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Title: A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximummore » tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.« less
Authors:
 [1] ;  [2] ;  [3] ; ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ; ;  [1] ; ; ; ; ;  [6] ;  [7] ;  [8] ;  [1] ;  [2]
  1. Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  2. (United States)
  3. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  4. Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  5. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  6. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  7. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
  8. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
Publication Date:
OSTI Identifier:
22267907
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 87; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARCINOMAS; COMBINED THERAPY; DOSES; HEAD; NECK; PHARYNX; PLATINUM COMPLEXES; RADIOTHERAPY; TOXICITY