title: Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.
abstract: OBJECTIVE
  TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy.
  
  
  METHODS
  In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity.
  
  
  RESULTS
  The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05).
  
  
  CONCLUSIONS
  SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.
authors: Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, 401 N. Broadway, Weinberg Suite 1440, Baltimore, MD 21231, USA. jherma15@jhmi.edu
authors: Joseph M
authors: JM
authors: Herman
authors: Aaron T
authors: AT
authors: Wild
authors: Hao
authors: H
authors: Wang
authors: Phuoc T
authors: PT
authors: Tran
authors: Kenneth J
authors: KJ
authors: Chang
authors: Gretchen E
authors: GE
authors: Taylor
authors: Ross C
authors: RC
authors: Donehower
authors: Timothy M
authors: TM
authors: Pawlik
authors: Mark A
authors: MA
authors: Ziegler
authors: Hongyan
authors: H
authors: Cai
authors: Dionne T
authors: DT
authors: Savage
authors: Marcia I
authors: MI
authors: Canto
authors: Jason
authors: J
authors: Klapman
authors: Tony
authors: T
authors: Reid
authors: Raj J
authors: RJ
authors: Shah
authors: Sarah E
authors: SE
authors: Hoffe
authors: Alexander
authors: A
authors: Rosemurgy
authors: Christopher L
authors: CL
authors: Wolfgang
authors: Daniel A
authors: DA
authors: Laheru
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D004247:DNA / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000069347:Erlotinib Hydrochloride; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D015552:Injections, Intralesional; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy*; D011799:Quinazolines / Q000008:administration & dosage; D018714:Radiotherapy, Adjuvant; D017211:Treatment Failure; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; C572333:TNFeraseBiologic; D003841:Deoxycytidine; D004247:DNA; D000069347:Erlotinib Hydrochloride; D005472:Fluorouracil; D000093542:Gemcitabine