title: Stereotactic body radiation therapy (SBRT) for lung malignancies: preliminary toxicity results using a flattening filter-free linear accelerator operating at 2400 monitor units per minute.
abstract: BACKGROUND
  Flattening filter-free (FFF) linear accelerators (linacs) are capable of delivering dose rates more than 4-times higher than conventional linacs during SBRT treatments, causing some to speculate whether the higher dose rate leads to increased toxicity owing to radiobiological dose rate effects. Despite wide clinical use of this emerging technology, clinical toxicity data for FFF SBRT are lacking. In this retrospective study, we report the acute and late toxicities observed in our lung radiosurgery experience using a FFF linac operating at 2400 MU/min.
  
  
  METHODS
  We reviewed all flattening filter-free (FFF) lung SBRT cases treated at our institution from August 2010 through July 2012. Patients were eligible for inclusion if they had at least one clinical assessment at least 30 days following SBRT. Pulmonary, cardiac, dermatologic, neurologic, and gastrointestinal treatment related toxicities were scored according to CTCAE version 4.0. Toxicity observed within 90 days of SBRT was categorized as acute, whereas toxicity observed more than 90 days from SBRT was categorized as late. Factors thought to influence risk of toxicity were examined to assess relationship to grade > =2 toxicity.
  
  
  RESULTS
  Sixty-four patients with >30 day follow up were eligible for inclusion. All patients were treated using 10 MV unflattened photons beams with intensity modulated radiation therapy (IMRT) inverse planning. Median SBRT dose was 48 Gy in 4 fractions (range: 30-60 Gy in 3-5 fractions). Six patients (9%) experienced > = grade 2 acute pulmonary toxicity; no non-pulmonary acute toxicities were observed. In a subset of 49 patients with greater than 90 day follow up (median 11.5 months), 11 pulmonary and three nerve related grade > =2 late toxicities were recorded. Pulmonary toxicities comprised six grade 2, three grade 3, and one each grade 4 and 5 events. Nerve related events were rare and included two cases of grade 2 chest wall pain and one grade 3 brachial plexopathy which spontaneously resolved. No grade > =2 late gastrointestinal, skin, or cardiac toxicities were observed. Tumor size, biologically effective dose (BED10, assuming α/β of 10), and tumor location (central vs peripheral) were not significantly associated with grade > =2 toxicity.
  
  
  CONCLUSIONS
  In this early clinical experience, lung SBRT using a FFF linac operating at 2400 MU/min yields minimal acute toxicity. Preliminary results of late treatment related toxicity suggest reasonable rates of grade > =2 toxicities. Further assessment of late effects and confirmation of the clinical efficacy of FFF SBRT is warranted.
authors.affiliation: Space Coast Cancer Center, Titusville, FL, USA. prendergastb@spacecoastcancer.com.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Prendergast
authors.forename: Michael C
authors.initials: MC
authors.lastname: Dobelbower
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.forename: Richard A
authors.initials: RA
authors.lastname: Popple
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Baden
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Minnich
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cerfolio
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Spencer
authors.forename: John B
authors.initials: JB
authors.lastname: Fiveash
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D016015:Logistic Models; D008168:Lung / Q000528:radiation effects; D008175:Lung Neoplasms / Q000532:radiotherapy*; D009362:Neoplasm Metastasis; D010315:Particle Accelerators; D016634:Radiosurgery / Q000295:instrumentation* / Q000379:methods*; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D012189:Retrospective Studies; D012306:Risk; D013997:Time Factors; D016896:Treatment Outcome