Page 3 - Canadian Urological Association/Genitourinary Medical Oncologists of Canada consensus statement: Management of unresectable locally advanced and metastatic urothelial carcinoma

CUAJ – Consensus Statement Warren et al
Unresectable locally advanced and metastatic urothelial carcinoma

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as low as 35 – 40mls / min and reported acceptable safety outcomes. In practice, cisplatin is
rarely used in patients with a GFR < 45mls/min.

First-line systemic therapy
1. Patient eligible for cisplatin-based chemotherapy:
– In patients suitable for cisplatin based chemotherapy, the preferred routine
regimen is gemcitabine / cisplatin (GC).
– Dose dense methotrexate, vinblastine, doxorubicin and cyclophosphamide
(DD- MVAC) with growth factor support may be considered in select cases
where a more aggressive treatment approach is being considered.
Gemcitabine/cisplatin was compared to the earlier standard of methotrexate, vinblastine,
doxorubicin and cyclophosphamide (MVAC) in a phase III randomized trial. GC demonstrated
similar efficacy but with reduced toxicity. In an updated analysis with a minimum of 5 years of
follow up, median overall survival (OS) was 14 months in the GC arm, with a 13% 5 year
survival rate, which was not significantly different from the MVAC arm. The hazard ratio of GC
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compared to MVAC was 1.09 (95% CI 0.88 – 1.34; P=0.66). Toxicity was increased in the
MVAC arm with a higher rate of grade 3-4 neutropenic sepsis (12% vs 1%), mucositis (22% vs
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1%) and toxic death (3% vs 1%).
The small proportion of long-term survivors is seen predominantly in patients with good
performance status (ECOG 0 – 1, KFS > 80) and in those patients without visceral metastases
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(bone, lung, liver). Further attempts have been made to improve on these results by
intensifying doses and adding additional chemotherapy agents. One notable regimen is DD-
MVAC tested in the phase III EORTC 30924 study. This regimen consists of two weekly MVAC
with growth factor support and was compared to standard MVAC. Seven year follow up
demonstrated a statistically borderline improvement in overall survival with a 5 year OS of
21.8% in DD-MVAC treated patients compared to 13.5% with standard MVAC. The hazard
ratio of DD-MVAC compared to standard MVAC was 0.76 (95% CI 0.58 – 0.99, P=0.042). A
compete response (CR) was seen in 21% of those receiving DD-MVAC compared with 9% of
those receiving standard dose MVAC. The addition of growth factor support reduced
neutropenic complications and mucositis in the DD-MVAC arm compared with the standard
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MVAC arm, however there was still one death due to toxicity in each treatment arm.
Evidence for other regimens is not sufficiently robust to endorse their inclusion as
recommended treatments. Dose dense GC (DD-GC) was compared to the DD-MVAC regimen
in a phase III study performed by the Hellenic Oncology group. Although DD-GC demonstrated
similar efficacy to DD-MVAC with reduced toxicity, the study was underpowered with
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imbalances in the treatment arms. Concerns regarding vascular toxicity with this regimen were
raised as a result of a neoadjuvant study of DD-GC for muscle invasive bladder cancer in which
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23% of patients experienced grade 3-4 venous and arterial events. The addition of paclitaxel to
GC (PGC) was tested in the phase III EORTC Intergroup 30987 study consisting of 626 patients.