EUROPEAN UROLOGY 60 (2011)

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Bladder Cancer Gemcitabine or Gemcitabine Plus Oxaliplatin in the First-Line Treatment of Patients With Advanced Transitional Cell Carcinoma of the Urothelium Unfit for Cisplatin-Based Chemotherapy: A Randomized Phase 2 Study of the French Genitourinary Tumor Group (GETUG V01) Stéphane Culine a, *, Aude Fléchon b, Aline Guillot c, Sylvestre Le Moulec d, Damien Pouessel a, Frédéric Rolland e, Alain Ravaud f, Nadine Houédé g, Laurent Mignot h, Florence Joly i, Stéphane Oudard j, Sophie Gourgou a a CRLC Val d Aurelle, Montpellier, France; b Centre Léon Bérard, Lyon, France; c Institut de Cancérologie de la Loire, Saint-Etienne, France; d Hôpital du Val de Grâce, Paris, France; e Centre René Gauduchau, Nantes, France; f CHU Saint-André, Bordeaux, France; g Institut Bergonié, Bordeaux, France; h Hôpital Foch, Suresnes, France; i Centre François Baclesse, Caen, France; j Hôpital Européen Georges Pompidou, Paris, France Article info Article history: Accepted August 29, 2011 Published online ahead of print on September 10, 2011 Keywords: Bladder cancer Chemotherapy Unfit for cisplatin Abstract Background: The optimal chemotherapy for patients with advanced transitional cell carcinoma of the urothelium who are not eligible for cisplatin remains to be defined. Objective: To assess the activity of gemcitabine alone (GEM) or in combination with oxaliplatin (GEMOX) in a randomized phase 2 trial. Design, setting, and participants: The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors criteria. The sample size was based on a two-stage Fleming design with p0 = 35% and p1 = 55%. At the end of the first stage designed to register 20 patients on each treatment arm, the observation of seven or more objective responses would have led to the inclusion of 30 more patients in each arm. Results and limitations: From July 2004 to March 2009, 44 patients in 10 centers were randomly assigned into the GEM or the, 22 on each treatment arm. The median age was 76 yr. Seven patients were included for a performance status (PS) of 2 only. The remaining 37 patients had an impaired renal function, 11 of whom also had a PS of 2. The median creatinine clearance was 45 ml/min (range: ml/min). The trial was closed after the first part because the did not reach the targeted objective response rate to proceed further. Conclusions: Oxaliplatin does not add any significant activity (in terms of response rates) compared with gemcitabine alone in patients with advanced transitional cell carcinoma of the urothelium who are ineligible for cisplatin. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Hôpital Saint-Louis, Department of Medical Oncology, 1, Avenue Claude Vellefaux, Paris, France. address: stephane.culine@sls.aphp.fr (S. Culine) /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 1252 EUROPEAN UROLOGY 60 (2011) Introduction Transitional cell carcinoma of the urothelium (TCCU) is a chemosensitive disease. In the late 1980s, the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) emerged as the standard regimen for advanced TCCU. In spite of overall response rates of approximately 50%, survival beyond 5 yr is rare with median survivals of about 14 mo in randomized trials [1 3]. This combination has also been associated with severe toxicity. During the past decade, the combination of gemcitabine and cisplatin, although not superior, has increasingly become a standard alternative to MVAC due to its better toxicity profile [4,5]. Because of cisplatin toxicity, enrollment in past and present trials exploring chemotherapy in TCCU required adequate renal function. However, it has long been appreciated that a large proportion of patients (up to 50%) are not eligible for cisplatin because of impaired renal function (IRF), poor performance status, or heavy comorbidities. The treatment of these so-called unfit patients is a subject of much controversy considering the number as well as the types of drugs to be delivered. The combination of gemcitabine and carboplatin (GC) has been studied in a number of phase 2 trials as well as in one phase 2/3 trial [6]. However, randomized phase 2 data suggest the inferiority of carboplatin-based chemotherapy compared with cisplatin-based chemotherapy [7 9]. In 2004, the French Genitourinary Tumor Group (GETUG) designed a randomized phase 2 trial to assess the activity of gemcitabine either alone (GEM) or combined with oxaliplatin (GEMOX) in unfit patients. Both agents have the main advantage of being used safely in patients with IRF (glomerular filtration rate [GFR] 30 ml/min). A supraadditive effect of GEMOX has been shown in several human cancer cell lines [10]. 2. Patients and methods concomitant, second, or previous malignancy except for basal cell skin cancer or carcinoma in situ of the cervix. All patients provided written consent Treatment schedule Treatment after randomization consisted of gemcitabine 1200 mg/m 2 intravenously (IV) on days 1, 8, and 15 every 4 wk () or gemcitabine 1000 mg/m 2 IV on days 1 and 15 and oxaliplatin 100 mg/m 2 IV on days 2 and 16 every 4 wk (). In both arms, gemcitabine was given with a fixed dose-rate infusion of 10 mg/m 2 per minute (ie, 120 min in arma and100 min inarmb). Cycles were notstarted unless neutrophils were 1500/ml and platelets were /ml. If patients required >2 wk for hematologic recovery or if there was grade 4 febrile neutropenia or grade 4 thrombocytopenia lasting >5 d or thrombocytopenia with active bleeding, treatment was continued with 75% of all drugs. Granulocyte colony-stimulating factor was reserved for patients with febrile neutropenia or grade 4 neutropenia >7 d. Oxaliplatin was given with 25% dose reduction in cases of grade 2 peripheral neuropathy and was stopped in cases of grade 3. Gemcitabine was withheld in cases of GFR <30 ml/min according to the CG formula. Other grade 3 (except for vomiting or alopecia) and 4 nonhematologic toxicities required 25% dose reduction of all drugs and withdrawal from the study, respectively. A total of six cycles of chemotherapy was planned. Beyond six cycles, the duration of treatment was the investigator s decision Treatment evaluation The primary objective of the study was the assessment of antitumor efficacy in terms of objective response rates. Tumor measurements were assessed with computed tomography scans before the start of treatment and after every two cycles. Responses were assessed according to the RECIST criteria. Toxicity was evaluated using Common Toxicity Criteria, v.2.0 [12]. During treatment, blood counts were determined weekly. Before each cycle, physical examination, blood count, blood chemistries (serum creatinine, AST/ALT, alkaline phosphatase, bilirubin, lactate dehydrogenase, calcium), and calculated creatinine clearance according to the CG formula were required. If the primary tumor was to be evaluated, a cystoscopy was performed before start of treatment and then every 2 mo. Treatment was continued until disease progression, unacceptable toxicity, or the decision of the investigator Patients 2.4. Statistical design The study was approved by the Board for the Protection of Persons Subjected to Biomedical Research of Montpellier and conducted in 10 French cancer centers from July 2004 to March Eligibility criteria included age >18 yr, histologically proven transitional cell carcinoma of the urinary tract (including renal pelvis, ureters, urinary bladder, and urethra), first-line chemotherapy for locally advanced (T4 or regional lymph nodes) or metastatic disease, ineligibility for cisplatin-based chemotherapy defined by either a performance status (PS) of 2 (Eastern Cooperative Oncology Group scale) and/or IRF (GFR <60 ml/min but >30 ml/min according to the Cockroft-Gault [CG] formula), measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) [11], no previous treatment with gemcitabine or oxaliplatin, adequate bone marrow function (white blood count >4000/ml; platelets > /ml) and liver function (aspartate aminotransferase/alanine aminotransferase [AST/ALT] <2 times the upper limit of normal [ULN] or <5 times ULN in the case of liver metastases and/or bilirubin <1.5 times ULN), and absence of any psychological, sociological, or geographic condition potentially hampering compliance with treatment and followup. Judged ineligible for the study were pregnant or lactating women, patients with brain (or other central nervous system) lesions, or The primary end point was the objective response rate (ORR) according to RECIST criteria. The sample size was based on a two-stage Fleming design with p0 = 35%, p1 = 55%, a = 0.05, and b = In the first stage, 20 patients would be registered on each treatment arm. At the end of the first stage, the observation of seven objective responses or more in the would have led to the inclusion of 30 more patients in each arm. Inactivity would correspond to six or fewer objective responses and would have led to stopping the trial because of an inadequate ORR in the. Patients were randomized at the Montpellier Cancer Center to receive gemcitabine or gemcitabine plus oxaliplatin with stratification for PS (0 vs 1 vs 2) and renal function (GFR between 30 and 59 ml/min vs 60 ml/min). Randomization was performed by the block random method. Statistical analyses were performed using Stata v.10 software (StataCorp, College Station, TX, USA). 3. Results From July 2004 to March 2009, 44 patients in 10 centers of the GETUG were randomly assigned into the or

3 EUROPEAN UROLOGY 60 (2011) Table 1 Patient characteristics Characteristic the, 22 on each treatment arm. Initial characteristics were overall well balanced between the two arms except for prognostic factors defined according to the Memorial Sloan-Kettering Cancer Center (MSKCC) classification [13] (Table 1). The study clearly involved an elderly patient population with a median age of 76 yr (range: yr). Regarding stratification factors, seven patients were included for a PS of 2 only. The remaining 37 Table 2 Stratification factors Factor Sex (%) Male 16 (73) 20 (91) Female 6 (27) 2 (9) Age, yr Median Range Primary tumor (%) Bladder 16 (73) 15 (68.5) Upper urinary tract 5 (22.5) 6 (27) Urethra 1 (4.5) 1 (4.5) Previous treatments (%) Surgery 21 (95.5) 20 (91) Chemoradiotherapy 0 1 (4.5) Adjuvant chemotherapy 1 (4.5) 1 (4.5) Extent of disease (%) Locally advanced 2 (9) 0 (0) Metastatic 20 (91) 22 (100) Performance status (%) 0 2 (9) (55) 12 (55) 2 8 (36) 10 (45) Creatinine clearance, ml/min Median Range No. of metastatic sites (%) 0 1 (4.5) 0 (0) 1 11 (50) 14 (64) 2 6 (27.5) 4 (18) >2 4 (18) 4 (18) Metastatic sites (%) Lymph nodes 12 (55) 15 (68.5) Lung 7 (31.5) 8 (36) Liver 9 (41) 5 (22.5) Others 7 (31.5) 6 (27) MSKCC risk factors (%) [13] 0 4 (18) 7 (32) 1 14 (64) 6 (27) 2 4 (18) 9 (41) Hemoglobin, g/dl Median Range GEM = gemcitabine; GEMOX = gemcitabine plus oxaliplatin; MSKCC = Memorial Sloan-Kettering Cancer Center. PS = 2 only (%) 3 (13.5) 4 (18) GFR <60 ml/min only (%) 14 (64) 12 (55) PS = 2 and GFR <60 ml/min (%) 5 (22.5) 6 (27) GEM = gemcitabine; GEMOX = gemcitabine plus oxaliplatin; PS = performance status; GFR = glomerular filtration rate. patients had an impaired renal function, 11 of whom also had a PS of 2 (Table 2). The median creatinine clearance was 45 ml/min (range: ml/min). One patient in the GEM arm was not treated because of rapidly progressive disease that led to death. Therefore 43 patients were included in the intent-to-treat analysis and fulfilled the criteria for toxicity and activity assessment, respectively (Fig. 1) Treatment delivery and toxicity The median number of cycles was three (range: one to eight) in the and three (range: one to six in the ) (Table 3). Nine patients (four in the and five in the ) received only one cycle of chemotherapy. Reasons for early discontinuation were toxicity (one patient who died from treatment-related Staphylococcus pneumonia in the ) or rapidly progressive disease (eight patients). Seven patients in each arm received six cycles. The number of cycles with dose reduction was 15 of 79 (19%) in the and 11 of 78 (14%) in the. Chemotherapy was delayed in 19% and 25% of cycles in the GEM and, respectively. The median relative dose intensity was 0.8 for gemcitabine in the. The median relative dose intensities of gemcitabine and oxaliplatin were 1.0 and 0.9 in the, respectively. Regarding toxicity, a greater percentage of patients experienced grade 3 4 neutropenia and anemia in the, whereas nausea and peripheral neuropathy were more frequent in the (Table 4) Activity Because chemotherapy was stopped after the first cycle in 9 patients, 34 patients (17 in each arm) had a radiologic assessment after two cycles of chemotherapy. Nine confirmed partial responses were observed in the, for an overall response rate of 43% (95% confidence interval [CI], 22 66). One complete and five partial responses were confirmed in the for an overall response rate of 27% (95% CI, 11 50) (Table 5). According to the statistical design, the trial was closed after the first part because the had not reached the targeted ORR to proceed further. Median progression-free survival was 3.8 mo in the and 3.4 mo in the. After a median follow-up of 21 mo, 39 patients had died. Median survival was 5.4 mo (95% CI, ) in the and 8.1 mo (95% CI, ) in the (Fig. 2). Median survival of patients with IRF only or PS of 2 only was 10 mo (95% CI, ) and 2.7 mo (95% CI, ), respectively (Fig. 3). 4. Discussion The management of unfit patients with advanced TCCU is a daily challenge for uro-oncologists because the optimal drug regimen along with the true impact of chemotherapy on survival remains undefined. In 2004, the GETUG designed a randomized phase 2 study with the primary goal of assessing the activity of a one-drug regimen (GEM)

4 1254 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 60 (2011) Patients randomly allocated to treatment (n = 44) Allocated to GEM n = 22 Eligible and started allocated treatment n = 21 Allocated to GEMOX n = 22 Eligible and started allocated treatment n = 22 Did not start treatment Died of disease before starting chemotherapy n = 1 Included in response and toxicity analysis n = 21 Excluded Did not start treatment n = 1 Included in toxicity analysis n = 22 Included in response analysis n = 22 Fig. 1 Consolidated Standards of Reporting Trials diagram. versus a two-drug regimen (GEMOX) in this population. The activity of gemcitabine alone in unfit patients was unknown, and its combination with oxaliplatin was promising in terms of activity in preclinical models and toxicity profile in other human tumors. The hypothesis was that the confirmation of a higher response rate in the could be the basis for a randomized phase 3 Table 4 Toxicity (n = 21) Table 3 Treatment delivery Chemotherapy (n = 21) No. of cycles (%) 1 4 (19) 5 (22.5) 2 4 (19) 3 (13.5) 3 2 (10) 3 (13.5) 4 2 (10) 4 (18) 5 1 (5) 0 (0) 6 7 (34) 7 (31.5) 7 0 (0) 0 (0) 8 1 (5) 0 (0) Duration, d Median Range Dose intensity, mg/m 2 per week (range) Gemcitabine 730 ( ) 477 ( ) Oxaliplatin NA 47 (0 51) Relative dose intensity (range) Gemcitabine 0.8 (0.25 1) 1.0 ( ) Oxaliplatin NA 0.9 (0 1.03) Reason for stopping treatment (%) Progressive disease 12 (57) 12 (55) Toxicity 1 (5) 2 (9) End of treatment 5 (24) 5 (22.5) Investigator s decision 3 (14) 3 (13.5) GEM = gemcitabine; GEMOX = gemcitabine plus oxaliplatin; NA = not applicable. Neutropenia (%) Grade 3 8 (38) 6 (27) Grade 4 5 (24) 1 (4.5) Febrile neutropenia 3 (14) 2 (9) Thrombopenia (%) Grade 3 3 (14) 4 (18) Grade 4 1 (5) 1 (4.5) Anemia (%) Grade 2 11 (52) 15 (68.5) Grade 3 9 (43) 3 (13.5) Nausea (%) Grade 2 4 (19) 9 (41) Grade 3 0 (0) 1 (4.5) Vomiting (%) Grade 2 2 (10) 3 (13.5) Grade (4.5) Diarrhea (%) Grade 1 5 (24) 9 (41) Grade 2 3 (14) 0 (0) Mucositis (%) Grade 1 3 (14) 2 (9) Grade 2 1 (5) 2 (9) Peripheral neuropathy (%) Grade 1 1 (5) 6 (27) Grade (31.5) Grade (9) Asthenia (%) Grade 1 5 (24) 5 (22.5) Grade 2 11 (52) 6 (27) Grade 3 4 (19) 7 (31.5) Grade (4.5)

5 EUROPEAN UROLOGY 60 (2011) [(Fig._3)TD$FIG] Table 5 Responses (n = 21) Complete response (%) 0 1 (4.5) Partial response (%) 9 (43) 5 (23) Stable disease (%) 3 (14) 6 (27) Progressive disease (%) 5 (24) 8 (36.5) Nonevaluable * (%) 4 (19) 2 (9) * Nonevaluable patients were considered as having progressive disease. trial comparing the impact of GEMOX versus GC the most frequently used combination in this setting on overall survival. Commonly used regimens in bladder cancer for gemcitabine [14] and pancreatic cancer for GEMOX [15] were chosen. However, although toxicity appeared quite manageable, the activity of GEMOX turned out to be disappointing because the response rate did not reach the targeted objective, leading to discontinuation of the trial after the first stage. The activity and toxicity of oxaliplatin in combination with gemcitabine in advanced TCCU patients were reported in two previous phase 2 studies. In a French monocentric study, gemcitabine (1500 mg/m 2 ) and oxaliplatin (85 mg/m 2 ) weregivenondays1and15ofa28-dcyclein30patients fit for cisplatin [16]. Most patients had good PS and normal renal function. A response rate of 47% with a median progression-free survival of 7 mo and an overall survival of 15 mo along with minimal toxicity were observed. In Spain, 46 unfit patients were treated in a multicenter study with a different schedule: gemcitabine 1200 mg/m 2 on days 1 and 8 and oxaliplatin 100 mg/m 2 on day 8 of a 21-d cycle [17]. Median age was 69 yr; median creatinine clearance was 50 ml/min. Half of the patients had a PS of 2. Hematologic toxicity was mild with grade 3 4 peripheral neuropathy occurring in 4% of patients. Only 20 patients completed six cycles of treatment. Ten patients received only one cycle because of rapid disease progression. The overall response rate was 48%. Median time to disease progression was 5 mo; median overall survival was 6.5 mo. In the present study, the delivery scheme for gemcitabine and oxaliplatin [(Fig._2)TD$FIG] Probability Number at risk GEM Months GEMOX GEM GEMOX Fig. 2 Overall survival according to treatments. Probability Months Number at risk GFR< PS2 and GFR< PS GFR<60 PS2 and GFR<60 PS2 Fig. 3 Overall survival according to stratification factors. GFR = glomerular filtration rate; PS = performance status. was similar to that used in the French trial, with slightly different doses of drugs. However, the patient population was close to that included in the Spanish study, with even older patients (median age: 76 yr) and a lower median creatinine clearance (45 ml/min). The response rate was about half as much as that reported in the trials previously described, whereas median progression-free survival and overall survival were in the range of results expected in a population of unfit patients. Once again a significant proportion of patients received only one cycle of treatment, mainly because of rapid progression of the disease. Regarding the activity of gemcitabine alone in unfit patients, the present trial clearly confirmed an activity with a 43% response rate but a disappointing median survival of 5 mo. In an Italian population of 25 elderly patients (median age: 76 yr; PS of 2 in half of them), a similar response rate of 45% with a median overall survival of 8 mo was observed [18]. Results from the current trial suggest that oxaliplatin does not add any significant activity as compared with gemcitabine alone in patients with advanced TCCU who are ineligible for cisplatin. However, several limitations related to the design of the study must be discussed. The first one is related to the primary end point, that is, the objective response rate and its correlation with survival. Obviously the small number of patients precludes drawing any firm conclusion regarding the respective impact on overall survival of the regimens used. Nonetheless, the progression-free survivals were quite similar. The second limitation concerns the imbalance of prognostic factors between the two arms. In the MSKCC classification, poor PS and the presence of visceral metastases were shown to be independent adverse prognostic factors [13]. The fact that patients were actually stratified for PS only in the present study could have interfered with the interpretation of results. A final limitation is related to the lower dose intensity of gemcitabine delivered in the. Although mandatory because of the combination with oxaliplatin, the reduction in gemcitabine doses could explain, at least in part, the disappointing results observed with the GEMOX regimen.

6 1256 EUROPEAN UROLOGY 60 (2011) So what is the optimal chemotherapy regimen in unfit patients with advanced TCCU in 2011? In daily practice, GC certainly is the most frequently used combination. In the only randomized phase 2/3 trial reported so far in unfit patients, GC was compared with a combination of carboplatin with methotrexate and vinblastine (M-CAVI) [6,19]. Among 238 patients, reasons for cisplatin ineligibility were PS alone in 18%, IRF alone in 55%, and PS and IRF in 27%. The median number of cycles was five and four, respectively. The confirmed response rate was superior in the GC arm (43% vs 25%; p = 0.01). With a median follow-up of 4.5 yr, the median survivals were not statistically different (9.3 mo in the GC arm and 8.1 months in the M-CAVI arm). Severe acute toxicities (SATs) were observed in 9% and 21% of patients, respectively. The rate of SATs was particularly high in patients with PS of 2 and IRF and in patients with adverse prognostic factors according to the MSKCC classification. 5. Conclusions In 2011, there is no standard chemotherapy to recommend for patients with advanced TCCU unfit for cisplatin. The expected median survival is clearly poorer (<1 yr)than that reported in fit patients (14 mo in randomized trials). This could be related to the inability to deliver cisplatin and/or to its own adverse prognostic value. From the present trial, it can be concluded that the addition of oxaliplatin to gemcitabine does not improve the activity as compared with gemcitabine alone, at least in terms of response rate. Patients with a PS of 2 and IRF in particular should be offered gemcitabine alone or best supportive care. In other patients, clinical trials using consensus inclusion criteria [20] should be designed with new cytotoxic drugs or investigational drugs with new mechanisms of action. In randomized trials, the combination of gemcitabine and carboplatin probably would be the most acceptable standard arm. Author contributions: Stéphane Culine had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Culine. Acquisition of data: Culine, Fléchon, Guillot, Le Moulec, Pouessel, Rolland, Ravaud, Houédé, Mignot, Joly, Oudard, Gourgou. Analysis and interpretation of data: Culine, Gourgou. Drafting of the manuscript: Culine, Gourgou. Critical revision of the manuscript for important intellectual content: Culine, Fléchon, Guillot, Le Moulec, Pouessel, Rolland, Ravaud, Houédé, Mignot, Joly, Oudard, Gourgou. Statistical analysis: Gourgou. Obtaining funding: Culine. Administrative, technical, or material support: Gourgou. Supervision: Culine, Gourgou. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: Eli Lilly helped design and conduct the study. References [1] Logothetis CJ, Dexeus FH, Finn L, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8: [2] Saxman SB, Propert KJ, Einhorn LH, 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. 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