Page 4 - 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

There was a non-significant 3.2 month median OS improvement favoring PGC in the
intention-to-treat (ITT) patient population which reached statistical significance when 47 patients
not meeting the eligibility criteria were excluded. An unplanned subgroup analysis revealed
benefit in the 81% of patients with bladder primary. Febrile neutropenia was increased in the
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PGC arm at 13.2% compared to 4.3%.
Currently, there are no completed clinical trials supporting the use of first line immunotherapy in
cisplatin eligible patients. However, numerous trials are currently evaluating the role of first line
immunotherapy (table 5).
2. Patient ineligible for cisplatin-based chemotherapy
• In patients ineligible for cisplatin-based chemotherapy, the preferred regimen is
gemcitabine / carboplatin (GCa)
• In patients not suitable for combination chemotherapy, single agent gemcitabine,
paclitaxel or docetaxel is recommended.
• Immunotherapy is not routinely recommended in the first line setting for
cisplatin-ineligible patients.

Chemotherapy in cisplatin-ineligible patients
Carboplatin based regimens are inferior to cisplatin-based regimens with lower response rates
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and trend towards inferior survival. . Nonetheless, carboplatin is active in urothelial carcinoma
and is the cornerstone of preferred regimens in cisplatin-ineligible patients. Gemcitabine /
carboplatin (GCa) was compared to M-CAVI (methotrexate, carboplatin, vinblastine) in the
phase III EORTC 30986 study. The population studied was ineligible for cisplatin on the basis of
a GFR of 30 – 60mls/min (55% of patients), WHO PS of 2 (17.6%) or both (27.3%). Visceral
metastases were present in 51% of patients. Efficacy was similar in both regimens with a median
OS of 9.3 months for GCa and 8.1 months with M-CAVI. Only 8% of patients were still alive
after a median follow up of 4.5 years. Toxicity was reduced with GCa compared to M-CAVI
with 9% cases of severe acute toxicity (SAT) and 2 toxic deaths compared to 21% cases of SAT
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and 4 toxic deaths, respectively. Gemcitabine / carboplatin has thus become the preferred
regimen in this generally less robust group of patients.
Several other carboplatin and non carboplatin based regimens have been evaluated in
phase II studies. Although demonstrating encouraging results, none of these regimens has been
further assessed in phase III studies and are not considered standard regimens. 14–21 Paclitaxel
and gemcitabine has demonstrated overall response rates of between 37 – 70%, however
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pulmonary toxicity has been noted.
In patients not suitable for combination therapy, single agent gemcitabine, paclitaxel or
docetaxel has been studied in small single arm phase II studies. 22–25 Response rates have varied
between 25 – 47% but have generally been of short duration with median OS ranging between 8
– 12 months in these series.