular subtypes that were prognostic of outcomes and suggested potential treatment approaches with either cisplatin-based chemotherapy, immunotherapy, or targeted agents. An important recent study published by Seiler and colleagues was the first to use a single-sample classifier (Decipher assay) to retrospectively generate molecular subtypes based on whole transcriptome profiling of TURBTs in 343 patients with MIBC.26 This genomic subtyping classifier was able to accurately predict the previously described consensus molecular subtypes and suggested improved clinical outcomes in patients with luminal tumors. Exploratory analysis additionally suggested that tumors with the basal subtype derived the most benefit from NAC. Following publication of this study, GenomeDx Biosciences launched Decipher Bladder Cancer Classifier, the first commercially available clinical assay to subtype individual MIBC samples.

These are all preliminary findings that need to be validated prospectively. However, the evidence for the eventual individualization of treatment patterns in MIBC based on tumor genomics and molecular subtyping is growing. In the near future, these emerging diagnostic tools may be utilized to help make difficult treatment decisions about prioritizing certain MIBC patients for cisplatin-based NAC and others for targeted agents and/or immunotherapy. This will both help improve outcomes in this patient population and help avoid cisplatin-related toxicity in patients least likely to benefit from this treatment approach. It may additionally suggest potential treatment options in patients with MIBC who are cisplatin-unfit and who currently lack proven systemic treatment options.

Cisplatin Ineligibility and Low Rates of NAC Utilization

Despite the proven OS benefit of cisplatin-based NAC prior to cystectomy, NAC utilization rates for patients with MIBC remain low and are thought to be under 20%.27,28 The main concerns raised by healthcare providers about recommending NAC use for patients with MIBC include questions regarding treatment toxicity and potential delay of curative radical cystectomy.29 Many patients with MIBC are unfortunately ineligible for cisplatin-based chemotherapy. Currently established criteria for cisplatin ineligibility are derived from a survey of genitourinary medical oncologists and include any of the following: ECOG performance status ≥2, creatinine clearance <60 mL/min, grade ≥2 neuropathy, grade ≥2 hearing loss, and/or New York Heart Association class ≥III heart failure (Table 1).30 These guidelines are not based on prospective evidence and efforts are underway to better define specific eligibility thresholds for treatment with cisplatin, especially for patients with diminished renal function. Improvement in definitions of cisplatin eligibility and continued education of providers, especially in community settings, can go a long way toward increasing utilization rates of this potentially life-prolonging treatment.



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