title: Continuous hyperfractionated accelerated radiotherapy - Escalated dose (CHART-ED): A phase I study.
abstract: BACKGROUND
  Patients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared CHART and conventional radical radiotherapy (60 Gy/30f) given over 6 weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) - fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009.
  
  
  METHODS
  Patients with WHO performance status 0-2 histologically confirmed, inoperable, stage I-III non-small cell lung cancer were recruited into an open phase I dose escalation trial. Three cohorts of six patients were recruited sequentially. Total dose was escalated from standard CHART radiotherapy of 54 Gy/36f/12 days to 57.6G y (2 × 1.8 Gy fractions on day 15, Group 1), 61.2 Gy (4 × 1.8 Gy fractions on days 15-16, Group 2) and 64.8 Gy (6 × 1.8 Gy fractions on days 15-17, Group 3).
  
  
  RESULTS
  Between April 2010 and May 2012, 18 patients were enrolled from 5 UK centres and received escalated dose radiotherapy. 14 were male, 16 squamous cell histology and 12 were stage IIIA or IIIB. The median age was 70 years and baseline characteristics were similar across the three dose cohorts. One patient did not start escalated radiotherapy but all remaining patients completed their planned radiotherapy schedules. Of these 9 patients have died to date with a median survival of 2 years across the three cohorts. Grade 3 or 4 adverse events (fatigue, dysphagia, nausea and anorexia - classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) were reported in 6 patients but the pre-specified dose limiting toxicities (grade 4 early oesophagitis; grade 3 cardiac, spinal cord and pneumonitis) were not observed.
  
  
  CONCLUSIONS
  CHART remains a radiotherapy schedule in routine use across the UK and in this dose escalation study no dose limiting toxicities were observed. We feel the dose of 64.8 Gy/42f/17 days should be taken forward into further clinical trials. The sample size used in this study was small so we plan a randomised phase II study that includes other radiotherapy schedules to confirm safety and select an accelerated sequential chemo-radiotherapy schedule to take into phase III studies.
authors.affiliation: Dept Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom.
authors.forename: Matthew Quintin Fielding
authors.initials: MQ
authors.lastname: Hatton
authors.affiliation: CaCTUS - Cancer Clinical Trials Unit, NHS National Services Scotland, Edinburgh, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Hill
authors.affiliation: Department of Oncology, University of Oxford, United Kingdom.
authors.forename: John David
authors.initials: JD
authors.lastname: Fenwick
authors.affiliation: Dept Clinical Oncology, City Hospital, Nottingham, United Kingdom.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Morgan
authors.affiliation: Dept Clinical Oncology, Bristol Haematology and Oncology Centre, United Kingdom.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Wilson
authors.affiliation: Dept Clinical Oncology, Northern Centre for Cancer Treatment, Freeman Hospital, Newcastle, United Kingdom.
authors.forename: Philip James
authors.initials: PJ
authors.lastname: Atherton
authors.affiliation: Dept Clinical Oncology, Mount Vernon Hospital, Middlesex, United Kingdom.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Dickson
authors.affiliation: CaCTUS - Cancer Clinical Trials Unit, NHS National Services Scotland, Edinburgh, United Kingdom.
authors.forename: Kirsten Eleanor
authors.initials: KE
authors.lastname: Murray
authors.affiliation: CaCTUS - Cancer Clinical Trials Unit Scotland, Institute of Cancer Sciences, University of Glasgow, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Paul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000855:Anorexia / Q000209:etiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D003680:Deglutition Disorders / Q000209:etiology; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D011785:Quality Assurance, Health Care; D000069473:Radiation Dose Hypofractionation
keywords: Continuous Hyper-fractionated Accelerated Radiotherapy – escalated dose (CHART-ED); Inoperable non-small cell lung cancer; Radiotherapy