title: Modern Image-Guided Intensity-Modulated Radiotherapy for Oropharynx Cancer and Severe Late Toxic Effects: Implications for Clinical Trial Design.
abstract: Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer.
  
  
  
  Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer.
  
  
  
  For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited.
  
  
  
  Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin.
  
  
  
  The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method.
  
  
  
  One-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia.
  
  
  
  These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Ward
authors.affiliation: School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Richard Blake
authors.initials: RB
authors.lastname: Ross
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Shlomo A
authors.initials: SA
authors.lastname: Koyfman
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Head & Neck Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Robert
authors.initials: R
authors.lastname: Lorenz
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Head & Neck Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Lamarre
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Head & Neck Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Joseph
authors.initials: J
authors.lastname: Scharpf
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Head & Neck Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Burkey
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Nikhil P
authors.initials: NP
authors.lastname: Joshi
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Woody
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Head & Neck Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Brandon
authors.initials: B
authors.lastname: Prendes
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Narcissa
authors.initials: N
authors.lastname: Houston
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Chandana A
authors.initials: CA
authors.lastname: Reddy
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John F
authors.initials: JF
authors.lastname: Greskovich
authors.affiliation: Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adelstein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use; D004750:Enteral Nutrition; D004940:Esophageal Stenosis / Q000209:etiology; D005260:Female; D005355:Fibrosis / Q000209:etiology; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009333:Neck / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000473:pathology / Q000628:therapy*; D010025:Osteoradionecrosis / Q000209:etiology; D011015:Pneumonia, Aspiration / Q000209:etiology; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects*; D012189:Retrospective Studies; D014832:Voice Disorders / Q000209:etiology; D014987:Xerostomia / Q000209:etiology
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin