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Originally published as JCO Early Release 10.1200/JCO.2004.02.152 on December 9 2003 © 2004 American Society of Clinical Oncology. Docetaxel and Cisplatin With Granulocyte Colony-Stimulating Factor (G-CSF) Versus MVAC With G-CSF in Advanced Urothelial Carcinoma: A Multicenter, Randomized, Phase III Study From the Hellenic Cooperative Oncology GroupFrom the Departments of Clinical Therapeutics, Urology, Hygiene, and Epidemiology, University of Athens School of Medicine; the Medical Oncology Department, Agii Anargyri; Hygia Hospital; the Second Department of Internal Medicine, Evangelismos Hospital; the Oncology Department, Ippokration Hospital, Athens; the Department of Internal Medicine, University of Patra, Patra; the School of Medicine, Rio; the Department of Medical Oncology, Herakleion University Hospital, Herakleion; and Metaxa Hospital, Piraeus, Greece Address reprint requests to Aristotle Bamias, MD, 31 Komninon St, Haidari 124 62 Athens, Greece; e-mail: abamias{at}med.uoa.gr
PURPOSE: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC.
PATIENTS AND METHODS: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status RESULTS: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P = .017), median time to progression (TTP; 9.4 v 6.1 months; P = .003) and median survival (14.2 v 9.3 months; P = .026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P = .005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P = .089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P = .006), thrombocytopenia (5.7% v 0.9%; P = .046), and neutropenic sepsis (11.6% v 3.8%; P = .001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.
Urothelial cancer is a common malignancy worldwide. The crude incidence in the European Union is 23 cases per 100,000 persons per year, and the mortality is 10 cases per 100,000 persons per year. Urinary bladder is the most common primary site, but this cancer also originates from the renal pelvis, ureters, urethra, and prostatic ducts. Prognosis of metastatic or inoperable disease has been improved by the introduction of systemic combination chemotherapy, but it remains poor, with long-term disease-free survival less than 5% [1]. The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), developed in 1983 [2], is universally considered the standard treatment, with response rates (RRs) more than 50%, 3-year survival of 20% to 25%, and median survival past 1 year consistently reported [3-5]. Furthermore, MVAC was shown to be superior to single-agent cisplatin [6] and the regimen of cisplatin, cyclophosphamide, and doxorubicin [7].
Although MVAC has shown considerable efficacy in advanced urothelial carcinoma, there is still room for improvement: long-term survival is rare, whereas the toxicity of this combination is significant. Neutropenic sepsis has been reported in more than 10% of patients treated with MVAC [4,6], and it has also been associated with a toxic-death rate of 3% to 4% [6,8]. Myelotoxicity has been shown to be reduced by the routine use of granulocyte colony-stimulating factor (G-CSF) [9] or granulocyte-macrophage colony-stimulating factor [10]. The use of growth factors also allowed for the administration of MVAC in a more dose-dense fashion [11,12]. The results of these phase II studies suggested that the efficacy of MVAC might be improved by dose intensification. Newer agents, including the taxanes paclitaxel and docetaxel, have shown promising single-agent efficacy in advanced urothelial cancer [13-15], whereas the combination of paclitaxel with cisplatin and ifosfamide produced encouraging efficacy results, with manageable toxicity [16]. We have recently reported the results of a phase II study of the combination of docetaxel and cisplatin (DC) as first-line treatment in 66 patients with advanced urothelial carcinoma [17]. Both agents were administered at 75 mg/m2 every 3 weeks with G-CSF support. That study showed a 52% RR, with 12% of patients achieving a complete response (CR). Median survival was 8 months, which was somewhat inferior to that reported in previous phase II studies using MVAC. Nevertheless, patients with several adverse baseline characteristics had been included in that study (performance status [PS] 3, age > 75 years, administration of previous adjuvant or neoadjuvant chemotherapy), which could account for this result, given that median survival
Selection and Randomization Patients with histologically confirmed inoperable, metastatic, or recurrent (after surgery and/or radiotherapy) carcinoma of the urothelial tract (renal pelvis, ureter, bladder, or urethra) were included in the study. Patients were to be no older than 75 years, with adequate bone marrow and liver function (absolute neutrophil count [ANC] > 1,500/µL, platelets > 100,000/µL, bilirubin  1.5x upper limit of normal, and aminotransferases 3x upper limit of normal), creatinine clearance (Cockroft formula)  50 mL/min, Eastern Cooperative Oncology Group PS 0 to 2, and the absence of moderate or severe heart failure or chronic obstructive airway disease. No previous chemotherapy for advanced disease was allowed. Prior adjuvant or neoadjuvant treatment was allowed, provided that it had ended at least 12 months before randomization and the total doses of previously administered agents did not exceed the following levels: cisplatin 300 mg/m2, epirubicin 400 mg/m2, and doxorubicin 300 mg/m2. The protocol of the study was approved by the Scientific Committee of the Hellenic Cooperative Oncology Group and the institutional review board of each participating center. Patients gave informed consent before random assignment to treatment. Baseline evaluation included full blood count (FBC), renal and liver function tests, calculation of creatinine clearance, electrolyte level tests, chest x-ray (computed tomography [CT] scan of the thorax if the chest x-ray was abnormal) and CT scan of the whole abdomen. CT or magnetic resonance imaging of the brain and a bone scan were performed if clinically indicated. Randomization was performed centrally after stratification for disease site (visceral metastases v locoregional disease [unresectable tumor and/or lymph node metastases at any site including pelvis, retroperitoneum, mediastinum, and neck]) and prior adjuvant or neoadjuvant chemotherapy (yes v no).
Treatment Schedule
Efficacy and Toxicity Evaluation
Statistical Considerations and Analysis
All analyses were performed using the SPSS statistical software (SPSS for Windows, version 10; SPSS Inc, Chicago, IL). Frequency distributions were used to describe the categoric variables, whereas continuous variables were presented as means and standard deviations. Differences across treatment arms regarding all categoric variables were examined with a Survival curves for TTP and survival data were produced with the Kaplan and Meier method [22] and compared between arms with the stratified log-rank test [22]. For univariate and multivariate analyses of TTP and survival, the Cox proportional hazards model was used [23]. Throughout the analysis a level of 5% was used to denote statistical significance except as indicated.
Patients Between June 1997 and May 2002, 224 patients were entered onto the study. Four patients were not randomly assigned because they did not have inoperable disease. From the remaining 220 patients, 109 were randomly assigned to arm A (MVAC) and 111 patients were assigned to arm B (DC). Characteristics of randomly assigned patients (Table 1) were well balanced across treatment arms except for WHO PS: there were more patients with PS 0 and fewer with PS 2 in the MVAC arm compared with the DC arm, and this difference was statistically significant (P = .040). Thirteen patients did not receive study treatment (MVAC arm, six patients; DC arm, seven patients): three patients died before initiation of treatment and five patients had deterioration of renal function before treatment initiation, whereas five patients refused to receive the allocated treatment. One hundred three patients had had their primary site removed: 39 of these patients also received adjuvant radiotherapy, whereas 26 had chemotherapy before (n = 9) or after (n = 17) radical surgical removal of their primary tumor. One hundred ninety patients had transitional-cell carcinomas. The other histologies included squamous carcinoma (MVAC, five patients; DC, four patients), adenocarcinoma (MVAC, three patients; DC, one patient), mixed carcinomas (MVAC, six patients; DC, three patients), sarcomatoid carcinoma (DC, two patients), poorly differentiated carcinoma (DC, two patients), small-cell carcinoma (MVAC, one patient), large-cell carcinoma (MVAC, one patient), giant cell carcinoma (MVAC, one patient) and plasmatocytoid carcinoma (MVAC, one patient).
Survival All randomly assigned patients were included in survival analysis on an intention-to-treat basis. Efficacy data are shown in Table 2. At the time of analysis, 158 patients (MVAC, 74 patients [67.89%]; DC, 84 patients [75.68%]) had died (150 disease-related deaths, three treatment-related deaths, and five deaths resulting from other causes [myocardial infarctions in two patients, fulminant hepatitis in one patient, stroke in one patient, and one sudden death resulting from unknown etiology]). Median follow-up for surviving patients was 25.3 months (range, 3.2 to 51 months). Survival curves for both arms are depicted in Figure 1. Median survival was statistically significantly better in patients who received MVAC compared with DC chemotherapy (14.2 v 9.3 months, respectively; P = .026). Two-year survival was also superior in patients receiving MVAC compared with patients receiving DC (28.6% v 18.9%, respectively).
Univariate analysis, including the characteristics listed in Table 1 of all 220 randomly assigned patients, showed that female sex (P = .041), no adjuvant chemotherapy (P = .002), neoadjuvant chemotherapy (P = .038), performance status of 0 or 1 (P = .004), and absence of visceral metastases (P < .001) were associated with improved survival. Multivariate Cox regression analysis showed that only visceral metastases (P = .004) and PS (P = .005) were independently associated with prognosis. When adjusted for these factors (Table 3), the effect of treatment with MVAC became nonsignificant compared with DC treatment (HR, 1.31; P = .089). The survival curves for the two treatment arms across categories of PS and metastatic sites are presented in Figures 2 and 3. The relative effect on survival of MVAC compared with DC did not vary across categories of PS (P = .894 for interaction between treatment arm and PS) or metastatic site (P = .531 for interaction between treatment arm and presence of visceral metastases).
TTP During follow-up there was disease relapse in 141 patients: 65 patients in the MVAC arm and 76 patients in the DC arm. TTP curves for both treatment arms are depicted in Figure 4. Median TTP was statistically significantly better in patients who received MVAC chemotherapy compared with patients receiving DC (9.4 v 6.1 months, respectively; P = .003).
Univariate analysis showed that PS 0 or 1 (P = .029) and absence of visceral metastases (P < .001) were associated with improved TTP. Multivariate analysis showed that both factors were independently associated with TTP (P = .052 and P < .001, respectively). When adjusted for these factors (Table 3), treatment with MVAC was still statistically significantly better than treatment with DC (HR, 1.61; P = .005). The relative effect on TTP of MVAC compared with DC did not vary across categories of PS or metastatic sites (P = .412 for PS and TTP interaction; P = .449 for metastatic sites and TTP interaction).
Tumor Response
Toxicity
There were three toxic deaths (two in the MVAC arm and one in the DC arm); all were due to neutropenic sepsis. Treatment with MVAC resulted in significantly more frequent grade 3 or 4 neutropenia than did treatment with DC (35.9% v 19.2%, respectively; P = .006), thrombocytopenia, (5.7% v 0.9%, respectively; P = .046) and episodes of neutropenic sepsis (11.6% v 3.8%, respectively; P = .001). Nonhematologic toxicities were infrequent except for nausea and vomiting, which was encountered in 56 patients (51.4%) in the MVAC arm and 44 patients (39.6%) in the DC arm (P = .084). Nevertheless, grade 3 and 4 toxicity was rare in both arms (occurring in three patients in the MVAC arm and two patients in the DC arm). Renal toxicity was equally distributed, with 14 patients (13.6% for the MVAC arm and 14.5% for the DC arm) experiencing it in both arms, although grade 3 or 4 renal toxicity was encountered only in the DC arm. Neurotoxicity was the only other toxicity (not shown in Table 4) that exceeded 2% of patients in each arm: 18 patients who received MVAC (17.4%) and 19 patients who received DC (18.2%) experienced grade 1 or 2 neurotoxicity.
This multicenter, randomized, phase III trial showed that MVAC with G-CSF support is more effective than DC in advanced urothelial cancer. This study was based on our previous experience with DC, which showed promising efficacy in 66 patients, many of whom had unfavorable prognostic characteristics [17]. These results confirmed those of a previous, smaller study, which showed a 60% overall RR with 26% CR, and a median survival time of 13.6 months in 25 patients with metastatic urothelial cancer [24]. The baseline characteristics of the patients included in the present study are similar to those of our previous study, and our results are similar regarding TTP and survival after treatment with DC. Despite confirmation of the activity of DC in advanced urothelial cancer, our study showed that DC was inferior to MVAC. Overall survival of patients treated with MVAC was significantly longer than that of patients treated with DC, as shown by stratified log-rank test (P = .025). Nevertheless, this difference was no longer statistically significant when treatment effect was adjusted for PS and presence or absence of visceral metastases (P = .089). This lack of significance most probably is due to an imbalance in baseline PS. Not including PS as a stratification factor at randomization represents a drawback of our study. This was due to the lack of prognostic significance of PS in the multivariate analysis performed in our phase II study [17]. Furthermore, data regarding the prognostic significance of PS were not robust at the time of the initiation of our study, and PS was not included as a stratification factor in older randomized studies [7]. Nevertheless, other studies have proved its independent prognostic significance, and PS should be a stratification factor in future randomized studies. To investigate the effect of this imbalance on our results, we performed secondary analyses, which showed a lack of an interaction between PS or presence of visceral metastasis, and treatment effect. Although firm conclusions should not be based on secondary analyses, we believe that in this case they are informative and further strengthen our conclusion that MVAC is more effective than DC. Furthermore, the adjusted (for PS and presence of visceral metastases) effect of MVAC on survival was statistically significantly better compared with DC at the 10% level of significance, meaning that the possibility that this result has been produced by pure chance is still low (ie, 10%). TTP was significantly longer in the MVAC arm even after correcting for the prognostic role of PS and the presence of visceral metastases. The RR was higher with MVAC, although this difference was not statistically significant when nonassessable patients were included in the analysis. Taking into account the results on all three end points in our study, DC does not appear to represent an improvement over MVAC and, therefore, should not be investigated further in this context. After the initiation of our study, two randomized studies comparing MVAC with G-CSF-supported intensified MVAC and with gemcitabine and cisplatin in combination were reported [25,26]. The results of these studies showed that gemcitabine with cisplatin is equally effective but significantly less toxic than MVAC, whereas intensified MVAC achieved significantly longer progression-free survival, although overall survival did not differ significantly from that of classic MVAC. The authors of both studies concluded that these regimens may represent an improvement over MVAC and are worthy of further investigation. The characteristics of patients included in these studies were comparable with those of our patients, and survival, TTP, and RRs in the MVAC arm are strikingly similar in all three studies (Table 5), validating our results. These results also indicate that the superiority of MVAC compared with DC should be attributed to the activity of the combination and not better delivery of the drugs resulting from the use of G-CSF.
MVAC was well tolerated in our study: grade 3 and 4 neutropenia was reported in only 35.9% of patients, thrombocytopenia in 5.7% of patients, and stomatitis in 2.9% of patients. In addition, the percentages of 100% RDI (no reductions or delays) were 41.6% for cisplatin, 44.6% for doxorubicin, and 37.6% for vinblastine and methotrexate. These data show that toxicity and drug delivery were more favorable in our study than reported in earlier and more recent trials for classic MVAC [6,25-27], as shown in Table 5. Lower incidence of neutropenia, neutropenic sepsis, and stomatitis can be attributed to the routine use of G-CSF. Lower incidence of thrombocytopenia is more difficult to explain, but it could be because days 15 and 22 were omitted if the platelet count was less than 100,000/µL, which is higher than the threshold used in previous studies. In addition, some cases of grade 3 or 4 thrombocytopenia may have been undetected because weekly FBC was not obligatory in our study. Our results indicate that G-CSF-supported MVAC is better tolerated than classic MVAC. Furthermore, the toxicity profile of MVAC, administered in our study, compares favorably with that of both combination gemcitabine plus cisplatin and intensified MVAC (Table 5), with the exception of neutropenic sepsis in patients who received combination gemcitabine and cisplatin. We therefore believe that G-CSF-supported MVAC could be considered as a reference regime for advanced urothelial cancer instead of the more toxic classic MVAC. Admittedly, this should be viewed in the context of the possible changes that may result from the publication of the two aforementioned randomized studies regarding the choice of first-line chemotherapy in advanced urothelial cancer. In the last decade, research has been focused on the improvement of treatment of advanced urothelial cancer. Our study has shown that DC cannot substitute for MVAC because of the lower efficacy of DC. Nevertheless, the addition of G-CSF significantly ameliorates the toxicity of MVAC, and G-CSF-supported MVAC could be considered as a substitute for classic MVAC if this regimen is to be used in patients with advanced urothelial cancer.
Authors' Disclosures of Potential Conflicts of Interest
Preliminary analysis presented at the 39th American Society of Clinical Oncology Annual Meeting, May 29-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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27. Scher HI, Geller NL, Curley T, et al: Effect of relative cumulative dose-intensity on survival of patients with urothelial cancer treated with M-VAC. J Clin Oncol 11:400-407, 1993 Submitted February 28, 2003; accepted August 13, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test; for continuous variables, the t test was used to test the equality of the appropriate means. 
