title: Dose-escalated intensity-modulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers.
abstract: OBJECTIVE
  To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H).
  
  
  METHODS
  A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded.
  
  
  RESULTS
  Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2.
  
  
  CONCLUSIONS
  At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study.
authors.affiliation: Head and Neck Unit, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Aisha B
authors.initials: AB
authors.lastname: Miah
authors.forename: Shreerang A
authors.initials: SA
authors.lastname: Bhide
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Guerrero-Urbano
authors.forename: Catharine
authors.initials: C
authors.lastname: Clark
authors.forename: A Margaret
authors.initials: AM
authors.lastname: Bidmead
authors.forename: Suzanne
authors.initials: S
authors.lastname: St Rose
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Barbachano
authors.forename: Roger
authors.initials: R
authors.lastname: A'hern
authors.forename: Mary
authors.initials: M
authors.lastname: Tanay
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hickey
authors.forename: Robyn
authors.initials: R
authors.lastname: Nicol
authors.forename: Kate L
authors.initials: KL
authors.lastname: Newbold
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage; D003251:Constriction, Pathologic / Q000209:etiology / Q000628:therapy; D003680:Deglutition Disorders / Q000209:etiology; D003872:Dermatitis / Q000209:etiology; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D060828:Induction Chemotherapy / Q000009:adverse effects / Q000379:methods; D007822:Laryngeal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D007830:Larynx; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D059351:Organ Sparing Treatments / Q000379:methods; D010608:Pharyngeal Diseases / Q000209:etiology / Q000628:therapy; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects / Q000379:methods*; D013280:Stomatitis / Q000209:etiology
chemical_list: D002945:Cisplatin; D005472:Fluorouracil