The standard therapy for metastatic TCC of the urothelium was a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), developed about 15 years ago by Logothetis and colleagues in Texas. In separate randomised trials MVAC was shown to provide a survival advantage over cisplatin alone (median survival, 12.5 months v 8.2 months) and a combination of cisplatin, cyclophosphamide, and doxorubicin (median survival, 48 weeks v 40 weeks).r However, the MVAC regimen is fairly toxic and difficult to give in a disease where the median age of patients is 72 years. The MVAC trials that studied patients with a median age of about 67 years had a mortality rate of almost 5% from neutropenic sepsis.
Gemcitabine was found to have significant single agent activity in patients failing MVAC and was well tolerated. An international randomised trial compared a combination of gemcitabine and cisplatin (GC) with MVAC in 405 patients with metastatic or locally advanced (T4b, N2 or N3) urothelial cancer. The survival was similar (14.0 months for GC and 15.2 months for MVAC) and the GC arm was considerably less toxic. The 5-year overall survival rates for patients with and without visceral metastases were 6.8% and 20.9%. When adjusting for prognostic factors, the hazard ratio was 0.99 for overall survival and 1.01 for progression-free survival.
MVAC is still the gold standard for metastatic bladder cancer. However, given in the traditional manner, MVAC was associated with myelosuppression and hospitalisation. The von der Maase study was designed as a superiority study (and was not powered to be an equivalence study). Gemcitabine-cisplatin did not meet the endpoints of statistical significance to demonstrate superiority; however gemcitabine-cisplatin has become the standard practice due to its tolerability.r
Efficacy
von der Masser |
Gemcitabine/cisplatin |
Methotrexate/vinblastine/doxorubicin/cisplatin |
p-value |
Median progression-free survival |
7.7 months |
8.3 months |
- |
5 year progression-free survival rates |
9.8% |
11.3% |
0.63 |
Overall survival |
14 months |
15.2 months |
0.66 |
Kaplan-Meier curves for overall survivalr:
© Journal of Clinical Oncology 2005
Toxicity
Toxicityr |
Gemcitabine/cisplatin |
Methotrexate/vinblastine/doxorubicin/cisplatin |
Grade 3 (%) |
Grade 4 (%) |
Grade 3 (%) |
Grade 4 (%) |
Anaemia |
23 |
3 |
15 |
2 |
Thrombocytopenia |
28 |
28 |
8 |
13 |
Neutropenia |
41 |
30 |
17 |
65 |
Mucositis |
1 |
0 |
18 |
4 |
Nausea/vomiting |
22 |
0 |
19 |
2 |
Alopecia |
10 |
0 |
54 |
1 |
Infection |
2 |
0.5 |
10 |
5 |
Diarrhoea |
3 |
0 |
8 |
0.5 |
Pulmonary |
2 |
0.5 |
3 |
3 |
Haematuria |
4 |
0 |
2 |
0 |
Constipation |
1 |
0 |
3 |
0.5 |
Haemorrhage |
2 |
0 |
2 |
0 |
© Journal of Clinical Oncology 2000