Since the advent of cisplatin-based combination therapy in the management of muscle-invasive and advanced bladder cancer, there has been little progress in improving outcomes for patients. Novel therapies beyond cytotoxic chemotherapy are needed. The neoadjuvant paradigm lends to acquiring ample pretreatment and posttreatment tumor tissue as a standard of care, which enables comprehensive biomarker analyses to better understand mechanisms of both response and resistance, which will aid drug development. This article discusses the evolution of neoadjuvant therapy as standard treatment and the role it may serve toward the development of novel therapies.
Key points
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Neoadjuvant cisplatin-based chemotherapy before radical cystectomy is the standard of care in the management of muscle-invasive bladder cancer.
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Pathologic response to neoadjuvant chemotherapy is prognostic for survival following radical cystectomy.
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The neoadjuvant setting is the context in which novel treatments should be tested in muscle-invasive bladder cancer and strengths unique to this paradigm include in vivo assessment of treatment effectiveness and the availability of ample pretreatment and posttreatment tumor tissue to perform correlative studies.
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Challenges inherent to the neoadjuvant paradigm include the potential requirement to coadminister novel therapy with standard chemotherapy, as well as potential delay of curative surgery.
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The neoadjuvant model is an ideal platform to test and better understand novel molecularly targeted therapy and immunotherapy in patients with bladder cancer.
Introduction
Despite 3 decades of clinical trials investigating novel agents and combinations, cisplatin-based chemotherapy remains the only therapy shown to improve survival in both muscle-invasive and metastatic urothelial cancer. Better-tolerated, more efficacious treatments are desperately needed.
The neoadjuvant setting has been a feasible and effective platform for the testing of novel therapies in a variety of solid tumors. One of the earliest trials, the National Surgical Adjuvant Breast and Bowel Project B18 study, randomized women undergoing surgery for localized breast cancer to either neoadjuvant or adjuvant chemotherapy and demonstrated similar outcomes with both approaches but showed that neoadjuvant therapy permitted more breast-conserving surgery and allowed for correlation of pathologic response to clinical outcomes.
Cisplatin-based chemotherapy in the neoadjuvant setting for muscle-invasive bladder cancer is considered the gold standard, supported by 3 randomized phase III clinical trials and a meta-analysis of 11 randomized trials and, therefore, may serve as a framework in which novel treatments can be tested in this disease. Strengths unique to the neoadjuvant approach include in vivo assessment of treatment effectiveness, access to pretreatment and posttreatment tumor tissue to allow for the study of molecular factors that predict for response or resistance, and more precise prognostic information to guide surveillance strategies and/or decisions related to investigational adjuvant therapy. Therefore, muscle-invasive bladder cancer is an ideal disease state to provide timely and accurate information regarding a novel treatment’s efficacy, including mechanisms of response, thereby accelerating the identification of more effective and better-tolerated treatments.
Introduction
Despite 3 decades of clinical trials investigating novel agents and combinations, cisplatin-based chemotherapy remains the only therapy shown to improve survival in both muscle-invasive and metastatic urothelial cancer. Better-tolerated, more efficacious treatments are desperately needed.
The neoadjuvant setting has been a feasible and effective platform for the testing of novel therapies in a variety of solid tumors. One of the earliest trials, the National Surgical Adjuvant Breast and Bowel Project B18 study, randomized women undergoing surgery for localized breast cancer to either neoadjuvant or adjuvant chemotherapy and demonstrated similar outcomes with both approaches but showed that neoadjuvant therapy permitted more breast-conserving surgery and allowed for correlation of pathologic response to clinical outcomes.
Cisplatin-based chemotherapy in the neoadjuvant setting for muscle-invasive bladder cancer is considered the gold standard, supported by 3 randomized phase III clinical trials and a meta-analysis of 11 randomized trials and, therefore, may serve as a framework in which novel treatments can be tested in this disease. Strengths unique to the neoadjuvant approach include in vivo assessment of treatment effectiveness, access to pretreatment and posttreatment tumor tissue to allow for the study of molecular factors that predict for response or resistance, and more precise prognostic information to guide surveillance strategies and/or decisions related to investigational adjuvant therapy. Therefore, muscle-invasive bladder cancer is an ideal disease state to provide timely and accurate information regarding a novel treatment’s efficacy, including mechanisms of response, thereby accelerating the identification of more effective and better-tolerated treatments.
The neoadjuvant paradigm in bladder cancer: how did we get here?
Despite definitive treatment strategies such as radical cystectomy and concurrent chemoradiotherapy for muscle-invasive bladder cancer, up to 50% of patients will develop metastatic bladder cancer, a devastating and incurable disease. The proven efficacy of perioperative chemotherapy in breast and colon cancers, and the observed efficacy of chemotherapy in metastatic bladder cancer, ultimately led to the investigation of perioperative chemotherapy in muscle-invasive bladder cancer in an effort to eradicate micrometastatic disease and, ultimately, reduce the risk of recurrence and improve survival.
Perioperative chemotherapy, whether given before (neoadjuvant) or after (adjuvant) definitive local therapy, should achieve identical outcomes because the intent is to eliminate micrometastatic disease that may already be present at initial diagnosis. Micrometastases, relative to their macrometastatic counterparts, should be, in principle, more chemotherapy-sensitive and, furthermore, patients are more likely to tolerate chemotherapy in the perioperative setting compared with treatment at the time of systemic relapse. In the design of perioperative trials of chemotherapy in muscle-invasive bladder cancer there have been compelling arguments for both the adjuvant and neoadjuvant approaches.
Arguments in favor of neoadjuvant chemotherapy include (1) improved tolerability of chemotherapy before, rather than after surgery when postsurgical morbidity may be high; (2) the ability for in vivo assessment of chemotherapy effectiveness which has been shown to be prognostic for long-term disease-free survival; and (3), in the context of locally advanced disease, tumor downstaging and potentially more effective surgical resection. Clear limitations for neoadjuvant chemotherapy are the reliance on clinical rather than pathologic staging to determine its use and the lack of validated predictive biomarkers for response, potentially leading to overtreatment in some patients.
Up-front radical cystectomy eliminates the inherent limitations of clinical staging and allows for risk-adapted decision making whereby both pathologic and clinical factors, such as age, performance status, and medical comorbidities, can be used to determine if adjuvant chemotherapy is indicated. The adjuvant approach has clear strengths in this context; for instance, patients with high-risk features for recurrence can be selected for adjuvant treatment. However, radical cystectomy is a morbid surgery and, when combined with the comorbidities that commonly coexist in bladder cancer patients, surgery may pose significant obstacles to the administration of adjuvant chemotherapy.
In practice, both adjuvant and neoadjuvant trials in muscle-invasive bladder cancer have been met with obstacles related to both accrual and planned treatment delivery. Nonetheless, perioperative therapy ultimately prevailed, definitively leading to a prolongation of survival in muscle-invasive bladder cancer with the collective data to date strongly favoring the neoadjuvant approach. Looking toward the future, the neoadjuvant treatment platform provides a framework for the development of novel therapies as we continually seek to improve outcomes for patients with both localized and advanced bladder cancer.
Adjuvant Chemotherapy
In muscle-invasive bladder cancer, radical cystectomy confers a 50% to 60% long-term survival rate for all-comers. Pathologic tumor stage is strongly linked to the risk of recurrence and, therefore, patients with more advanced disease, such as extravesical or lymph node involvement, have the highest risk for recurrence and, consequently, the poorest long-term survival estimated at 40% and 10%, respectively. It stands to reason that these high-risk patients should be selected for clinical trials of adjuvant chemotherapy because they are most likely to derive benefit from additional treatment. Initial reports of adjuvant chemotherapy from prospective trials from single institutions, as well as retrospective studies, were promising, but ultimately led to randomized trials that closed early due to slow accrual and inadequate delivery of assigned therapy. Currently, despite the widespread use of adjuvant chemotherapy, there is no high-level evidence to support its use.
Two relatively small, single-center experiences suggested a survival benefit with adjuvant chemotherapy although, in 1 study, subjects randomized to the observation arm were not offered salvage chemotherapy at the time of relapse. However, subsequent reports have been mixed. A systematic review of 8 randomized trials demonstrated no benefit in survival, even for those with extravesical or lymph node involvement. However, a retrospective analysis of a multicenter, international collaborative database demonstrated a significant improvement in survival associated with the use of adjuvant chemotherapy after radical cystectomy, particularly in subjects with high-risk features.
More contemporary trials have continued to address the role for adjuvant chemotherapy however, each was closed prematurely due to poor accrual. An Italian multicenter study randomized subjects with high-grade pT2, pT3/4, or lymph node–positive bladder cancer to adjuvant gemcitabine and cisplatin (GC) versus observation and demonstrated no difference in disease-free or overall survival for the 194 enrolled of 610 planned patients.
Risk-adapted approaches have also led to mixed results. A European Organization for Research and Treatment of Cancer (EORTC) study focused on high-risk subjects with pT3/4 or lymph node–positive bladder cancer with randomization to adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), high-dose MVAC, or GC versus deferred therapy at relapse. The EORTC study, presented at the 2014 American Society of Clinical Oncology Annual Meeting, demonstrated a significant improvement in progression-free survival (PFS) but not overall survival in the 284 enrolled of 660 planned subjects. Median PFS was 2.9 years for the immediate and 0.9 years for the deferred treatment arms ( P <.0001). Median overall survival was 6.8 years for the immediate and 4.6 years for the deferred treatment arms (hazard ratio [HR] 0.78, 95% CI 0.56–1.10, P = .13). A trial led by the Southwest Oncology Group (SWOG) and the University of Southern California that randomized subjects with p53 overexpression by immunohistochemistry to adjuvant MVAC chemotherapy versus observation was also terminated early after slow accrual and a high-rate of noncompliance with the study design. An analysis of the 499 subjects enrolled demonstrated neither a survival benefit with adjuvant chemotherapy nor a prognostic or predictive value to p53 testing. The Spanish Oncology Group Trial 99/01, a randomized trial of adjuvant chemotherapy also focused on high-risk subjects and ultimately did provide some evidence that adjuvant chemotherapy can perhaps improve survival. Subjects with pT3/4 or lymph node–positive bladder cancer were randomized to observation versus paclitaxel and GC for 4 cycles with a planned enrollment of 340 subjects. In 2007, this study was also closed early due to poor accrual. However, a preliminary analysis of the 142 subjects enrolled demonstrated a significant improvement in survival at 5 years (60% vs 30%, HR 0.44, P <.0009, median follow-up 51 months).
A recently reported updated meta-analysis, including a total of 945 subjects from 9 randomized trials (5 previously analyzed in the 2005 meta-analysis), demonstrated a pooled HR of 0.77 ( P = .049) for survival and an HR of 0.66 ( P = .014) for disease-free survival, with the greatest benefit observed in subjects with lymph node involvement. Criticisms of this meta-analysis include the inclusion of trials that were of poor quality and terminated early or not yet published, leaving the role for adjuvant chemotherapy in muscle-invasive bladder cancer undefined.
Neoadjuvant Therapy
Although the clinical evidence supporting the use of neoadjuvant chemotherapy in muscle-invasive bladder cancer is well established, this treatment approach remains relatively underused. Data from 3 large randomized studies of neoadjuvant cisplatin-based therapy have demonstrated definitive evidence for a survival benefit. The pivotal SWOG 8710 study randomized 317 subjects with cT2-T4aN0 muscle-invasive bladder cancer to 3 cycles of neoadjuvant MVAC followed by radical cystectomy versus radical cystectomy alone. Radical cystectomy alone carried a 33% higher risk of death compared with treatment with combination therapy (HR 1.33; 95% CI 1.00–1.76). The Medical Research Council of the United Kingdom and EORTC BA06 phase III trial randomized 976 subjects to cisplatin, methotrexate, and vinblastine (CMV) versus no therapy before definitive treatment (radical cystectomy or radiation) for muscle-invasive bladder cancer and was powered to detect a 10% absolute improvement in survival at 3 years. Data for the 484 subjects who underwent radical cystectomy at a median follow-up of 4 years did not demonstrate a significant difference in survival with a 3-year survival rate 55.5% for the chemotherapy arm versus 50% in the no chemotherapy arm ( P = .075). A recent long-term update, however, did demonstrate a significant reduction in the risk of death (HR 0.84, 95% CI 0.72–0.99, P <.037) corresponding to an increase in 10-year survival from 30% to 36% for subjects receiving neoadjuvant CMV. Similar outcomes were observed in an additional randomized study of neoadjuvant MVAC, as well as a large meta-analysis of 11 randomized trials; therefore, neoadjuvant cisplatin-based chemotherapy before radical cystectomy is the standard of care in patients with muscle-invasive bladder cancer.
Subgroup analysis from the SWOG-Intergroup 8710 study demonstrated that, although all subjects benefited from neoadjuvant chemotherapy, the benefit was greatest in subjects with clinical T3 or greater disease, again raising the question of whether certain high-risk patients benefit more. Further, the rate of complete response (pT0) to neoadjuvant chemotherapy (38% for neoadjuvant chemotherapy vs 15% for no chemotherapy; P <.001) strongly predicted improved long-term survival, with 85% of subjects with pT0 alive at 5 years. Post hoc analysis demonstrated a similar benefit for subjects who achieved eradication of the muscle-invasive component (<pT2) and negative surgical margins versus those who had residual muscle-invasive disease. This seminal observation highlights the prognostic value of in vivo assessment of response to neoadjuvant chemotherapy and supports pathologic response as a meaningful clinical endpoint in neoadjuvant studies.
GC, a standard regimen in metastatic disease, has not been prospectively evaluated in the neoadjuvant setting. Two recent neoadjuvant trials are evaluating GC but administered in a dose-dense fashion. The first, led by the Fox Chase Cancer Center, was closed early due to a high rate of vascular toxicity. The second is an ongoing trial led by Memorial Sloan-Kettering Cancer Center (MSKCC). A retrospective report from a single institution demonstrated a similar rate of pT0 between MVAC and GC, suggesting that survival outcomes may be similar. In practice, MVAC, CMV, and GC are all commonly used neoadjuvant regimens and serve as the backbone for ongoing trials incorporating novel agents ( Table 1 ).
Related posts:
Multidisciplinary Care of the Urothelial Cancer Patient
Management of High Grade Bladder Cancer: A Multidisciplinary Approach
Neoadjuvant Chemotherapy in the Management of Muscle-Invasive Bladder Cancer
Radical Transurethral Resection Alone, Robotic or Partial Cystectomy, or Extended Lymphadenectomy
Potential Role for Targeted Therapy in Muscle-Invasive Bladder Cancer
Novel Biomarkers to Predict Response and Prognosis in Localized Bladder Cancer
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