Overview of gemcitabine triplets in metastatic bladder cancer

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1 Critical Reviews in Oncology/Hematology 45 (2003) 191/197 Overview of gemcitabine triplets in metastatic bladder cancer Ronald de Wit a, *, Joaquim Bellmunt b a Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands b Hospital General Universitari Vall d Hebron, Barcelona, Spain Accepted 19 June 2002 Contents 1. Introduction New active agents and combinations; single agents and doublets Gemcitabine triplets Conclusions Reviewers References Biography Abstract For more than a decade the MVAC regimen has been gold standard chemotherapy in bladder cancer, albeit that the toxicity associated with this therapy hampered its use in many of the typical elderly patients with metastatic disease. New active agents have been identified, combinations of these new agents with platinum compounds (doublets) followed, and results have become available of a phase III randomized trial of the gemcitabine and cisplatin doublet versus MVAC, that has revealed an efficacy-toxicity profile in favor of the gemcitabine/cisplatin regimen. During the conduct of this study, investigators in Spain and in the United States have incorporated both gemcitabine and paclitaxel in either cisplatin- or carboplatin based triplet regimens that, albeit thus far only in phase II studies, have indicated notable activity and favorable median survival figures, particularly in patients with visceral disease. A randomized study of the paclitaxel/cisplatin/gemcitabine triplet versus gemcitabine /cisplatin is ongoing. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bladder cancer; Urothelial cell cancer; Chemotherapy; Gemcitabine; Paclitaxel; Cisplatin 1. Introduction In the 1980s the chemosensitivity of urothelial cell cancer was recognized when phase II studies had demonstrated activity of cisplatin, methotrexate, adriamycin, vinblastine and 5FU in advanced and/or metastatic disease. The next step to the development of effective therapy was to combine these most effective * Corresponding author. Tel.: / ; fax: / address: wit@onch.azr.nl (R. de Wit). agents known at that time into two-, three-, and fourdrug combinations [1]. Regimens that were developed and tested were two-drug combinations such as cisplatin and methotrexate (CM), and the three-drug regimens of cisplatin, methotrexate, vinblastine (CMV) and cisplatin, cyclophosphamide and adriamycin (CISCA). In 1985 investigators from Memorial Sloan Kettering Cancer Center reported on a four-drug regimen of cisplatin, doxorubicin, methotrexate and vinblastine (MVAC) [2]. The initial study on 24 patients gave an overall response rate of 71%. In an updated report on a larger series of 121 evaluable patients, the overall /02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S ( 0 2 )

2 192 R. de Wit, J. Bellmunt / Critical Reviews in Oncology/Hematology 45 (2003) 191/197 response rate to MVAC was 72%, with a clinical complete response rate to chemotherapy alone of 18% and an additional 11% rendered disease free with postchemotherapy surgery [3]. With increasing experience the overall response rate became slightly lower, ranging from 40 to 57%, with complete response rates 13/19% [4/6], but the median survival of 12/13 months was maintained. Subsequent randomized phase III trials demonstrated the superiority of MVAC compared with single agent cisplatin, and with CISCA, both in terms of response rates and overall survival [7,8]. Hence, MVAC was adopted as the gold standard chemotherapy regimen. Unfortunately MVAC therapy is associated with significant morbidity. The median age of patients presenting with metastatic urothelial cell cancer is 70 years, and due to smoking as an associated risk factor many patients have pulmonary and/or cardiovascular diseases. In addition, many patients have an impaired renal function, which hampers the safe administration of this type of chemotherapy. Even in patients who are still in good clinical condition MVAC causes clinical significant myelosuppression with up to a 25% incidence of granulocytopenic fever at any time during the course of MVAC therapy, up to a 50% grade 2/3 mucositis, and a 3% drug-related mortality [2 /8,11,12]. Previous studies have also shown that impaired performance status, weight loss, high alkaline phosphate, and metastases to liver, lung and bone are adversely related with response to chemotherapy [7,9]. In a report on 199 patients treated with MVAC at Memorial Sloan Kettering Cancer Center, the investigators were able to identify performance status and the presence of visceral metastases as the two most important independent prognostic factors that had an impact on median survival [10]. Median survival times for patients who had zero, one, or two risk factors were 33, 13.4, and 9.3 months, respectively (P /0.0001). Overall, long term follow-up of M-VAC treated patients shows that only 3.7% of patients experience more than 6 years disease free survival [11,12]. Therefore, because both impaired performance status is adversely related with treatment outcome, and the associated increased toxicity of the treatment, the use of MVAC in the characteristically poor performance status patients, particularly if there are visceral metastases as well, is to be discouraged. In view of the toxicity associated with MVAC, particularly in patients with impaired performance status and/or impaired renal function carboplatin has been substituted for cisplatin in various combinations to produce a more convenient, less toxic regimen, although carboplatin and carboplatin-based chemotherapy have never been tested for therapeutical equivalence. Single agent activity of carboplatin derived from pooled data from seven phase II studies is 12% (range, 6 /21%), [13,14] and this appears slightly inferior to that obtained with cisplatin, which gave an overall response rate of 17% (range, 9 /31%) in more recent trials [7]. Combinations of carboplatin with methotrexate and vinblastine (Carbo-MV and M-CAVI) have shown response rates of 30/40%, and a median survival of 8/10 months [14,15], and again these results appear inferior to those obtained with MVAC [16]. Of note, some of these inferior results may be explained by higher percentages of patients with less favorable prognostic factors in the carboplatinbased chemotherapy studies. Particularly disproportionate percentages of visceral metastases and/or impaired performance status patients may have had a considerable impact on the outcome in carboplatin-based phase II trials [10]. As a result, in the lack of randomized data that would be the only means to answer a noninferiority issue, the choice for a carboplatin based regimen will mainly depend either on concerns for cisplatin based therapy in patients with mild or moderate renal function impairment, or strong preferences for outpatient therapy. 2. New active agents and combinations; single agents and doublets In the past decade, substantial single agent activities have been demonstrated for the taxanes paclitaxel and docetaxel, and gemcitabine [17 /27]. Responses in phase II trials with either paclitaxel or docetaxel in patients not previously treated with chemotherapy ranged from 25 to 40%, which compare favorably with the 17% obtained with single-agent cisplatin [17,20]. Unfortunately, in patients who have previously been treated with cisplatin-based chemotherapy these agents appear considerably less effective [18,19,21]. Initial phase II studies of two-drug combinations of docetaxel, or paclitaxel, with cisplatin, have shown activity in untreated patients, with response rates that are in the same range as is obtained with MVAC, [28/33], but to date there are no comparative data with MVAC. Several phase II studies have tested the combination of paclitaxel with carboplatin [34 /39], but again, as several of these studies showed median survival figures as low as 8.5 /9.5 months [37 /39], it can be questioned whether carboplatin should be substituted for cisplatin in those patients who are potentially fit to tolerate a cisplatinbased regimen. Gemcitabine is a new antimetabolite that has been tested in one phase I and five phase II studies in locally advanced and metastatic urothelial cell cancer [22 /27]. Interestingly, the overall 27% response rate appears not to be influenced by previous cisplatin-based chemotherapy, suggesting that there is no complete cross-resistance between these agents. Moreover, in view of evidence of synergistic effects between cisplatin and gemcitabine

3 R. de Wit, J. Bellmunt / Critical Reviews in Oncology/Hematology 45 (2003) 191/ Table 1 Phase II and III trials of GC doublet in bladder cancer Agents Schedule interval (days) Patients (N ) RR (%) MST (month) Reference Gemcitabine (mg/m 2 ) Cisplatin (mg/m 2 ) 1000 D1, 8, D1, 8, [42] 1000 D1, 8, 15 75/ [44] 1000 D1, 8, [43] 1200 D1, NA [46] 1000 D1, 8, a [45] a Denotes 203 patients on gemcitabine-cisplatin of the randomized phase III study of GC versus MVAC. [40,41] and the favorable toxicity profile of gemcitabine, the two-drug combination of gemcitabine and cisplatin (GC) was a next logical step. Three phase II studies of the GC combination have demonstrated the feasibility of the 2-drug combination and have produced response rates similar to that obtained with MVAC [42 /44]. The two key reference studies that used cisplatin at 21- or 28- day intervals were recently published. One study was conducted in the United States [44], the other study by investigators in Canada [43]. Overall response rates in these studies were 41 and 57%, respectively, and median survival was 14.3 and 13.2 months, respectively, Table 1. Based upon the results obtained with this two-drug combination, from 1996 to 1998 a large multinational phase III trial comparing GC with MVAC was conducted [45]. The study was designed to detect a 4 months improvement in the median survival, and for this purpose 400 patients were required. A total of 405 patients were entered. With a median follow-up of 19 months, overall survival was found to be similar on both arms, GC 13.8, MVAC 14.8 months (Hazard Ratio 1.04, 95% CI 0.82 /1.32, P /0.75), as were time to progressive disease (7.4 months on both arms), and overall response (GC, 49%; MVAC, 46%). Fewer patients on GC, compared with MVAC patients, had grade 3/4 neutropenia (71 vs 82%, respectively), neutropenic fever (2 vs 14%), neutropenic sepsis (1 vs 12%), and grade 3/4 mucositis (1 vs 22%). The toxic death rate was 1% on GC and 3% on MVAC. More GC than MVAC patients had grade 3/4 anemia and thrombocytopenia, but this did not result in clinical sequela. Due to the higher incidence of neutropenic fever and mucositis more hospital admissions were required on MVAC (49 admissions for a total of 272 days) as compared with GC (nine admissions for a total of 33 days). Although the study failed to detect a significant difference in survival, which was the primary endpoint after all, the favorable risk-benefit ratio justifies considering these results for the lesser objective of establishing therapeutical non-inferiority. The adjusted hazard ratio for survival, adjusted for prognostic factors, as was prespecified in the protocol for the original primary endpoint in the study, was 0.95, 95% CI 0.74/1.22. With the upper bound of the confidence interval of the adjusted HR for survival close to 1.2 non-inferiority is generally assumed by registration authorities. Therefore, GC can be considered a valuable alternative for the vast majority of patients with metastatic bladder cancer who may have an equal gain of the chemotherapy with the benefit of fewer side effects. 3. Gemcitabine triplets In view of the activity of gemcitabine and the taxanes, the partially non-overlapping toxicities of these agents and their different mechanisms of action, combining these compounds, incorporating platinum as the backbone in a three-drug regimen was the next logical step, investigators in Spain have conducted phase I/II trials of the triplet combination of paclitaxel, cisplatin, gemcitabine (PCG) in a total of 61 patients [47]. The investigators began their study in a formal phase I setting, escalating the dose levels of both paclitaxel and gemcitabine, administered weekly, days 1 and 8, with a fixed dose cisplatin 70 mg/m 2, day 1, every 3 weeks, Table 2. At dose level 4, with paclitaxel at 90 mg/m 2 weekly, grade 3 asthenia was determined to be the dose limiting toxicity. The asthenia typically occurred in the first or second cycle, and was felt to hamper the safe administration of six cycles. Therefore, dose level 3 was chosen for the purpose of the subsequent phase II study. With this schedule- and dose intensity, asthenia, as well as myelotoxicity were manageable. G-CSF was used only for secondary prophylaxis in patients in whom either neutropenic fever or grade 4 neutropenia had been observed in the preceding cycle. The phase I study (15 patients) and phase II study (46 evaluable patients) together gave an overall response rate of 78% and a median survival time for the phase I and the phase II part of the study of 24 and 16 months, respectively. In view of these results, the EORTC, the South West Oncology Group (SWOG), the National Cancer Institute of Canada (NCIC), the Radiation Therapy Oncology Group (RTOG), the Spanish Oncology Genito Urinary Group (SOGUG) and several other European

4 194 R. de Wit, J. Bellmunt / Critical Reviews in Oncology/Hematology 45 (2003) 191/197 Table 2 PCG, phase I study dose levels Dose levels Paclitaxel (mg/m 2 ) (days 1, 8) Gemcitabine (mg/m 2 ) (days 1, 8) Cisplatin (mg/m 2 ) (day 1) Level Level Level Level Bellmunt et al. [47]. collaborative groups have begun the largest randomized trial ever designed in metastatic bladder cancer to compare the three-drug regimen of PCG with the twodrug combination of GC. A total of 610 patients will be needed to detect a difference in survival of 4 months (from 14 to 18 months). The study is restricted to patients with a good clinical performance status (WHO- PS 0 or 1) and creatinine clearance of at least 60 ml/min. Based on their previous experience with the combination of carboplatin and paclitaxel in bladder cancer [38] investigators at Wayne State University, Detroit incorporated gemcitabine in the carboplatin/paclitaxel combination in a phase II trial in 49 previously untreated patients with advanced urothelial malignancy and normal renal function [48]. In this study gemcitabine 800 mg/m 2, days 1 and 8, combined with paclitaxel 200 mg/m 2 day 1 and carboplatin AUC 5, day 1, was given every 3 weeks, Table 3. This regimen was well tolerated. With neutropenia as the major side effect, and 272 cycles delivered, there were no more than four episodes of febrile neutropenia (1.4%). Asthenia was not reported to be a major toxic side effect. A total of 47 patients were assessable for response, of whom 15 obtained a CR and 15 obtained a PR, for an overall response rate of 68%. The median survival was 14.7 months. Interestingly, in both these gemcitabine triplets responses were seen at all sites, including visceral metastases, and the median survival in the cohort of patients with visceral disease was still as high as 14.3 and 11.4 months. Table 4 shows, patients characteristics and the main prognostic factor distributions for the two studies. The overall response rate in patients with visceral metastases was 66% for the cisplatin-based regimen and 68% for the carboplatin-based therapy, and these figures compare favorably with historical data from MVAC series, that showed response rates as low as 20% Table 4 Main patient characteristics and prognostic factors of the two gemcitabine containing triplet studies P carbo G study (n/49) PCG study (n/58) Median age WHO-PS 0/1/2 24/20/5 21/34/6 % Metastatic % Visceral mets %Overall response (OR) % Complete response (CR) %ORvisceral Median survival in visceral disease (month) in patients with visceral disease. Also the median survival time for patients with visceral disease who received the PCG-triplet regimen of 14.3 months was superior to that observed with MVAC series, which without exception has been less than 10 months in the patient subsets with visceral disease. Unlike with conventional chemotherapy regimens, such as MVAC, there is no data available on key predictive factors for response and survival with these novel agents. Since this information is needed for selection of patients who are likely to benefit from these new combinations and for stratification purposes in randomized trials, an analysis of the predictive factors for response and survival with the regimen containing PCG has been performed [49]. The pretreatment characteristics analyzed were age, gender, ECOG performance status, histopathology (pure transitional versus other), visceral (liver, lung or bone) metastasis, number of sites of disease, LDH and hemoglobin. The factors that were associated with decreased survival in univariate analysis were performance status /0, presence of visceral metastasis, and more than one site of malignant disease. Table 3 Gemcitabine containing triplets, schedules Regimen Schedule interval (days) Reference Gemcitabine (mg/m 2 ) Paclitaxel (mg/m 2 ) Platinum compound (mg/m 2 ) 1000 D1, 8 80 D1, 8 Cisplatin 70 D1 21 [47] 800 D1, D1 Carboplatin AUC 5 D1 21 [48]

5 R. de Wit, J. Bellmunt / Critical Reviews in Oncology/Hematology 45 (2003) 191/ In multivariate models, performance status (P /0.044), and visceral disease (P /0.008) showed independent statistical significance for decreased survival. Patients were then grouped based on these two independent prognostic factors; i.e. performance status /0 and presence of visceral metastasis. Median survival in the groups of patients with zero, one or two of these risk factors were 32.8, 17 and 9.6 months, respectively (P / ). The median overall survival was remarkably similar for each category compared to the reported in the initial MVAC series reported by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York (10); i.e. zero risk factors groups had a median overall survival of 32.8 months for PCG and 33.0 for MVAC; one risk factor groups had a median overall survival of 18 months for PCG and 13.4 for MVAC; and two risk factors groups had a median overall survival of 10.6 months for PCG and 9.3 for MVAC. More data are needed to establish the potential of these gemcitabine based triplet regimens, both for survival improvement in the unselected advanced bladder cancer population, and particularly for patients with poor prognostic features. Although, as mentioned earlier, cisplatin single agent and cisplatin-based MVAC type of chemotherapy appears slightly superior to the carboplatin counterparts, it can be questioned whether such modest differences are clinically relevant if the platinum agent is combined with multiple new agents, each with a single activity superior to that of the platinum compound. Therefore, at the present time, the choice to prefer the carboplatin-containing triplet over the cisplatin counterpart will depend on demands for outpatient treatment, personal preferences, and concern to administer cisplatin in patients with mildly impaired renal function. 4. Conclusions In conclusion, at the present time the GC doublet is the only regimen that has demonstrated similar efficacy in randomized comparison with MVAC. In view of its favorable toxicity profile the GC regimen can be considered a valuable alternative to MVAC. Other cisplatin-based doublets, and carboplatin-based regimens have not been tested in randomized studies and should not readily be adopted as alternative treatment options in unselected patient populations who are potentially fit to tolerate cisplatin. Patient-tailored decisions, considering renal function impairment in individual patients, however, may very well include the use of carboplatin-based therapy options. Of note, the results reported by the investigators from Wayne State University, using the carboplatin-based triplet, were obtained in unselected patients, all of whom basically had preserved renal function, and most of whom had performance status 0 or 1. As chemotherapy dose-intensity which can be achieved may considerably depend on factors such as renal function, performance status, and comorbidity, one should be cautious to adopt the carboplatin-based triplet in the unfit patient category. As an example, we have recently reported a dose-finding study of the carboplatin-gemcitabine doublet, that was conducted in patients who were selected for either impaired renal function, or impared performance status (WHO-PS 2) [50]. At a carboplatin AUC dose of 5, which was the dose that could easily be administered in basically fit patients with bladder cancer and other solid tumors, pronounced myelotoxicity was observed, that prompted the use of a lower dose of carboplatin in our study. Both the gemcitabine and paclitaxel containing cisplatin triplet and the carboplatin triplet have shown very high overall response rates and survival figures in phase II studies, with notable efficacy in patients with visceral disease. The results in these studies warrant these triplet regimens to be compared with the existing standard chemotherapy regimens of either GC or MVAC. 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7 R. de Wit, J. Bellmunt / Critical Reviews in Oncology/Hematology 45 (2003) 191/ [41] Van Moorsel CJ, Veerman G, Vermorken JB, et al. Mechanisms of synergism between gemcitabine and cisplatin. Source Adv Exper Med Biol 1998;431:581/5. [42] Von der Maase H, Andersen L, Crino L, et al. Weekly gemcitabine and cisplatin combination therapy in patients with transitional cell carcinoma of the urothelium: a phase II clinical trial. Ann Oncol 1999;10:1461/5. [43] Moore MJ, Winquist EW, Murray N, et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1999;17:286/2881. [44] Kaufman D, Raghavan D, Carducci M, et al. Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 2000;18:1921/7. [45] Von der Maase H, Hansen SW, Roberts JT, 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;17:3068/77. [46] Lippert CM, Koser MF. Gemcitabine and cisplatinum in a 21 day schedule in the first-line treatment of locally advanced or metastatic transitional cell carcinoma; preliminary results of a phase II study. Proc Am Soc Clin Oncol 2001;20:196 (abstr. 783). [47] Bellmunt J, Guillem V, Paz-Ares L, et al. Phase I/II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. J Clin Oncol 2000;18:3247/55. [48] Hussain M, Vaishampayan U, Du W, et al. Combination carboplatin, paclitaxel and gemcitabine. Is an active teatment for advanced urothelial carcinoma. J Clin Oncol 2001;19:2527/ 33. [49] Bellmunt J, Albanell J, Paz-Ares L, et al. Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine, Cancer 2002 (in press). [50] Bellmunt J, Wit de R, Albanell J, et al. A feasibility study of carboplatin with fixed dose of gemcitabine in unfit patients with advanced bladder cancer. Eur J Cancer 2001;37:2212/5. Biography R. de Wit, medical oncologist. Chairman of the chemotherapy committee of the EORTC Genito-Urinary Group.