title: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer.
abstract: OBJECTIVE
  We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients.
  
  
  METHODS
  Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients.
  
  
  RESULTS
  Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP.
  
  
  CONCLUSIONS
  No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.
authors.affiliation: National Cancer Institute-Navy Medical Oncology Branch, Uniformed Services University of the Health Sciences, Bethesda, MD.
authors.forename: D C
authors.initials: DC
authors.lastname: Ihde
authors.forename: J L
authors.initials: JL
authors.lastname: Mulshine
authors.forename: B S
authors.initials: BS
authors.lastname: Kramer
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: R I
authors.initials: RI
authors.lastname: Linnoila
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: M
authors.initials: M
authors.lastname: Edison
authors.forename: R M
authors.initials: RM
authors.lastname: Phelps
authors.forename: M
authors.initials: M
authors.lastname: Lesar
authors.forename: J C
authors.initials: JC
authors.lastname: Phares
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012074:Remission Induction; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced; D015431:Weight Loss / Q000187:drug effects
chemical_list: D005047:Etoposide; D002945:Cisplatin