title: Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.
abstract: OBJECTIVE
  To determine the maximum-tolerated doses (MTD), the principal toxicities, and the pharmacologic behavior of high doses of Taxol (paclitaxel; Bristol-Myers Squibb, New York, NY) combined with cisplatin and granulocyte colony-stimulating factor (G-CSF).
  
  
  METHODS
  Untreated and minimally pretreated solid-tumor patients received 24-hour infusions of Taxol on day 1 followed by cisplatin on day 2 and G-CSF, 5 micrograms/kg/d subcutaneously (SC), beginning on day 3. Treatment was repeated every 3 weeks. Starting doses of Taxol and cisplatin were 135 and 75 mg/m2, respectively.
  
  
  RESULTS
  The development of a severe peripheral neuropathy and/or severe myalgias precluded the chronic administration of Taxol and cisplatin with G-CSF at doses greater than 250 mg/m2 and 75 mg/m2, respectively. At this dose, the mean Taxol steady-state plasma concentration (Css) exceeds concentrations capable of inducing pertinent antimicrotubule effects in vitro. The severity of the neuropathy was related to the cumulative dose of Taxol, the magnitude of the dose administered during each treatment, and the presence of a pre-existing medical disorder associated with peripheral neuropathy. A proximal myopathy of modest severity also was documented. Although severe neutropenia occurred frequently, especially at the MTD, it was rarely associated with fever (8% of courses), and absolute neutrophil counts (ANCs) less than 500/microL never persisted for more than 5 days. Responses were noted in non-small-cell lung cancer (NSCLC) and head and neck, breast, and esophageal cancers.
  
  
  CONCLUSIONS
  Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.
authors.affiliation: Johns Hopkins Oncology Center, Division of Pharmacology and Experimental Therapeutics, Baltimore, MD 21287-8934.
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: V
authors.initials: V
authors.lastname: Chaudhry
authors.forename: A A
authors.initials: AA
authors.lastname: Forastiere
authors.forename: S E
authors.initials: SE
authors.lastname: Sartorius
authors.forename: D S
authors.initials: DS
authors.lastname: Ettinger
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: B G
authors.initials: BG
authors.lastname: Lubejko
authors.forename: D R
authors.initials: DR
authors.lastname: Cornblath
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009468:Neuromuscular Diseases / Q000139:chemically induced*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D017239:Paclitaxel; D002945:Cisplatin