title: Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer.
abstract: BACKGROUND
  Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-α gene, with chemoradiotherapy in locally advanced esophageal cancer.
  
  
  OBJECTIVE
  To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic.
  
  
  METHODS
  Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 × 10(8) to 4 × 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment.
  
  
  METHODS
  U.S. multicenter study.
  
  
  METHODS
  Patients with stage II and III esophageal cancer were enrolled.
  
  
  METHODS
  Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival.
  
  
  RESULTS
  Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 × 10(11) PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively.
  
  
  CONCLUSIONS
  We included primarily adenocarcinoma.
  
  
  CONCLUSIONS
  Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 × 10(10) PU and is associated with long survival. This regimen warrants additional studies.
authors.affiliation: University of California, Irvine, H.H. Chao Comprehensive Digestive Disease Center, Orange, California, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Chang
authors.forename: Tony
authors.initials: T
authors.lastname: Reid
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: Stephen
authors.initials: S
authors.lastname: Swisher
authors.forename: Harlan
authors.initials: H
authors.lastname: Pinto
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.forename: Amitabh
authors.initials: A
authors.lastname: Chak
authors.forename: Roy
authors.initials: R
authors.lastname: Soetikno
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects; D023341:Chills / Q000209:etiology; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D019160:Endosonography; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D004941:Esophagitis / Q000209:etiology; D005221:Fatigue / Q000209:etiology; D005260:Female; D005334:Fever / Q000209:etiology; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D015552:Injections, Intralesional; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D013923:Thromboembolism / Q000209:etiology; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018084:Ultrasonography, Interventional; D014839:Vomiting / Q000209:etiology; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin; D005472:Fluorouracil