title: Phase I trial of high-dose fosfestrol in hormone-refractory adenocarcinoma of the prostate.
abstract: Androgen deprivation displays the mean therapy of advanced stage prostatic cancer. The development of hormone-resistant disease leads to a fatal tumor progression. High-dose fosfestrol (diethylstilbestrol disphosphate) has been suggested to circumvent hormone resistance and to induce a direct cytotoxic effect. Twenty-one patients with hormone-refractory prostate cancer were enrolled in a phase I trial of continuous infusion of high, daily escalating dose of fosfestrol. Fosfestrol was given in a 3.5 hr infusion in 0.9% normal saline at a starting dose of 1.5 g/d. The dose was increased daily in the same patient according to the following schedule: 1.5, 1.8, 2.4, 3.0, 3.6, 3.9, 4.5, 5.1 and 5.7 g/d. The duration of the infusion was prolonged to 7 or 10.5 hr, if a major side effect occurred. There was neither hematological nor cardiovascular toxicity. The main dose-limiting toxicities were nausea/vomiting in 17 patients, edema in 2 patients, and more than 5% weight gain in 3 patients. The planned maximal dose was reached in 10 patients during a 3.5 hr infusion, and in 3 additional patients, after infusion prolongation. Seven patients experienced a subjective improvement: Prostatic acid phosphatase and prostatic specific antigen decreased in 4 out of 11 and in 7 out of 12 patients, respectively. The suggested dose to phase II trial is 4 g/d in 3.5 hr infusion for a duration of up to 10 days.
authors.affiliation: Department of Medicine, Institut Gustave-Roussy, Villejuif, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Droz
authors.forename: E
authors.initials: E
authors.lastname: De Smedt
authors.forename: J
authors.initials: J
authors.lastname: Kattan
authors.forename: F
authors.initials: F
authors.lastname: Keuppens
authors.forename: S
authors.initials: S
authors.lastname: Khoury
authors.forename: C
authors.initials: C
authors.lastname: Mahler
authors.forename: L
authors.initials: L
authors.lastname: Denis
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001859:Bone Neoplasms / Q000556:secondary; D003131:Combined Modality Therapy; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004351:Drug Resistance; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004054:Diethylstilbestrol; C004955:fosfestrol; D000135:Acid Phosphatase; D017430:Prostate-Specific Antigen