Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.
OBJECTIVE
A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) in patients with androgen-independent prostate cancer (AI PCa).


METHODS
Thirty-nine consecutive patients whose disease progressed following castration were treated with oral ketoconazole (1,200 mg) daily and Adriamycin (20 mg/m2 in a 24-hour infusion) once weekly. Antitumor activity was assessed by the level of prostatic-specific antigen (PSA) decline.


RESULTS
PSA levels decreased > or = 50% from baseline in 21 (55%; 95% confidence interval, 38% to 71%) of 38 assessable patients. We observed partial responses (PRs) in seven (58%) of 12 patients with measurable soft tissue disease (in the lung, lymph nodes, and liver). Two patients with history of atherosclerotic heart disease had a sudden cardiac death. Serious toxic reactions included grade III to V stomatitis and grade III to IV acral erythema in 11 patients (29%), and grade III to IV anal and urethral mucositis in five patients (13%). Grade III to IV neutropenia occurred in 11 patients (29%). Seventeen patients (45%) required hospitalization for complications. Fifteen patients (39%) developed hypokalemia, and 24 patients (63%) developed clinical adrenal insufficiency.


CONCLUSIONS
The combination of ketoconazole and Adriamycin has a 55% PSA response rate in patients with AI PCa and is worthy of additional study. This treatment results in frequent adrenal insufficiency. Therefore, future studies should incorporate routine corticosteroid replacement. The cardiac complications caused by this combination should be studied further before it is widely used.
Sella
A
A
Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Kilbourn
R
R
Amato
R
R
Bui
C
C
Zukiwski
A A
AA
Ellerhorst
J
J
Logothetis
C J
CJ
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007654:Ketoconazole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
D004317:Doxorubicin; D017430:Prostate-Specific Antigen; D007654:Ketoconazole