Muscle-Invasive Urothelial Carcinoma of the Bladder: Neoadjuvant Chemotherapy Enables Organ-Preserving Therapy in Carefully Selected Patients

european urology 54 (2008) 21–24

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Editorial and Rebuttal from Author referring to the article published on pp. 126–132 of this issue

Muscle-Invasive Urothelial Carcinoma of the Bladder: Neoadjuvant Chemotherapy Enables Organ-Preserving Therapy in Carefully Selected Patients Axel Heidenreich Division of Oncological Urology, Department of Urology, University of Ko¨ln, Ko¨ln, Germany

Currently, radical cystectomy represents the treatment of choice for patients with muscle-invasive urothelial carcinoma of the bladder, resulting in a 5-yr disease-specific survival rate of 68% [1]. In patients with organ-confined and lymph nodenegative tumours, the 5-yr overall recurrence-free survival rate is as high as 92% in P0 disease, whereas it decreases to 50% and 35% in patients with locally advanced and lymph node-positive tumours, respectively [2]. The drawbacks of radical cystectomy, however, are a significant morbidity rate of about 30% even in experienced centres [3] and functional results concerning continence and sexuality, which still can be improved, despite nerve-sparing procedures and continent urinary diversions being applied [4,5]. Transurethral resection of the bladder (TURB) and imaging procedures such as abdominal and pelvic computed tomography scanning are associated with a significant staging error; according to earlier studies about 50–60% of patients with muscleinvasive disease are under-staged by TURB when compared to the histopathologic findings of the radical cystectomy specimens [6]. The incidence of pathologically proved lymph node metastases in patients with pT2/pT3a tumours is 15–20%. Neoadjuvant chemotherapy has been administered to patients with muscle-invasive bladder cancer in bladder-preserving strategies to eliminate systemic

microscopic disease early and to improve cancerspecific survival [7–9]. In addition, the potential advantages of neoadjuvant chemotherapy include (1) the unique opportunity of in vivo evaluation of tumour response allowing proper patient selection for organ-sparing procedures, (2) less and less invasive surgery, (3) no need for urinary diversion in the majority of patients, and (4) preservation of sexual function. Herr [10] reports on the therapeutic efficacy of neoadjuvant cisplatin-based chemotherapy in a unique cohort of 63 patients with muscle-invasive bladder cancer who refused to undergo scheduled radical cystectomy after a complete clinical tumour response had been achieved. After a minimum follow-up of 5 yr, 64% of the patients survived without metastatic disease and about half of them survived with an intact functioning bladder. The author concludes that neoadjuvant chemotherapy in combination with a complete transurethral resection of the bladder tumour (TURBT) represents a feasible therapeutic strategy for a select group of patients with good prognostic features. The data presented are in line with some previous trials on neoadjuvant chemotherapy for bladder preservation [7–9]. The Memorial SloanKettering Cancer Center (New York, NY, USA) group analysed the outcome of 111 patients who underwent neoadjuvant methotrexate, vinblas-

DOI of original article: 10.1016/j.eururo.2007.12.031 E-mail address: [email protected]. 0302-2838/$ – see back matter # 2008 Published by Elsevier B.V. on behalf of European Association of Urology.

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european urology 54 (2008) 21–24

tine, Adriamycin, cisplatin (MVAC) treatment followed by TURB of the primary tumour site [7]. Sixty patients (54%) achieved a complete pathologic response and 43 of these 60 patients underwent bladder-sparing strategies resulting in a long-term survival rate of 74% with an intact functioning bladder in 56%. In an Italian trial [8], 104 patients with muscle-invasive bladder cancer underwent neoadjuvant MVAC followed by TURB and 49 (49%) achieved a pT0 stage. After a median follow-up of 56 mo, the survival rate was 69% as compared to only 26% for those patients with persistent muscle-invasive disease after chemotherapy. About half the patients maintained an intact functioning bladder. Similar data have been presented with regard to chemoradiation of muscleinvasive bladder cancer [9]. In a series of 415 consecutive patients undergoing extensive TURB and re-TURB followed by pelvic radiation or chemoradiation, the Erlangen group achieved a complete remission in 72% of the patients who were all candidates for bladder preservation; 35% of the patients developed local recurrences with a 5-yr survival rate of 75% and 28% in the presence of non–muscle-invasive and muscle-invasive recurrences, respectively. According to the authors an intact functioning bladder was maintained in 79% of the patients. As already demonstrated for the series of neoadjuvant chemotherapy alone, complete TURB prior to radiation therapy seems to be the most important prognostic risk factor to achieve a complete pathologic response: the 5-year overall survival was 81% and 30–50% if a complete or incomplete TURB was performed, respectively. Despite these promising results, some points of criticism have to be raised. As outlined before, preservation of an intact functioning bladder is one of the most important considerations for organ-preserving strategies. However, none of the studies including the trial presented by Herr [10] adequately analysed bladder and sexual function. In only one trial [11] urodynamic studies were reported in 32 (30%) of 106 patients and a normal functioning bladder in disease-free bladders was identified in 75% of the patients. No information is available about bladder function in patients who had to undergo additional treatment for local recurrences. As we learned from the present study, 25% and 38% of the patients developed recurrent superficial and muscle-invasive bladder tumours, respectively. All patients with superficial recurrences underwent multiple repeat TURB procedures and all were treated with intravesical bacillus Calmette-Gue´rin (BCG) instil-

lations. BCG by itself has a significant negative effect on bladder function and about 20% of patients stop therapy due to severe BCG-induced cystitis and another 30–40% develop significant local side-effects [12]. Therefore, a formal qualityof-life analysis and a state-of-the-art urodynamic evaluation are mandatory prior to just describing the imprecise and undefined term ‘‘normal functioning bladder.’’ There are no data at all on preservation of sexual function associated with neoadjuvant chemotherapy and organ-preserving strategies. There are, however, some reports demonstrating an association between BCG instillations, radical radiotherapy, and erectile dysfunction [13,14]. On the other hand, we know that sexual function can be preserved in 70–80% of the patients who undergo nerve-sparing radical or prostate-sparing cystectomy. Therefore, further clinical trials should evaluate sexual and bladder function and by standardised questionnaires to assess one major goal of bladder-preserving strategies, which is the functional integrity of the urogenital tract. Despite the promising results presented by Herr [10] and other groups [7–9], the indication for bladder-preserving strategies after neoadjuvant chemotherapy should be made with caution due to the lack of prospective randomised trials. Based on the trials performed so far, prognostic risk factors can be established that are associated with positive oncologic results comparable to radical cystectomy: (1) complete resection of the primary bladder tumour by fractionated TURB and re-TURB, (2) solitary, small (<5 cm) and muscle-invasive but organ-confined bladder cancer (pT2), (3) complete pathologic response at time of restaging TURB 6 wk after completion of chemotherapy, and (4) salvage cystectomy at time of muscle-invasive relapse. These parameters and their influence on the future course of the disease have to be thoroughly discussed with the individual patient who might choose to refuse radical cystectomy despite muscleinvasive bladder cancer. In accordance with the current guidelines on the management of muscle-invasive bladder cancer, neoadjuvant chemotherapy and bladder preservation might be chosen in carefully selected patients who refuse radical cystectomy or who are poor candidates for radical cystectomy [1]. The data presented by Herr [10] should form the basis of prospective randomised clinical trials comparing neoadjuvant chemotherapy and bladder preservation versus radical cystectomy. Conflicts of interest: The author has nothing to disclose.

european urology 54 (2008) 21–24

References [1] Jakse G, Algaba F, Fossa S, Stenzl A, Sternberg C. Guidelines on bladder cancer. Muscle-invasive and metastatic. European Association of Urology, Guidelines. 2007 edition. p. 1–24. [2] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666–75. [3] Barbieri CE, Lee B, Cookson MS, et al. Association of procedure volume with radical cystectomy in a nationwide database. J Urol 2007;178:1418–21. [4] Kessler TM, Burkhard FC, Studer UE. Clinical indications and outcomes with nerve-sparing cystectomy in patients with bladder cancer. Urol Clin North Am 2005;32:165–75. [5] Bhatta Dhar N, Kessler TM, Mills RD, Burkhard F, Studer UE. Nerve-sparing radical cystectomy and orthotopic bladder replacement in female patients. Eur Urol 2007;52:1006–14. [6] Cheng L, Neumann RM, Weaver AL, et al. Grading and staging of bladder carcinoma in transurethral resection specimens. Correlation with 105 matched cystectomy specimens. Am J Clin Pathol 2000;113:275–9. [7] Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 1998;16:1298–301. [8] Sternberg CN, Pansadoro V, Calabro` F, et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 2003;97:1644–52.

Rebuttal from Author re: Axel Heidenreich. Muscle-Invasive Urothelial Carcinoma of the Bladder: Neoadjuvant Chemotherapy Enables Organ Preserving Therapy in Carefully Selected Patients. Eur Urol 2008;54:21–23 Harry W. Herr * Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, United States

Neoadjuvant chemotherapy and radical cystectomy has become the standard treatment for operable muscle-invasive bladder cancer. Although better survival is associated with chemotherapy and completion of a high-quality cystectomy [1], an unintended consequence of this new treatment paradigm is that some patients refuse surgery, especially if they have no evidence of tumor in the bladder after chemotherapy. The outcome of such patients is widely believed to be dismal. For example, of 39 DOIs of original articles: 10.1016/j.eururo.2007.12.031, 10.1016/j.eururo.2008.01.045 * Tel. +1 646 422 4411; Fax: +1 212 988 0768. E-mail address: [email protected].

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[9] Ro¨del C, Grabenbauer GG, Ku¨hn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061–71. [10] Herr HW. Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscleinvasive bladder cancer. Eur Urol 2008;54:126–32. [11] Zietman AL, Sacco D, Skowronski U, et al. Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J Urol 2003;170:1772–6. [12] van der Meijden APM, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV, for the EORTC Genito-Urinary Tract Cancer Group. Maintenance bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group phase III trial. Eur Urol 2003;44:429–34. [13] Sighinolfi MC, Micali S, De Stefani S, et al. Bacille Calmette-Gue´rin intravesical instillation and erectile function: is there a concern? Andrologia 2007;39:51–4. [14] Fokdal L, Høyer M, Meldgaard P, von der Maase H. Longterm bladder, colorectal, and sexual functions after radical radiotherapy for urinary bladder cancer. Radiother Oncol 2004;72:139–45. doi:10.1016/j.eururo.2008.01.045

patients who did not undergo cystectomy in the US intergroup trial, only 11% survived [2]. The current paper shows that the prognosis is not so bad for some patients, since two thirds survived, half with their bladders. These patients had organconfined tumors that were completely and verifiably resected both macroscopically and microscopically (R0 resection) before chemotherapy, received at least four cycles of a cisplatin-based regimen, and achieved a complete clinical response (no residual cancer) in the bladder on postchemotherapy transurethral resection (TUR) biopsies. Patients failing such strict criteria soon had relapses (and many died). They should be strongly encouraged to undergo planned cystectomy or at least definitive radiotherapy. In his editorial, Heidenreich appropriately points out the inherent weaknesses of this and other retrospective reports [3]. He also mentions lack of measures used to document bladder and sexual function, although the patients reported satisfactory bladder function similar to before treatment with chemotherapy and TUR procedures. If patients empty their bladders without pain or incontinence, do we need formal quality-of-life analysis and