title: Phase II study of mitoxantrone and ketoconazole for hormone-refractory prostate cancer.
abstract: BACKGROUND
  Doxorubicin plus ketoconazole has exhibited significant activity in patients with advanced prostate cancer. However, overall and cardiac-specific toxicity was reported to be high. Mitoxantrone has activity similar to that of doxorubicin, is less cardiotoxic, and is widely used to treat prostate cancer. The current study sought to evaluate the toxicity and activity of mitoxantrone plus ketoconazole in a cohort of patients with hormone-refractory prostate cancer.
  
  
  METHODS
  Progression after medical or surgical castration and, for those patients receiving antiandrogens, progression after withdrawal was required, as was objective evidence of metastasis, castrate levels of testosterone, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and intact cardiac function. After enrollment onto a multicenter local consortium study, subjects were treated with mitoxantrone at a dose of 12 mg/m2 intravenously every 3 weeks plus continuous oral ketoconazole at a dose of 400 mg 3 times daily and ascorbic acid at a dose of 250 mg. Replacement doses of hydrocortisone were given.
  
  
  RESULTS
  For 40 enrolled subjects, the median prostate-specific antigen and ECOG performance status were 68 and 1, respectively, 53% had Gleason scores of 8 to 10, and all had metastasis. Predominant Grade 3/4 toxicities were: neutropenia in 13%, neutropenic fever in 10%, and anemia in 13%. Of 37 evaluable patients, 8% achieved a complete remission (CR) and 62% achieved a partial remission (PR), for a CR plus PR rate of 70%. For soft tissue and bone disease, overall response rates were 13% and 8%, respectively. The median progression-free survival and overall survival were 10 months and 18 months, respectively.
  
  
  CONCLUSIONS
  Mitoxantrone plus ketoconazole is well tolerated, is active in hormone-refractory prostate cancer, and should be studied further.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Northwestern University Medical School, Chicago 60611-3008, and Ingalls Hospital, Harvey, Illinois, USA.
authors.forename: John
authors.initials: J
authors.lastname: Eklund
authors.forename: Mark
authors.initials: M
authors.lastname: Kozloff
authors.forename: Joy
authors.initials: J
authors.lastname: Vlamakis
authors.forename: Alexander
authors.initials: A
authors.lastname: Starr
authors.forename: Margaret
authors.initials: M
authors.lastname: Mariott
authors.forename: Lilia
authors.initials: L
authors.lastname: Gallot
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schilder
authors.forename: Erwin
authors.initials: E
authors.lastname: Robin
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D007654:Ketoconazole