Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours

doi:10.1016/j.ejca.2005.08.032

European Journal of Cancer

Volume 42, Issue 1, January 2006, Pages 50-54

https://doi.org/10.1016/j.ejca.2005.08.032 Get rights and content

Abstract

EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% .The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.

Introduction

In Europe, cancer of the bladder is the fourth most frequent cancer among men [1]. Systemic chemotherapy is the only modality that has been shown in phase III trials to improve survival in responding patients with advanced bladder cancer 2, 3 The M-VAC (methotrexate, vinblatine, adriamycin and cisplatin) regimen, first reported in 1985 at Memorial Sloan Kettering Cancer Center (MSKCC), revealed that urothelial carcinoma was sensitive to chemotherapy [4]. Patients with measurable lesions were found to have a 72% response rate (RR) and 36% attained a complete response (CR) [5]. Long-term survival was achieved in patients who attained CR. Overall survival for the entire population was 13.1 months. Chemotherapy was more effective in patients with nodal disease than in those with visceral metastases 3, 5.

In an update of 5 different M-VAC regimens from MSKCC 194/203 patients were evaluable; 46 patients achieved CR (24%) and 84 patients PR (43%), with overall RR of 67%. The median survival for all 203 patients was 14.8 months, with a 5-year survival rate of 17% [6]. The 5-year survival for 46 CR patients after chemotherapy alone was 40%. An additional 30 patients achieved CR after chemotherapy was followed by surgery with a 5-year survival rate of 33% [7].

Prognostic factors were predictive of response and survival in these patients. Three risk categories on the basis of Karnofsky performance status (KPS) and the presence or absence of visceral metastases. Two factors had independent prognostic value: KPS less than 80%; and visceral (lung, liver, or bone) metastasis. Median survival times for patients who had 0, 1, or 2 risk factors were 33, 13.4, and 9.3 months, respectively (P = 0.0001). The median survival time of patient cohorts could vary from 9 to 26 months simply by altering the proportion of patients from different risk categories [6].

In an attempt to improve upon the results obtained with M-VAC chemotherapy, the present trial was initiated as a randomized phase II trial in June 1993 evaluating toxicity and activity and became a randomized phase III trial from April 1996 until November 1998. European Organization for the Research and Treatment of Cancer (EORTC) Genitourinary Group members from institutions in 8 countries participated in this protocol. The 3.2 year median follow-up results were first reported at ASCO in 2000 and published in 2001 [8]. The primary objective was to demonstrate an improvement in survival with HD-M-VAC. The current report seeks to update our experience with a median follow-up in both groups of 7.3 years.

Section snippets

Patients and methods

Patients with bidimensionally measurable distant metastases or unresectable TCC of the urinary tract (bladder, ureter, or renal pelvis) with no prior systemic cytotoxic or biologic treatment, and a WHO performance status of 0 or 1 were eligible for this trial. Patients were randomized 1:1 between HD-M-VAC which consisted of Methotrexate (MTX) 30 mg/m² d 1,Vinblastine (VBL) 3 mg/m² d 2, Adriamycin (ADM) 30 mg/m² d 2 and Cisplatin (CDDP) 70 mg/m² d 2 with Granulocyte Colony Stimulating Factor (G-CSF)

Results

Patient characteristics were well balanced between the two groups and are described in Table 2. One hundred and thirty four patients were randomized to the HD-M-VAC arm and 129 patients to the M-VAC arm. The median WHO Performance Status was 1. 40% and 31% had visceral metastases; 60% and 69% did not have lung, liver or bone metastases; 20% and 15% had prior radiation therapy; and 73% and 75% had prior surgery, respectively, for HD-M-VAC and M-VAC arms.

Generally, the patients who participated

Discussion

Table 6 describes the randomized trials in the literature which have sought to improve upon the results with M-VAC chemotherapy. The Gemcitabine-Cisplatin (GC) combination has been shown to have similar results with a better toxicity profile and has become a widely accepted second standard chemotherapy regimen [9].

Triplet regimens have been evaluated primarily in phase II settings with promising results. The Spanish regimen of gemcitabine, cisplatin, and paclitaxel (GCP) led to a RR of 78% [10]

Conflict of interest statement

None declared.

Acknowledgements

This publication was supported by Grants No. 5U10-CA11488-22 through 5U10-CA11488-35 from the National Cancer Institute (Bethesda, MD, USA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Contributing institutions: San Camillo and Forlanini Hospitals, Roma – UMC St. Radbound, Nijmegan – AVL, Amsterdam,Gustave Roussy, Villejuif – Radiumhospital, Oslo – Cent. Di Rif. Oncol, Aviano AZ VU, Amsterdam –

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Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest statement

Acknowledgements

Ann Oncol

J Urol

Crit Rev Oncol Hematol

A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a Cooperative Group Study

J Clin Oncol

A prospective randomized trial comparing CISCA to MVAC chemotherapy in advanced metastastic urothelial tumours

J Clin Oncol

M-VAC for advanced transitional cell carcinoma of the urothelium: efficacy, and patterns of response and relapse

Cancer

Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy

J Clin Oncol