Radical cystectomy versus organ-sparing trimodality treatment in muscle-invasive bladder cancer: A systematic review of clinical trials

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Abstract

Background

Radical cystectomy (RC) represents the mainstay of treatment in patients with muscle-invasive urinary bladder cancer but how it compares with the best organ preservation approach is not known.

Materials and methods

The objective of our review is to compare the 5-year overall survival (OS) rates from retrospective and prospective studies of RC and trimodality treatment (TMT), i.e. concurrent delivery of chemotherapy and radiotherapy after a transurethral resection of bladder tumor (TURBT), involving a total of 10,265 and 3131 patients, respectively. We used random-effect models to pool outcomes across studies and compared event rates of combined outcomes for TMT and RC using an interaction test.

Results

The median 5-year OS rate was 57% in the TMT group, when compared with 52% (P = 0.04), 51% (P = 0.02) and 53% (P = 0.38) in the whole group receiving RC or the group treated with RC alone or RC + chemotherapy, respectively. The hazard risk (HR) of mortality of patients treated with TMT or RC was 1.22 (95% CI = 1.13–1.32) with an absolute benefit of 5% in favor of the former. The HR of mortality from TMT persisted significantly better not only versus the group treated with RC alone (HR = 1.22; 95% CI = 1.12–1.32), but also versus the group receiving RC + chemotherapy (HR = 1.22; 95% CI = 1.09–1.36). Multivariate analysis confirmed TMT as a significant prognostic variable for both RC alone and RC + chemotherapy.

Conclusion

Compared with RC, TMT seems to be associated with a better outcome for patients with muscle-invasive bladder cancer (MIBC). The addition of chemotherapy may improve the RC outcome in some subgroups of patients with a higher probability of micrometastases. Prospective randomized trials are urged to verify these findings and better define the role of organ preservation and radical treatment strategy in the management of patients with MIBC.

Introduction

Based on the 2012 cancer incidence estimates, urinary bladder cancer represents the fourth most common cancer in men and the 12th most common cancer in women in the United States and Europe [1], [2]. A total of 15–25% of bladder tumors are muscle-invasive and require radical treatment. Radical cystectomy (RC), with the primary goal of maximizing survival, represents the mainstay of treatment in these patients and involves removal of the bladder, prostate, seminal vesicles, proximal vas deferens and proximal urethra in men, and bladder, uterus, ovaries, fallopian tubes, urethra and part of vagina in women. However, as in other tumor sites (breast, larynx, anus, prostate, etc.), also in bladder cancer, secondary goals as the organ preservation and the quality of life are increasingly being requested by patients. Trimodality treatment (TMT), based on the concurrent delivery of chemotherapy and radiotherapy after a transurethral resection of a bladder tumor (TURBT), has been largely demonstrated as the most effective bladder sparing treatment (BST) [3], [4], [5]. This approach can be considered a competing alternative to RC in muscle-invasive bladder cancer (MIBC), with the advantage of preserving a normal functioning bladder [6] in most of the patients, reserving cystectomy as a salvage option only in cases with a locally confined infiltrating failure. Yet, bladder preservation strategy by TMT is still perceived by many urologists to be inferior in terms of survival when compared with RC, although no randomized trials support this bias. The few attempts of a randomized comparison of RC versus BST have proven to be unfeasible [7]. Indeed, retrospective and prospective non-randomized studies can be affected by several sources of bias including the difference in tumor staging, which is pathological in RC and clinical in TMT. Clinical staging is known to under-stage a large portion of patients compared with surgical staging. The stage discrepancy can occur in up to 50% of patients [8], [9], making an appropriate comparison between the two treatment strategies by non randomized studies very difficult. Advanced age, worse performance status and co-morbidities that are more frequent in patients receiving TMT than RC are important variables that can further confound the comparison of the two treatment approaches.

In the absence of controlled randomized trials, regardless of several confounding variables, we investigated the outcomes of patients with MIBC by conducting a systematic review of published prospective and retrospective studies to compare treatment outcomes after TMT or RC.

Section snippets

Study selection criteria

In order to assess the best-treatment approach for MIBC, a PubMed literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) literature selection process [10]. A search of English medical literature in PubMed from 1990 until 2013 was carried out, using the following terms: bladder cancer, transitional cell carcinoma, urothelial cancer, radical cystectomy, combined chemoradiation treatment, trimodality treatment, bladder preservation,

Results

Fig. 1 shows the flow diagram of identification and inclusion of trials as recommended by PRISMA [10]. Overall 220 and 293 references were identified and screened for TMT and RC, respectively. We excluded 122 and 190 papers in the TMT and RC screened groups, respectively, because of stage or treatment not fitting our inclusion criteria, or purposes and outcomes different from our requirements. The remaining 102 and 103 studies were selected and retrieved for full-text analysis. After discarding

Discussion

Although clinical practice guidelines include both RC and TMT as standard of care [69], RC is still considered the “gold treatment standard” of MIBC. However, a high proportion of these patients do not receive a curative therapy due to advanced age and/or comorbidities that may limit therapeutic options. Age alone should not be the reason for not receiving a potentially curative treatment. Indeed, 25–35% of patients aged between 70 and 80 years and 35–55% aged over 80 years, do not receive

Funding

This manuscript was not funded by a specific grant.

Conflict of interest

The authors have declared no conflicts of interest.

Reviewers

Alberto Bossi, MD, Institut Gustave Roussy, Radiotherapy, 39, rue Camille Desmoulins, F-94805 Villejuif, France.

Barbara Alicja Jereczek-Fossa, MD PhD, Senior Deputy Director, University of Milan, European Institute of Oncology, Dept. of Radiotherapy, via Ripamonti 435, I-20141 Milan, Italy.

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