title: Dose escalation study for defining the maximum tolerated dose of continuous oral trofosfamide in pretreated patients with metastatic lung cancer.
abstract: BACKGROUND
  Trofosfamide is increasingly used in the treatment of patients with several types of malignancies. However, the optimal dose of trofosfamide for patients with advanced cancer has not been systematically investigated yet. The aim of this study was to define the maximum tolerated dose (MTD) of continuous oral trofosfamide.
  
  
  METHODS
  16 patients with advanced lung cancer (14 nonsmall cell lung cancer, 2 small cell lung cancer; 10 male, 6 female; median age 64 years (range 46-82); median Karnofsky status 70%; median number of organs involved 3 (range 1-6)) were enrolled. All patients were previously treated with chemotherapy (median 2x, range 1-6) and 8/16 (50%) with radiotherapy. Patients received trofosfamide p.o. administered in 3 doses per day for 3 weeks (1 cycle) using a 3-patient-cohort dose-escalation strategy. Toxicities were graded according to the WHO Criteria.
  
  
  RESULTS
  Patients received a median of 2 cycles of trofosfamide (range 1-4) at 3 dose levels (90, 125, and 175 mg/m2). Grade 3 and 4 neutropenia, anemia, and thrombocytopenia were observed in 20, 13.3, and 6.6%, respectively. Dose-limiting toxicities during the first cycle were grade 3 muscle weakness and anorexia observed in 1/6 patients in cohort 1 (trofosfamide 90 mg/m2), grade 3 neutropenia in 1/6, and encephalopathy in 1/6 patients in cohort 3 (trofosfamide 175 mg/m2). Therefore, the dose level of 125 mg/m2 was defined as the MTD.
  
  
  CONCLUSIONS
  Trofosfamide at 125 mg/m2 administered in 3 doses per day was well tolerated. This dose level is recommended for further clinical studies.
authors.affiliation: Krankenhaus Nordwest, Frankfurt/M., Germany.
authors.forename: S-E
authors.initials: SE
authors.lastname: Al-Batran
authors.forename: A
authors.initials: A
authors.lastname: Atmaca
authors.forename: F
authors.initials: F
authors.lastname: Bert
authors.forename: D
authors.initials: D
authors.lastname: Jäger
authors.forename: C
authors.initials: C
authors.lastname: Frisch
authors.forename: A
authors.initials: A
authors.lastname: Neumann
authors.forename: J
authors.initials: J
authors.lastname: Orth
authors.forename: A
authors.initials: A
authors.lastname: Knuth
authors.forename: E
authors.initials: E
authors.lastname: Jäger
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000556:secondary; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000556:secondary; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide; C003726:trofosfamide