title: Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity.
abstract: OBJECTIVE
  To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT).
  
  
  METHODS
  This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria.
  
  
  RESULTS
  The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents.
  
  
  CONCLUSIONS
  Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio. Electronic address: stephak@ccf.org.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Stephans
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Toufik
authors.initials: T
authors.lastname: Djemil
authors.affiliation: Cleveland Clinic Learner College of Medicine, Cleveland, Ohio.
authors.forename: Claudiu
authors.initials: C
authors.lastname: Diaconu
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Chandana A
authors.initials: CA
authors.lastname: Reddy
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Ping
authors.initials: P
authors.lastname: Xia
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Woody
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: John
authors.initials: J
authors.lastname: Greskovich
authors.affiliation: Department of Medical Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Vinit
authors.initials: V
authors.lastname: Makkar
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio.
authors.forename: Gregory M M
authors.initials: GM
authors.lastname: Videtic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D019583:Dose Fractionation, Radiation; D004937:Esophageal Fistula / Q000209:etiology*; D004947:Esophagus / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D058958:Organs at Risk / Q000528:radiation effects; D011832:Radiation Injuries / Q000150:complications / Q000473:pathology*; D011836:Radiation Tolerance; D016634:Radiosurgery / Q000009:adverse effects*; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D042461:Vascular Endothelial Growth Factor A