title: Phase I study of treatment with oral 13-cis-retinoic acid, subcutaneous interferon alfa-2a, cisplatin, and 24-hour infusion 5-fluorouracil/leucovorin.
abstract: A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs.
  
  
  OBJECTIVE
  To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types.
  
  
  METHODS
  Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily.
  
  
  RESULTS
  A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary.
  
  
  CONCLUSIONS
  The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.
authors.affiliation: Department of Medicine, University of Chicago Medical Center, IL 60637-1470, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Fleming
authors.forename: S M
authors.initials: SM
authors.lastname: O'Brien
authors.forename: P C
authors.initials: PC
authors.lastname: Hoffman
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: R L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: S E
authors.initials: SE
authors.lastname: Waggoner
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D015474:Isotretinoin / Q000008:administration & dosage / Q000009:adverse effects; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins; D012074:Remission Induction
chemical_list: D000931:Antidotes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D015474:Isotretinoin; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil