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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

From the Aarhus University Hospital, Aarhus; Herlev Hospital, University of Copenhagen, Herlev, Denmark; Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle; St Bartholomews Hospital, London, United Kingdom; University of Torino, St Luigi Hospital, Orbassano; Santa Chiara Hospital, Pisa, Italy; The Princess Margaret Hospital, Toronto, Canada; National Institute of Oncology, Budapest, Hungary; Department of Urology, Bonn University, Bonn; Krankenhaus Nordwest, Frankfurt; Klinikum Ludwigshafen, Ludwigshafen, Germany; Centre Eugene Marquis, Rennes, France; Hospital Ciudad De Jaen, Jaen, Spain; Karolinska Hospital, Stockholm, Sweden; and Eli Lilly and Company, Indianapolis, IN.

Address reprint requests to Hans von der Maase, MD, DMSc, Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus C; email hvdm{at}oncology.dk

ABSTRACT

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium.

PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m² days 1, 8, and 15; cisplatin 70 mg/m² day 2) or standard MVAC every 28 days for a maximum of six cycles.

RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue.

CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

BLADDER CANCER IS a common cancer worldwide whose incidence continues to increase. It is estimated that there are 261,000 cases of bladder cancer resulting in 115,000 deaths worldwide.¹ The most frequent histologic type is transitional-cell carcinoma (TCC). Without treatment, patients with locally advanced or metastatic bladder cancers die from their disease. Before the development of effective chemotherapy, median survival rarely exceeded 3 to 6 months. With combination chemotherapy, median survival times of 1 year can now be achieved. However, long-term survival is rare. Most combination chemotherapy used for the treatment of bladder cancer is cisplatin-based. The most commonly used combination is methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), which was developed about 15 years ago.² In a multicenter, phase III trial, treatment with MVAC was shown to provide a survival advantage over treatment with cisplatin alone (median survival, 12.5 months v 8.2 months, respectively.³ In another randomized study, MVAC was shown to be superior to a combination of cisplatin, cyclophosphamide, and doxorubicin, with higher response rates and longer survivals (median survival, 48 weeks v 40 weeks, respectively).⁴ MVAC is considered the standard chemotherapeutic regimen for metastatic bladder cancer throughout the United States, Europe, Canada, and Japan.

Treatment with MVAC, however, is associated with substantial toxicity, including neutropenia and its infectious complications, and significant mucositis causing difficulty in eating and drinking, which can lead to weight loss and weakness. Nausea and vomiting, renal, cardiac, and neurologic toxicities are also seen. These side effects are especially problematic for older patients, who often present with comorbidities and who comprise a significant proportion of the population of patients with TCC. Additionally, MVAC is associated with a toxic death rate of 3% to 4%,^3,5 and the long-term, disease-free survival rate with MVAC therapy is only 3.7% at 6 years.⁶

Thus, substantial room for therapeutic improvement exists in the care of these patients. In developing new regimens, it is important to show similar or improved survival and a better toxicity profile compared with that of MVAC.

Gemcitabine has been studied as a single agent for the treatment of metastatic bladder cancer.^7-10 These studies demonstrate that single-agent gemcitabine is active and safe in patients with TCC. By its mechanisms of action, gemcitabine has the potential to be synergistic with cisplatin, and studies have confirmed this synergism.¹¹ The combination of gemcitabine and cisplatin (GC) has been studied in patients with TCC. In three reported phase II trials, GC seemed to have comparable activity with MVAC with a seemingly better toxicity profile.^12-14 The experience with gemcitabine in bladder cancer has been reviewed recently.¹⁵ Thus, an active controlled, open-label, multinational, multicenter, randomized phase III study was performed to compare GC with MVAC in patients with advanced or metastatic TCC of the urothelium.

PATIENTS AND METHODS

Patients
Patients with measurable or assessable and histologically proven locally advanced (T4b, N2, N3) or metastatic (M1) TCC of the urothelium were considered eligible. Prior systemic chemotherapy or immunotherapy was not allowed, but prior local intravesical therapy, immunotherapy, or radiation therapy was allowed if completed at least 4 weeks before enrollment. Patients were required to have a Karnofsky performance status 70, adequate bone marrow reserve (WBC count 3.5 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 10 g/dL) and renal function (measured creatinine clearance 60 mL/min), and an estimated life expectancy of at least 12 weeks. Patients with nonmalignant systemic disease that precluded them from receiving study therapy (eg, active infection, any clinically significant cardiac arrhythmia, or congestive heart failure [functional New York Heart Association Class III or worse]) or patients who were pregnant were not eligible. Patients with CNS metastases, second primary malignancy (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin), or clinically significant pleural effusions or ascites (unless these were drained before methotrexate administration) or who used any investigational agent 1 month before enrollment were also not eligible. This study was conducted according to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for good clinical practice, or the applicable laws and regulations of the countries where the study was conducted, whichever represented the greater protection of the individual. Written informed consent was obtained from all patients before randomization.

Treatment Schedule
Patients were randomized to receive either GC or MVAC. Treatment allocation was performed by the Netherlands Cancer Institute using the Pocock and Simon¹⁶ minimization method. Before randomization, the following stratification factors were evaluated: performance status, stage, visceral metastases, alkaline phosphatase level, prior radiotherapy, measurable disease, and investigator site. Patients on the GC arm received gemcitabine 1,000 mg/m² over 30 to 60 minutes on days 1, 8, and 15 plus cisplatin 70 mg/m² on day 2. Gemcitabine was supplied by Eli Lilly and Company (Indianapolis, IN). Patients on the MVAC arm received methotrexate 30 mg/m² on days 1, 15, and 22; vinblastine 3 mg/m² on days 2, 15, and 22; doxorubicin 30 mg/m² on day 2; and cisplatin 70 mg/m² as a 1- to 8-hour infusion on day 2. Cisplatin was administered with adequate pre- and posthydration. Cycles were repeated every 28 days. On both arms, cycles were not started unless WBC was 3.0/dL and platelets were 100/dL. The patient was taken off study if a cycle was delayed for more than 4 weeks. On the GC arm, gemcitabine doses on day 8 or 15 were omitted for WBC 1.99/dL and platelets 49/dL; missed doses were not given, which could result in 21-day cycles. On the MVAC arm, methotrexate or vinblastine doses on day 15 or 22 were delayed for WBC 2.9/dL and platelets 74/dL. On both arms, dose was adjusted for nonhematologic toxicity, including mucositis. Although prophylactic leucovorin was not allowed, leucovorin was permitted 24 hours after methotrexate infusion in patients who had experienced grade 3 or 4 mucositis.

Supportive care could include blood transfusions and the administration of antiemetics and analgesics, as appropriate. Palliative radiotherapy was allowed for pre-existing, painful bony lesions in the absence of disease progression. Prophylactic use of growth factors was not recommended in either arm. No other antineoplastic therapy was permitted during the study.

Patients received treatment for a maximum of six cycles unless they developed progressive disease or unacceptable toxicity or the patient, attending physician, or sponsor requested discontinuation.

Treatment Evaluation
The primary objective of this study was the comparison of the overall survival of the patients in the two treatment arms. Secondary objectives were comparisons of objective tumor responses, duration of responses, times to progressive disease, times to treatment failure, toxicity, changes in performance status and weight, and evaluations of quality of life (QOL) and medical resource utilization.

During treatment, blood counts and serum chemistries were performed weekly, and creatinine clearance was calculated before chemotherapy. Patients were assessed weekly for weight and before each cycle for performance status. Tumor assessments were performed radiologically and by physical examination, as indicated. Tumors were reassessed every two cycles, and responses were confirmed after at least 4 weeks. QOL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 instrument, which was administered at baseline and before each cycle. Validated bladder cancer–specific questionnaires were not available at the time the study was started. Patients qualified for the QOL analysis if they completed a baseline and at least one postbaseline questionnaire. Data on medical resource utilization (hospitalizations, medical or surgical procedures performed, health care professional visits, inpatient or outpatient administration of chemotherapy, transfusions, and concomitant medications) were collected before each cycle.

Overall survival was measured from the date of randomization until death, and time to progressive disease was measured from date of randomization until death or progression. Time to treatment failure was measured from the date of randomization until discontinuation of treatment or progression or death. Standard criteria (World Health Organization) were used for classifying response. Complete response (CR) was defined as the disappearance of all known disease determined by two observations not less than 4 weeks apart. Partial response (PR) was achieved if total tumor size decreased by at least 50% of the measurable lesions by two observations not less than 4 weeks apart and no new lesions appeared or existing lesions progressed. Stable disease was reached if a 50% decrease in total tumor size or if a 25% increase in the size of one or more measurable lesions could not be established. Progressive disease occurred if the size of at least one measurable lesion increased by at least 25% or new lesions appeared. Investigator-determined responses were confirmed by independent blinded reviewers.

All randomized patients were included in the time-to-event and safety end points. Protocol-eligible patients with bidimensionally measurable disease who received at least one cycle of therapy and had at least one follow-up tumor assessment were assessable for response.

Safety evaluations included summaries of chemotherapy, including dose adjustments, dose intensity (amount of drug delivered per unit of time expressed in mg/m²/wk), and details of any toxicity, and deaths or discontinuations because of study drug toxicity. All toxicities were graded using the WHO scale, except for ototoxicity, which was graded using the National Cancer Institute common toxicity criteria scale. A data monitoring board including external members was involved in the conduct and evaluation of the study.

Statistical Considerations
The planned sample size for this study of 400 randomized patients (200 per arm) enabled the detection of a difference of 33% between arms in survival at an alpha of 0.05 (two-sided) and a beta of 0.20. All analyses were predefined in a research analysis plan.

Estimates of time-to-event end points were calculated using the Kaplan-Meier method and compared using the log-rank and Wilcoxon tests on an intent-to-treat basis. Only the results of the log-rank test are given, unless the results of the Wilcoxon test were significantly different from the log-rank test. Hazard ratios (HRs) and corresponding confidence intervals (CIs) were calculated using Cox’s proportional hazards model. All HRs were denoted as the ratio of the hazard of an event on the GC arm compared with the MVAC arm. An HR less than 1 indicates that, on average, patients on the GC arm are likely to have the event later than those on the MVAC arm. Responses were compared using the Pearson’s ² test. The effects of baseline factors (performance status, tumor-node-metastasis stage, presence of visceral metastases, alkaline phosphatase level, number of sites of disease, prior radiotherapy, disease measurability, age, sex, and time to diagnosis) were assessed for time-to-event end points using the Cox’s proportional hazards model and for response using logistic regression. Those factors that showed individual prognostic value in univariate models were assessed for joint prognostic value in a multivariate model. A final model was developed using a backward selection strategy. Treatment was added to the final model to assess its effect when adjusted for the presence of important prognostic factors. Other analyses included comparison of changes from baseline in performance status, weight, and median scores of functional and symptom QOL scales using a paired t test. Medical resource utilization data were summarized. Neutropenic sepsis (defined as absolute neutrophil count < 500/µL and grade 3 or 4 infection) and grade 3 and 4 mucositis were compared using Pearson’s ² test.

RESULTS

The study was open for enrollment between November 1996 and September 1998, during which time, 426 patients were entered onto the study. Of the 426 patients entered onto the study, 405 patients were randomized, 203 to the GC arm and 202 to the MVAC arm. Of the 21 patients entered but not randomized, 19 did not meet protocol entry criteria, one died from bladder cancer, and one did not continue because of personal reasons. Of the 405 patients randomized, 396 received study drug (GC, n = 200; MVAC, n = 196). On the GC arm, one patient died before treatment and two did not receive chemotherapy. On the MVAC arm, three patients did not receive chemotherapy and three refused treatment.

Patient Characteristics
Patient characteristics at study entry were generally well-balanced across treatment arms, although slightly more patients on the GC arm had adverse prognostic factors compared with the MVAC arm (Table 1). These differences were, however, not statistically significant.

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (9K): [in this window] [in a new window]   Fig 2. Time to progressive disease.

View larger version (9K): [in this window] [in a new window]   Fig 3. Time to treatment failure.

All responses were reconfirmed after at least 4 weeks. Investigator-assessed overall response rates were similar (GC = 54.3%, MVAC = 55.0%). Overall response rates based on independent radiologic review were also similar for both arms: 49.4% (81 patients) with 12.2% CR and 37.2% PR on the GC arm and 45.7% (69 patients) with 11.9% CR and 33.8% PR on the MVAC arm (P = .51). One third of the patients on both arms achieved stable disease (GC = 33.5%, MVAC = 32.5%). Using an intent-to-treat analysis, the overall response rate for all patients with measurable disease was 44.5% with GC and 38.1% with MVAC. The most common sites of disease progression were nodal, local, lung, bone, and liver for the GC arm, and nodal, local, liver, lung, and bone for the MVAC arm. Median durations of response for GC- and MVAC-treated patients were 9.6 months (95% CI, 8.0 to 10.8 months) and 11.0 months (95% CI, 9.4 to 12.6 months), respectively (P = .48).

Toxicity
Patients on the GC arm received a total of 943 cycles and a median of six cycles compared with a total of 792 cycles and a median of four cycles for patients on the MVAC arm. On the GC arm, 63% of cycles were given without any dose adjustments compared with 37% on the MVAC arm. The most common causes for dose adjustments on the GC arm were thrombocytopenia, abnormal renal function, and leukopenia; most gemcitabine omissions occurred on day 15. On the MVAC arm, the most common causes for dose adjustments were leukopenia, thrombocytopenia, and mucositis; most adjustments occurred on day 15 for methotrexate and vinblastine. Dose-intensity was 80% for gemcitabine and 102% for cisplatin on the GC arm, and 65% for methotrexate, 76% for vinblastine, 95% for doxorubicin, and 93% for cisplatin on the MVAC arm.

The toxicities seen in both treatment arms were expected, and no unusual trends were noted. World Health Organization grades 3 and 4 toxicities for hematologic and nonhematologic parameters are provided in Table 3. Grade 3 or 4 anemia was seen more often on the GC arm than on the MVAC arm (GC = 27%, MVAC = 18%). However, this did not result in higher transfusion rates. Thirteen patients received RBC transfusion per 100 cycles of therapy on both arms. Grade 3 or 4 thrombocytopenia was seen more often on the GC arm (GC = 57%, MVAC = 21%); but there was no grade 4 bleeding on either arm, and grade 3 or 4 thrombocytopenia was infrequently associated with grade 3 bleeding (GC = 2%, MVAC = 2%). Rates of platelet transfusion were low on both arms with four versus two patients receiving platelet transfusion per 100 cycles of therapy on GC versus MVAC, respectively. Patients on the MVAC arm experienced more grade 3 or 4 neutropenia (MVAC = 82%, GC = 71%), neutropenic fever defined as absolute neutrophil count < 500/m³ and fever > 38°C (MVAC = 14%, GC = 2%), and significantly more neutropenic sepsis (MVAC = 12% v GC = 1%; P < .001). Grade 3 or 4 mucositis was significantly more common on the MVAC arm (MVAC = 22% v GC = 1%; P = .001). On the MVAC arm, patients had an average of 3.6 days per cycle of moderate or severe mucositis compared with 0.5 days per cycle on the GC arm. The drug toxicity-related mortality rate was lower for the GC arm than for the MVAC arm (1% v 3%, respectively), although this was not statistically significant. Seven of the eight deaths were related to complications of neutropenia; one death on the MVAC arm was related to complications arising from mucositis. Grade 3 or 4 cutaneous toxicity and liver function abnormalities were infrequent (< 2%) and similar on both arms.

On the GC and MVAC arms, 165 (81%) and 161 (80%) patients were qualified for QOL analysis, respectively. The 165 GC-treated patients completed 959 questionnaires on-study and poststudy (median per patient, six; range, two to eight questionnaires). The 161 MVAC-treated patients completed 841 questionnaires on-study and poststudy (median per patient, five; range, two to nine questionnaires). On-study compliance was 87.2% for GC-treated patients and 84.4% for MVAC-treated patients. Based on changes from baseline in median scores after each cycle, QOL was maintained on both arms throughout the study with both arms noting improvement in emotional functioning and pain. Overall, the QOL profile was similar in both arms, with the exception of fatigue. Further analysis of the changes in fatigue on treatment showed that more GC-treated patients reported at least a 10-point improvement in fatigue from baseline up to cycle 4 compared with MVAC-treated patients (GC = 33%, MVAC = 28%). Fewer GC-treated patients reported at least a 10-point worsening of fatigue from baseline up to cycle 4 compared with MVAC-treated patients (GC = 44%, MVAC = 49%). However, these differences were not statistically significant.

Medical Resource Utilization
Medical resource utilization per cycle of therapy for managing adverse events was generally higher on the MVAC arm than on the GC arm (Table 4). Hospitalization for febrile neutropenia and use of growth factors, parenteral antibiotics, antiviral, and antifungal medication was at least two-fold higher on the MVAC arm. Granulocyte colony-stimulating factors and granulocyte-macrophage colony-stimulating factors were used more frequently on the MVAC arm than on the GC arm (42 patients v 13 patients, respectively). A total of 179 patients on the GC arm were hospitalized for any reason, including study drug administration, protocol tests, and adverse events, for a total of 2,854 days over 943 cycles (3 days/cycle), as were 176 patients hospitalized on the MVAC arm, for a total of 3,165 days over 792 cycles (4 days/cycle). On the MVAC arm, there were more hospital admissions (MVAC, n = 49 v GC, n = 9) and more days of hospitalization (MVAC, n = 272 v GC, n = 33 days) for neutropenic fever. Similar numbers of patients on each arm received 5-hydroxytryptamine-3 antagonists (GC, n = 168; MVAC, n = 172) for prevention and/or treatment of nausea and vomiting.

DISCUSSION

This multinational, multicenter phase III study demonstrates that GC and MVAC have a similar survival, but GC is more tolerable and safer, thus demonstrating that GC has a better risk-benefit ratio than MVAC.

Since the 1980s, treatment of locally advanced and metastatic bladder cancer has been cisplatin-based. Two randomized trials have led to the acceptance of MVAC as the standard therapy.^3,4 The study reported by Loehrer et al³ was conducted in multiple centers with 246 assessable patients accrued in 55 months. Although a survival advantage was noted with MVAC compared with cisplatin alone, MVAC was a toxic regimen with 4% toxic deaths, 10% granulocytopenic fever, 6% sepsis, and 17% grades 3 and 4 mucositis. Thus, there has been a need for less toxic regimens with similar efficacy, but because of the slow accrual rates, there have been few completed randomized studies in this patient population.

Gemcitabine has shown synergism with cisplatin in preclinical models.¹¹ This led to the development of GC in many tumor types, including bladder cancer. In the three phase II studies evaluating GC in bladder cancer, different schedules and dosages have been used.^12-14 The dosage and schedule of GC used in this study was chosen to allow administration of cisplatin on the same dose and schedule in both arms of the study and to limit differences and biases between the two arms.

This study completed accrual over 22 months. This short accrual period reduces problems often associated with long accrual periods, which can result in variations hampering the interpretation of differences between treatment arms. In this study, the two arms were generally well-balanced, although there were slightly more patients on the GC arm with M1 disease, visceral metastases, high alkaline phosphatase, and four or more sites of disease. Overall survival, time to progressive disease, and response rates were similar on both arms, both before and after adjustments for prognostic factors. The prognostic factors identified in this study were in accordance with those reported by others.¹⁷ Time to treatment failure was better on the GC arm during the treatment period, which reflects the safety of this regimen. This study also demonstrated that GC is less toxic than MVAC. Based on predefined toxicity end points, GC-treated patients had lower toxicity-related mortality and significantly lower rates of neutropenic sepsis and grade 3 or 4 mucositis. In addition, patients treated with GC used fewer resources for managing adverse events and supportive care and had fewer days with moderate or severe mucositis compared with patients treated with MVAC. Finally, more patients on the GC arm fared better with respect to weight, performance status, and fatigue during therapy. Although thrombocytopenia and anemia were seen more frequently on the GC arm, there were few clinical sequelae from these toxicities. Rates of hemorrhage and transfusions were low and similar on both arms. Newer regimens with GC using a 21-day schedule are being developed to reduce the need to administer a gemcitabine dose on day 15, which often needs to be adjusted because of hematologic toxicity.¹⁷ It should be noted that the dose-intensity of cisplatin on the MVAC arm was > 90% and is comparable with published reports in the literature.³ The dose-intensity of cisplatin on the GC arm was slightly higher than that on the MVAC arm, which, however, is not expected to influence the efficacy.¹⁹ The differences between arms in the number of cycles with dose modifications were likely a result of the differences in toxicities of the regimens, although it may have also been because of different threshold criteria for dose adjustments during the cycle on the two arms.

The efficacy and safety results on the GC arm are very consistent with the results from the phase II studies conducted by von der Maase et al¹² (n = 42), Moore et al¹³ (n = 31), and Kaufman et al¹⁴ (n = 46) and confirm the effectiveness and safety of GC. These results are listed in Table 5.

In conclusion, the results of this large randomized study confirm the activity of GC in bladder cancer and demonstrate the superior risk-benefit ratio of GC compared with MVAC. Thus, GC is a safer therapeutic alternative for patients with locally advanced and metastatic bladder cancer and should be considered a standard of care for these patients. Furthermore, the potential role of GC in the treatment of earlier-stage bladder cancer should be investigated.

APPENDIX

The investigators who participated in this trial are as follows: H. von der Maase, Department of Oncology, Aarhus University Hospital, Aarhus; S.W. Hansen, Department of Oncology, Herlev University Hospital, Herlev; N.V. Holm, Department of Oncology and Hematology, Odense Universitetshospital, Odense; K. Nielsen, Aalborg Sygehus Nord, Radiumstationen, Aalborg, Denmark; J.T. Roberts, Northern Centre for Cancer Treatment, Newcastle upon Tyne; P. Johnson, P. Patel, St James University Hospital Cancer Medicine Research Unit, Leeds; T. Oliver, Department of Medical Oncology, St. Bartholomews Hospital; M. Seckl, Radiotherapy Department, Charing Cross Hospital, London; J. Littler, Clatterbridge Hospital, Bebington, England; D. Bissett, Aberdeen Royal Infirmary, Aberdeen; S.B. Kaye, Western Infirmary, Beatson Oncology Centre, Glasgow, Scotland, United Kingdom; P.F. Conte, Ospedale Santa Chira Di Pisa, Pisa; L. Dogliotti, Ospedale S Luigi Gonzaga, Cattedra Di Oncologia Medica, Orbassano; C. Barone, Universita Cattolica Del Sacro Cuore, Istituto Di Medicina Interna E Geriatriai, Roma; A. Bianco, Universita Di Napoli Federico, Ii IIA Facolta’Di Medicina, Napoli; M. De Lena, Ospedale Oncologico Provinciale, Istituto Mater Dei, Bari; E. Villa, Istituto Scientifico S Raffaele, Servizio Radio Chemioterapia, Milano; F. Boccaardo, Ospedale San Martino, Universita’Genova, Genova; M. Tonato, Policlinico Monteluce, Divisione Oncologia Medica, Perguia; A. Amadori, Ospedale Pierantoni, Oncologia Medica, Forli; C. Bumma, Ospedale S Giovanni, Antica Sede, Oncologia Medica, Torino, Italy; M.J. Moore, Princess Margaret Hospital, Medical Oncologist Department of Medicine, Toronto; E.W. Winquist, Ontario Cancer Foundation London Centre, London, Ontario; P.M. Venner, Cross Cancer Institute, NW Edmonton, Alberta, S.C. Tang, Dr H Bliss Murphy Cancer Centre, St Johns, Newfoundland; A. Lavoie, Centre Hospitalier Universite De uebec, Quebec, Canada; I. Bodrogi, Orszagos Onkaologiai Intezet, Division of Oncology, Budapest, Hungary; P. Albers, Med. Einrichtungen Der Westfälischen Wilhelms-Universität, Bonn; A. Knuth, Nordwestkrankenhaus Steinbacher Hohl, Frankfurt; K.F. Stockamp, Klinikum Der Stadt Ludwigshafen, Ludwigshafen; H.G. Derigs, Klinikum Der Johannes-Gutenberg-Universität Mainz, Mainz; T. Käble, Klinikum Der Philipps-Universität Marburg/Lahn, Zentrum Operative Medizin II, Marburg; H.J. Melchior, Städtische Kliniken Kassel, Klinik Fuer Urologie, Kassel; H. Piechota, Med Einrichtungen Der Westfälischen Wilhelms-Universität, Muenster; M. Stoeckle, Universitaets Klinikum Kiel, Kiel; L. Weissbach, Krandenhaus Am Urban, Urologische, Berlin; J. Schabel, Martin-Luther-Universität Halle-Witt, Medizinische Fakultät, Halle; P. Bub, Klinikum Schwerin, Schwerin; H. Henss, Klinikum Der Albert-Ludwigs-Universität Freiburg, Abt. Haematolgie/Onkologie, Freiburg; R. Muschter, Klinikum Grobhadern Der Ludwig-Maximilians-Universität, Klinikum Grosshadernmed Klinik (3), Munich; S. Pomer, Klinikum Der Ruprecht-Karls-Universität Heidelberg, Heidelberg; S. Roth, Klinikum Wuppertal Gmbh, Wuppertal; W. Tunn, Städtische Kliniken Offenbach, Urologische Klinik Starkenburgring, Offenbach; P. Walz, Kreikrankenhaus Lüdenscsheid, Lüdenscsheid; J.H. Hartlapp, Staedtische Kliniken, Osnabrueck; G. Jaske, M. Wirth, Medizinische Einrichtungen Der Rwth Aachen, Aachen, Germany; P. Kerbrat, Centre Eugene Marquis, Rennes; A. Caty, Centre Oscar Lambret, Lille; S. Oudard, Hotel-Dieu De Paris; L. Boccon-Gobod, Hôpital Bichat, Professor of Infectiology, Paris; J. Peny, Centre Francois Baclesse, Caen; G. Gravis, Institut Paoli-Calmettes, Marseille; N. Mottet, Chu De Nimes Centre Gaston Doumergue, Nimes; J.P. Droz, Centre Leon Berard, Lyon; Prof Thyss, Centre Antoine Lacassagne, Nice; L. Mignot, Centre Medico-Chirurgical, Suresnes, France; P. Sanchez Rovira, Complejo Hospitalario Ciudad De Jaen, Servico De Oncologia, Jaen; P. Aramburo, Hospital Ruber Internacional, Mirasierra Unidad de Oncolgia, Madrid; M. Lomas Garrido, Hospital Infant Cristina, Servicio de Oncologia, Badajoz, Spain; P. Wersall, Karolinska Sjukhuset, Department of Oncology Radiumhemmet, Stockholm; A. Widmark, Umeå Regional Hospital, Department of Oncology, Umeå; Academic Hospital Uppsala, Department of Oncology, Uppsala, Sweden; M. Boyer, Royal Prince Alfred Hospital, Department of Oncology, Camperdown, New South Wales; P. Mitchell, Austin & Repatriation Medical Centre, Department of Oncology, Heidelberg West; E.A. Abdi, Bendigo Hospital, Bendigo; D. Bell, Royal North Shore Hospital, Department of Oncology, Leonards, Australia; A. Schorn, Kh Der Barmherzigen Schwestern Linz, Der Barmherzigen Schwestern Abtreilung Fuer Urologie, Linz, Austria; J. Novak, Vfn A l. Lf Univerzity Karlovy, Urologicka Klinika, Prague, Czech Republic; P. Kellokumpu-Lehtinen, Tampereen Yliopistollinen Keskussairaala, Syöpätautien Ja Sädehoidon Klinikka, Tampere; O. Lukkarien, Oulun Yliopistollinen Sairaala, Oulu; E. Salminen, Turun Yliopistollinen Keskussairaala, Syöpätautien Ja Sädehoidon Klinikka Kiinamyllynkatu, Turku, Finland; H.J. Keizer, Leids Universitair Medisch Centrum Afd., Klinische Oncologie, Leiden; G. Groenewegen, Utrecht Afdeling Inwendige Geneeskunde, Academisch Ziekenhuis, Utrecht; P.S. Hupperets, Maastricht Afdeling Inwendige Geneeskunde, Academisch Ziekenhuis, Maastricht; D.J. Richel, Medisch Spectrum Twente, Enschede, Netherlands; E. Joosens, Algemeen Zkhs Middelheim, Oncologie; J.B. Vermoken, Commissie Voor Medische Ethiek Oncologie, Antwerp; R. Paulus, Chr L Tourelle Oncologie, Verviers; Y. Humblet, Cliniques Universitaires Saint-Luc, Brussels, Belgium; R.P. Abratt, Groote Schuur Hospital, Radiotherapy Department; J. Raats, Delmar Medical Centre, Cape Town, South Africa; E. Frenkel, University of Texas Southwestern at Dallas Children’s Medical Center, Department of Medicine, Division of Hematology/Oncology, Dallas, TX; M.R. Modiano, Arizona Clinical Research Center, Tucson, AZ; J. Picus, Barnard Cancer Center, Washington University in St Louis, St Louis, MO; A.O. Sartor, Louisiana State University School of Medicine, LSU Medical Center at Shreveport, Shreveport; D.A. Rinaldi, Louisiana Oncology Associates, Lafayette, LA; W.M. Stadler, The University of Chicago Hospital, Chicago; W. Poplovic, Oncology Care Center, Belleville, IL; A. Chachoua, New York University Medical Center, New York; D.M. Sahasarabudhe, University of Rochester, Rochester, NY; T.J. Eervin, Maine Center for Cancer, Medicine/Blood Disorders, Scarborough, ME; P. Flynn, Metro Minnesota Ccop, St Louis Park, MN; F. Howard, Loma Linda University Cancer Institute, Loma Linda, CA; A. Koletsky, Comprehensive Cancer Center, Mt Sinai Medical Center, Miami Beach, FL; B.A. Mason, Pennsylvania Oncology, Hematology Associates, Philadelphia, PA; S. Zakonoen, Barrett Cancer Center, Cincinnati, OH, United States; T. Cerny, Inselspital Bern, Institut Fuer Medizinische Onkologieder Universitaet, Bern, Switzerland; and A.T. Huang, Sun Yat Sen Hospital, Taipei, Taiwan.

ACKNOWLEDGMENTS

Supported by a grant from Eli Lilly and Company.

We thank all the involved patients and institutions for their participation. We also thank Mary Alice Miller, PhD, for her excellent help in preparing the manuscript.

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Submitted March 6, 2000; accepted July 7, 2000.

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