Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder

Annals of Oncology : -5. 999. 999 Klimer Academic Publishers. Printed in the Netherlands. Original article Neo-adjuvant chemotherapy and bladder preservation in locally advanced transitional cell carcinoma of the bladder C. N. Sternberg, V. Pansadoro, F. Calabro, L. Marini, A. van Rijn, P. De Carli, D. Giannarelli, A. Platania & A. Rossetti San Raffaele Scientific Institute, Rome, Italy Summary Background: The possibility of bladder preservation as well as the utility of neo-adjuvant chemotherapy for invasive bladder cancer are controversial issues. The purpose of this study was the evaluation of neo-adjuvant chemotherapy and bladder preservation in patients with locally advanced transitional cell carcinoma of the bladder. Patients and methods: Eighty-seven consecutive evaluable patients with T -T a N x M TCC of the bladder were treated with three cycles of neo-adjuvant chemotherapy. After three cycles of, patients had TURB alone, patients underwent partial cystectomy, and patients were to undergo radical cystectomy. Results: Forty (5%) patients weret at the TURB following. Thirty (%) patients who had chemotherapy and TURB alone are alive; at a median follow-up of 5+ months (8+-9+). Twenty-four (5%) have maintained an intact Introduction Cisplatin-containing combination chemotherapy has become the gold standard of treatment for patients with advanced, metastatic transitional cell carcinoma (TCC). For those patients who attain complete remission, long term survival may be achieved []. In patients with locally advanced muscle-invasive bladder cancer, neoadjuvant chemotherapy was designed to treat micrometastatic disease, present in up to 5% of patients at the time of diagnosis []. In selected patients bladder preservation can be achieved with the use of neo-adjuvant chemotherapy plus radiotherapy, partial cystectomy or transurethral resection of the bladder (TURB) [-5]. The objectives of this study were to assess the value of neo-adjuvant chemotherapy and the feasibility of bladder-sparing following in selected patients with localized tumors. Patients and methods From January 988 until June 99, 88 consecutive patients with muscle-invasive TCC of the bladder were entered onto the protocol. bladder. Of responding patients with monofocal lesions who underwent partial cystectomy, 8 patients (%) are alive with a functioning bladder, at a median follow-up of 8+ months (-+ months). At a follow-up of months ( + months), (%) patients in the radical cystectomy group are alive. In patients who had downstaging to T o or superficial disease, median follow-up is 55 months (- + months) and five-year survival is %. Patients who failed to respond (T or greater after chemotherapy), at a median follow-up of months (-+ months), had five-year survival of only 9%. Conclusions: Bladder sparing in selected patients on the basis of response to neo-adjuvant chemotherapy is a feasible approach which must be confirmed in prospective randomized trials. Key words: bladder preservation, locally advanced bladder cancer, neo-adjuvant chemotherapy The median age was years and the Karnofsky performance status was uniformly good. According to the 99 UICCC TNM staging system, patients (%) were clinically T b, 9 were T a (%), were T (%), and 8 were T a (9%). All patients were N o by CT scan. Patient characteristics are illustrated in Table. Three cycles of neo-adjuvant chemotherapy were given [], Dose reductions are described in the toxicity section (see below). Prior to protocol entry, all patients underwent clinical staging which included a CT scan, urinary cytology, and transurethral resection of the bladder (TURB). After completion of three cycles of chemotherapy all patients were to undergo complete clinical re-staging (CT scan, cytology, and TURB). When necessary, patients were to undergo either partial or radical cystectomy within four weeks after completion of chemotherapy. Informed consent was obtained in all patients. Results After completion of chemotherapy, patients underwent TURB alone, patients underwent partial cystectomy, and patients were to undergo radical cystectomy. Only patients underwent radical cystectomy, because patient developed a deep venous thrombosis and was placed on anti-coagulant therapy. In Table the clinical stage prior to three cycles of and the clinical stage (TURB results) after Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on May 8,

Table. Patient characteristics. Evaluable Sex Male Female Age (in years) KPS T stage T T a T b T Prior intravesical therapy Cycles 8 8-8 - 9 8 - Table. Clinical restaging (TURB results) following neo-adjuvant chemotherapy. Clinical stage prior to n 9 Clinical stage after Total 8 Cis Abbreviation: Ref - patients who refused TURB after chemotherapy. Patients highlighted in 'italics' had reduction of two clinical stages at TURB after chemotherapy. chemotherapy are presented. Clinical downstaging was defined as reduction in stage of at least two clinical stages. This was observed in 8% of the patients who underwent TURB after. Forty patients (5%) became T o at the TURB after chemotherapy. Neo-adjuvant chemotherapy and TURB alone Forty-two patients attained a clinical CR, or had downstaging to superficial disease. These patients underwent TURB after chemotherapy, and did not undergo cystectomy. Thirteen of these patients were > years old (median age years, range -8 years), seven had cardiac disease, four had pulmonary disease, and three had diabetes. The clinical course of these patients is summarized in Table. Of these patients, 9 weret at the TURB, had T a, had CIS, had T ]5 T with rapid progression in bone, and refused TURB. Eighteen of the forty-two (%) patients have remained free of disease recurrence or progression (NED). In the 9 patients who were T o, superficial recurrence was observed in patients, and was successfully treated with BCG in 5 and cystectomy in. Ref Table. Neo-adjuvant and TURB alone: treatment outcome relative to clinical (TURB) response to. Post T stage ct ct, Refused All 9 NED Su- Invaperf sive 8 Mets. 9 Invasive + mets 9 Alive Dead Table Partial cystectomy: treatment outcome relative to pathologic response to. Post P stage pt, s PT, pt All 9 8 8 NED Superf. Invasive Mets. " One patient died of other causes than cancer. Intact bladder Functional bladder Alive J 8 5 Dead Seventeen percent of patients in the TURB group had superficial recurrences, % invasive disease, % developed metastases and % had both invasive and metastatic disease. Thirty of the forty-two (%) patients are alive. Twenty-four (5%) have maintained an intact bladder. follow-up for this group is 5+ months (8+- 9+). Five-year survival for this group is 9%. Of the 9 patients who were T o, (9%) are alive, and 9 (8%) have an intact bladder. Neo-adjuvant chemotherapy and partial cystectomy Candidates for partial cystectomy after neo-adjuvant chemotherapy were those who: a) attained a ccr or significant cpr to neo-adjuvant chemotherapy; b) who had solitary lesions in favorable anatomical locations (dome and anterior lateral walls of the bladder); c) with no history of previous or recurrent infiltrative bladder cancer; d) no carcinoma in situ (CIS); and e) who have a good bladder capacity. Table describes patients with monofocal lesions who responded to chemotherapy, and underwent partial cystectomy. Fifteen percent had superficial recurrences, % invasive disease and 8% developed metastases. At a median follow-up of 8+ months (-+ months), eight patients (%) are still alive with a functioning bladder. Five-year survival is 9%. Neo-adjuvant chemotherapy and radical cystectomy Thirty-one patients underwent radical cystectomy. The clinical course of these patients is described in Table 5. Forty-seven percent of the patients have had metastatic Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on May 8,

Table 5. Radical cystectomy: treatment outcome relative to pathologic response to. Post P stage pt, s pt TE Total + 8 + + 5+ NED Mets. 5 Alive Dead a 5 5 a One patient died of lung cancer. In each group designated '+' there was one patient with positive lymph nodes (pt N,, pt N,, pt b N > pt N ). Table Outcome and survival in 8 evaluable patients treated with neo-adjuvant n NED Alive Five-year follow-up survival TURB alone 8(%) (%) 5+months 9% (8+-9+) Partial 8(%) 8(%) 8+months 9% cystectomy (-+) Radical 5(%) (%) months 5% cystectomy (-+) Total 8 (%) 58(%) +months % (-5+) a a The median follow-up of the alive patients is months (+- + months). and % are alive without evidence of disease. Twenty (%) patients are alive at a follow-up of months (-+ months). Five-year survival is 5%. Bladder preservation, outcome, and overall survival Table outlines the outcome and survival for all three patient groups. The median survival for all patients has not yet been reached, however, 58 of the 8 (%) are alive at a median follow-up of + months (-5+ months). Thirty-two of the eighty-seven patients (%) are alive with a functional bladder. Fifty-five patients were managed with conservative therapy (TURB alone or partial cystectomy). Thirtyeight (9%) of these conservatively managed patients are alive, thirty-two (58%) with a functional bladder. In patients who had downstaging to T o or superficial disease, median follow-up is 55 months (- + months). Survival at five years is %. Patients who failed to respond were those who had persistent muscleinvasive disease (T or greater) after chemotherapy. At a median follow-up of months (-+ months), fiveyear survival was only 9%. Table. Overall WHO toxicity (%). WBC Hemoglobin Platelets Mucositis Renal 8 95 95 5 9 Pathologic staging compared to clinical staging Half of the patients in this study did not undergo pathologic staging. For those who had both TURB and pathologic confirmation after chemotherapy, there was a % difference in stage when comparing clinical and pathologic staging. These data are compatible with those in the literature []. Toxicity Toxicity in percentages according to the WHO scale is described in Table. No patients in this series had nadir sepsis or death due to chemotherapy. Alopecia was universal. Nephrotoxicity was not a serious problem in these patients with localized disease and a good performance status. Delays between the administration of cycles and were mainly due to hematological toxicity. The median period between cycle and was days (range -9 days). The median time period between cycle and was days with a range of to 5 days. Initially, growth factors were not routinely available. As the study progressed, growth factors were administered only to patients with neutropenia. Patients who experienced grade - neutropenia or leukopenia, were prophylactically treated with growth factors in subsequent cycles. Dose intensity ranged from %-% (median % of drugs administered). There were seven patients that had a dose reduction at the start of the protocol treatment, either due to concomitant medical problems, or age. Two patients were started at %, two at 5% and three at 8%. Toxicity among these patients was not remarkable except for one patient who experienced leukopenia grade and neutropenia grade. An additional four patients had a change in dosage after the administration of the first cycle. One of these patients had grade and leukopenia and neutropenia, respectively and had cycle at 8% and then cycle at % of the dose with growth factor support. Discussion Neo-adjuvant chemotherapy has been used in the treatment of several solid tumors. The major advantages to neo-adjuvant chemotherapy are the predictive information gained by evaluating the response to chemotherapy, and the potential for bladder preservation. The bladder Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on May 8,

tumor is an in vivo marker, which permits evaluation of response to chemotherapy. This may permit continuation of treatment to maximal response, or discontinuation of ineffective therapy. Response of micrometastases is presumed to reflect response in the primary lesion, although this has not been proven. The optimal time to treat micrometastases is when their volume is small []- In terms of survival, neo-adjuvant chemotherapy has not been shown to have a definite advantage in published randomized studies. The MRC/EORTC trial of neo-adjuvant CMV followed by either cystectomy, radiation, or both revealed only a 5.5% improvement in -year survival in patients given three cycles of neoadjuvant chemotherapy. survival in the chemotherapy group was months compared with.5 months for the no-chemotherapy group. This is the largest study in neo-adjuvant chemotherapy in bladder cancer, with participation of 9 patients from institutions in countries. Yet, the study was powered to demonstrate a % survival difference. For a 5.5% difference to be meaningful, 5 patients would have been required. A % decrease in the risk of locoregional disease or death with chemotherapy was observed. The pt rate was % with CMV and % without CMV. Chemotherapy demonstrated activity in the primary tumor and may have delayed loco-regional and metastatic progression [8]. The Nordic cystectomy trial is the only randomized trial which suggested an improvement in survival in a subset of patients treated with neo-adjuvant adriamycin and cisplatin. In this trial, patients with T a -T lesions, experienced a % difference in cancer-specific survival and a 5% difference in overall survival [9]. Results of the SWOG trial of neo-adjuvant followed by cystectomy should be available shortly. Although randomized trails have not definitely proven a survival advantage, response to chemotherapy is an important prognostic factor. In collected data on patients, treated in 8 centers with neo-adjuvant chemotherapy and radical or partial cystectomy, five-year survival was 5% for patients who had downstaging of the primary tumor to pt or superficial disease versus only % for those who had residual muscle-infiltrating disease (^ PT) []. These data are very similar to those presented in this paper. Newer molecular prognostic factors, such as p5, may be useful in selecting patients for chemotherapy in the future. Some authors have observed that TURB alone without chemotherapy may produce similar survival results to cystectomy in highly selected patients with T -T a tumors. In patients with superficial T muscle-infiltrating tumors, five-year survival may range between 5% and %. Patients with T tumors may survive %- % of the time. Herr reported on patients with T disease who underwent a second staging TURB. If the second TURB demonstrated clinical T o, patients were observed and did not undergo radical cystectomy. At a follow-up of 5. years (range -), of 5 (5%) patients were disease-free, although some did require repeat TURB and intravesical therapy []. More recently, Solsona reported results on patients with T -T a bladder tumors treated by radical TURB alone. For selected patients with repeat negative biopsies, the five- and -year cause-specific survival rates were 8% and 5%, with bladder preservation rates of8%and8%[]. Although partial cystectomy is still not routinely recommended for all patients with invasive bladder cancer, some investigators feel that neo-adjuvant chemotherapy plus partial cystectomy may be an alternative to radical cystectomy for some patients. Suitable patients may include selected patients with monofocal lesions, which respond to chemotherapy. Such an approach may offer local control equivalent to that attained by radical cystectomy, but longer follow-up is clearly needed prior to any definitive statements regarding its efficacy. In % of the patients in this study, the bladder was preserved. Patients who had T o at the restaging TURB have done exceptionally well, with a median survival that has not yet been reached. These results are similar to those attained by the Memorial group. Of surgical candidates who received neo-adjuvant, (5%) achieved T o status at the restaging TURB. Of patients who had either TURB alone or partial cystectomy, (%) are alive, which includes 5 (58%) with an intact bladder. The authors concluded that the majority of T o patients preserved their bladder for up to years, and that cystectomy salvaged most, but not all relapsing patients []. This paper supports the feasibility of a bladder sparing approach in patients selected on the basis of response to chemotherapy. Although, no firm conclusions can be drawn from non-randomized studies, candidates for neo-adjuvant chemotherapy and bladder preservation are those who respond to a well-performed TURB and to neo-adjuvant chemotherapy [, ]. It is not known whether or not immediate cystectomy could have saved the patients whose bladders were preserved but who subsequently develop metastases. Distant metastases generally appear at 8 to months, suggesting that they may have been undetected on initial presentation []. In addition, in our study metastatic disease occurred more frequently in the group who had radical cystectomy immediately following chemotherapy. Bladder preservation remains a controversial topic and radical cystectomy is still regarded as the gold standard of treatment for muscle-invasive bladder cancer. Bladder sparing in selected patients on the basis of response to neo-adjuvant chemotherapy is a feasible approach which must be confirmed in prospective randomized trials. Future research will also concentrate upon molecular markers which can determine prognosis and upon improving chemotherapy [5]. Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on May 8,

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