Hoosier Oncology Group randomized phase II study of docetaxel, vinorelbine, and estramustine in combination in hormone-refractory prostate cancer with pharmacogenetic survival analysis.
OBJECTIVE
To determine the safety and efficacy of two docetaxel doublets in hormone-refractory prostate cancer (HRPC) patients and to examine the prognostic role of polymorphisms in host genes important to docetaxel metabolism and transport.


METHODS
Sixty-four chemotherapy-naive patients with HRPC were randomized to docetaxel and vinorelbine (D, 20 mg/m2 i.v. days 1 and 8; V, 25 mg/m2 i.v. days 1 and 8) or docetaxel and estramustine phosphate (D, 60-70 mg/m2 i.v. day 1; E, 280 mg oral thrice daily days 1-5) administered q21d. Primary end point was clinically significant toxicity. A pharmacogenetic analysis of host genes was done in patients who received at least one cycle of docetaxel therapy.


RESULTS
Grade 3/4 toxicity occurred in 15.6% of DV patients and in 28.6% DE patients. Neither arm exceeded the threshold of clinically significant toxicity. In the DV arm, objective response rate was 33%, prostate-specific antigen response rate was 20%, and median survival was 16.2 months. In the DE arm, objective response rate was 67%, prostate-specific antigen response rate was 43%, and median survival was 19.7 months. Pharmacogenetic analyses showed a significant association between survival beyond 15 months and the ABCG2 421 C > A (Q141K) polymorphism compared with the wild-type (C/C) genotype (66% versus 27%; P = 0.05).


CONCLUSIONS
DV and DE doublets are active with a tolerable toxicity profile in patients with HRPC; however, efficacy does not seem superior to standard single-agent docetaxel. The ABCG2 421 C > A (Q141K) polymorphism may be an important predictor of response and survival in HRPC patients treated with docetaxel-based chemotherapy.
Hahn
Noah M
NM
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Marsh
Sharon
S
Fisher
William
W
Langdon
Robert
R
Zon
Robin
R
Browning
Mark
M
Johnson
Cynthia S
CS
Scott-Horton
Tiffany J
TJ
Li
Lang
L
McLeod
Howard L
HL
Sweeney
Christopher J
CJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D000077143:Docetaxel; D004961:Estramustine / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000633:toxicity; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D000077235:Vinorelbine
D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D014747:Vinblastine; D000077235:Vinorelbine