title: Sequential (gemcitabine/vinorelbine) and concurrent (gemcitabine) radiochemotherapy with FDG-PET-based target volume definition in locally advanced non-small cell lung cancer: first results of a phase I/II study.
abstract: BACKGROUND
  The aim of the study was to determine the maximal tolerated dose (MTD) of gemcitabine every two weeks concurrent to radiotherapy, administered during an aggressive program of sequential and simultaneous radiochemotherapy for locally advanced, unresectable non-small cell lung cancer (NSCLC) and to evaluate the efficacy of this regime in a phase II study.
  
  
  METHODS
  33 patients with histologically confirmed NSCLC were enrolled in a combined radiochemotherapy protocol. 29 patients were assessable for evaluation of toxicity and tumor response. Treatment included two cycles of induction chemotherapy with gemcitabine (1200 mg/m2) and vinorelbine (30 mg/m2) at day 1, 8 and 22, 29 followed by concurrent radiotherapy (2.0 Gy/d; total dose 66.0 Gy) and chemotherapy with gemcitabine every two weeks at day 43, 57 and 71. Radiotherapy planning included [18F] fluorodeoxyglucose positron emission tomography (FDG PET) based target volume definition. 10 patients were included in the phase I study with an initial gemcitabine dose of 300 mg/m2. The dose of gemcitabine was increased in steps of 100 mg/m2 until the MTD was realized.
  
  
  RESULTS
  MTD was defined for the patient group receiving gemcitabine 500 mg/m2 due to grade 2 (next to grade 3) esophagitis in all patients resulting in a mean body weight loss of 5 kg (SD = 1.4 kg), representing 8% of the initial weight. These patients showed persisting dysphagia 3 to 4 weeks after completing radiotherapy. In accordance with expected complications as esophagitis, dysphagia and odynophagia, we defined the MTD at this dose level, although no dose limiting toxicity (DLT) grade 3 was reached. In the phase I/II median follow-up was 15.7 months (4.1 to 42.6 months). The overall response rate after completion of therapy was 64%. The median overall survival was 19.9 (95% CI: [10.1; 29.7]) months for all eligible patients. The median disease-free survival for all patients was 8.7 (95% CI: [2.7; 14.6]) months.
  
  
  CONCLUSIONS
  After induction chemotherapy, the maximum tolerated dose and frequency of gemcitabine was defined at 500 mg/m2 every two weeks in three cycles during a maximum of 7 weeks of thoracic radiotherapy for the phase II study. This regimen represents an effective and tolerable therapy in the treatment of NSCLC.
authors.affiliation: Department of Radiotherapy, RWTH Aachen University, Germany. BGagel@UKAachen.de
authors.forename: Bernd
authors.initials: B
authors.lastname: Gagel
authors.forename: Marc
authors.initials: M
authors.lastname: Piroth
authors.forename: Michael
authors.initials: M
authors.lastname: Pinkawa
authors.forename: Patrick
authors.initials: P
authors.lastname: Reinartz
authors.forename: Thomas
authors.initials: T
authors.lastname: Krohn
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Kaiser
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.forename: Christian
authors.initials: C
authors.lastname: Breuer
authors.forename: Branka
authors.initials: B
authors.lastname: Asadpour
authors.forename: Axel
authors.initials: A
authors.lastname: Schmachtenberg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eble
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D003131:Combined Modality Therapy; D016001:Confidence Intervals; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011336:Probability; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012074:Remission Induction; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D019788:Fluorodeoxyglucose F18; D014747:Vinblastine; D000077235:Vinorelbine; D000093542:Gemcitabine