Elsevier

European Urology

Volume 62, Issue 3, September 2012, Pages 523-533
European Urology

Review – Bladder Cancer
A Systematic Review of Neoadjuvant and Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer

https://doi.org/10.1016/j.eururo.2012.05.048Get rights and content

Abstract

Context

Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC.

Objective

To review the data supporting perioperative chemotherapy and emerging regimens for MIBC.

Evidence acquisition

Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included.

Evidence synthesis

The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.

Introduction

With radical cystectomy (RC) alone, the 5-yr survival rate for urothelial carcinoma of the bladder (UCB) can be up to 80% for organ-confined lymph node–negative disease. However, it decreases to 40–50% in patients with extravesical disease, with a further reduction to 15–35% if lymph node metastases are present. Distant recurrences have been observed to occur more frequently than locoregional recurrences (approximately 20–50% vs 5–15% of cases), suggesting that perioperative systemic therapy may improve outcomes [1], [2], [3]. Despite improvements in imaging and surgical techniques, the overall mortality for patients with bladder cancers remains unchanged [4]. Thus improvements in survival will likely come from the strategies aimed at early disease detection and/or integration of new systemic therapies.

Despite the accumulating body of data supporting neoadjuvant chemotherapy (NC) for muscle-invasive operable UCB (T2–T4aN0M0), the perioperative timing, dose, schedule, and specific agents have been controversial. The ultimate goal is to improve survival for those with a high risk of recurrence while minimizing toxicity to those that will have minimal benefit, but limited clinical acceptance of this therapeutic approach allied with the paucity of data currently available limit informed decision making in this area of oncology. For example, perioperative chemotherapy was administered to only 11.6% of patients with stage III urothelial cancer in 1998, with 1.2% receiving NC and 10.4% receiving adjuvant chemotherapy (AC) [5]. A small increase of perioperative chemotherapy was then noted: 11.3% in 1998 and 16.8% in 2003. A more recent study of North American academic referral institutions demonstrated that only 12% of T2–T4aN0M0 UCB patients received NC, 22% received AC, and only 9% of all patients received neoadjuvant cisplatin-based chemotherapy [6]. Although many patients with UCB are older with comorbidities and poor renal function and performance status, we need a more comprehensive understanding of the barriers to the use of perioperative cisplatin-based multiagent chemotherapy. The goal of this systematic review is to describe the data currently supporting NC and AC in association with RC for muscle-invasive UCB.

Section snippets

Evidence acquisition

A literature review searching Medline and major cancer conferences for prospective trials and major preclinical and retrospective studies in the last 5 yr was performed in March 2012. The search strategy included the terms bladder cancer, urothelial carcinoma, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy.

Identifying the high-risk patient: baseline staging and prognosis

Clinical staging involves a complete physical examination, transurethral resection of bladder tumor (TURBT) with pre- and postresection bimanual examination, and cross-sectional imaging of the bladder and upper urinary tracts. Despite advances in technology, a large disparity remains between clinical and pathologic staging. Bimanual examination, for example, is accurate in only 57% of patients, with overstaging in 11% and understaging in 31%, with only 41% accuracy of predicting organ-confined

Conclusions

Data support the use of cisplatin-based combinations as NC preceding RC for patients with muscle-invasive resectable UCB. Despite the lack of robust data, high-risk patients who qualify for cisplatin may be offered AC in the absence of a trial. Future studies using the neoadjuvant paradigm and integrating biologic agents may improve the efficacy of systemic therapy and improve outcomes.

References (65)

  • R.W. deVere White et al.

    A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest Oncology Group Trial (S0219)

    J Urol

    (2009)
  • D.C. Smith et al.

    Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder

    J Urol

    (2008)
  • D.G. Skinner et al.

    The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial

    J Urol

    (1991)
  • M. Stockle et al.

    Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience

    J Urol

    (1995)
  • U.E. Studer et al.

    Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial

    J Urol

    (1994)
  • F. Cognetti et al.

    Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial

    Ann Oncol

    (2012)
  • S.M. Donat et al.

    Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience

    Eur Urol

    (2009)
  • A. Font et al.

    BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer

    Ann Oncol

    (2011)
  • G. Sonpavde et al.

    Disease-free survival at 2 or 3 years correlates with 5-year overall survival of patients undergoing radical cystectomy for muscle invasive bladder cancer

    J Urol

    (2011)
  • J.P. Stein et al.

    Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients

    J Clin Oncol

    (2001)
  • M.L. Quek et al.

    Natural history of surgically treated bladder carcinoma with extravesical tumor extension

    Cancer

    (2003)
  • A.T.J. Feifer et al.

    Multi-institutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder [abstract 240]

    J Clin Oncol

    (2011)
  • R.S. Svatek et al.

    Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort

    BJU Int

    (2011)
  • B.H. Bochner et al.

    Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

    J Clin Oncol

    (2006)
  • S.F. Shariat et al.

    Nomograms provide improved accuracy for predicting survival after radical cystectomy

    Clin Cancer Res

    (2006)
  • A.S. Kibel et al.

    Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma

    J Clin Oncol

    (2009)
  • D.F. Bajorin et al.

    Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy

    J Clin Oncol

    (1999)
  • H. von der Maase et al.

    Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study

    J Clin Oncol

    (2000)
  • H. von der Maase et al.

    Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer

    J Clin Oncol

    (2005)
  • S.B. Saxman et al.

    Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study

    J Clin Oncol

    (1997)
  • J. Bellmunt et al.

    Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine (PCG) and gemcitabine/cisplatin (GC) in patients with locally advanced (LA) or metastatic (M) urothelial cancer without prior systemic therapy; EORTC30987/Intergroup Study [abstract LBA5030]

    J Clin Oncol

    (2007)
  • M. De Santis et al.

    Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy [EORTC Study 30986]

    J Clin Oncol

    (2009)
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