title: Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma.
abstract: BACKGROUND
  This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS).
  
  
  METHODS
  Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected.
  
  
  RESULTS
  Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m(2). At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively.
  
  
  CONCLUSIONS
  The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.
authors.affiliation: Section of Surgical Oncology, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.|Sarcoma Program, Hoag Family Cancer Institute and Hoag Memorial Hospital Presbyterian, Newport Beach, California.
authors.forename: William W
authors.initials: WW
authors.lastname: Tseng
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Christina A
authors.initials: CA
authors.lastname: To
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Division of Surgical Oncology, James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.affiliation: Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Lin
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Janice N
authors.initials: JN
authors.lastname: Cormier
authors.affiliation: Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Valerae O
authors.initials: VO
authors.lastname: Lewis
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Barry W
authors.initials: BW
authors.lastname: Feig
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.affiliation: Department of Radiation Oncology, University of Tennessee Health Sciences Center, Memphis, Tennessee.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Ballo
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shreyaskumar
authors.initials: S
authors.lastname: Patel
authors.affiliation: University Health Network, Toronto, Canada.
authors.forename: Peter W T
authors.initials: PW
authors.lastname: Pisters
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D059186:Chemoradiotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005121:Extremities / Q000473:pathology*; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D060726:Torso / Q000473:pathology*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: gemcitabine; neoadjuvant; radiation; sarcoma; toxicity