title: Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.
abstract: OBJECTIVE
  A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.
  
  
  METHODS
  Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.
  
  
  RESULTS
  Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.
  
  
  CONCLUSIONS
  Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination.
authors.affiliation: Hematology-Oncology and Head and Neck Cancer Program, and Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.forename: Austin G
authors.initials: AG
authors.lastname: Duffy
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Simone
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Arai
authors.forename: Seungwon W
authors.initials: SW
authors.lastname: Kim
authors.forename: Susan F
authors.initials: SF
authors.lastname: Rudy
authors.forename: Vishnu R
authors.initials: VR
authors.lastname: Kannabiran
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.forename: Minyoung
authors.initials: M
authors.lastname: Jang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Nanette
authors.initials: N
authors.lastname: Suksta
authors.forename: Theresa
authors.initials: T
authors.lastname: Cooley-Zgela
authors.forename: Susmita G
authors.initials: SG
authors.lastname: Ramanand
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003131:Combined Modality Therapy / Q000009:adverse effects; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014157:Transcription Factors / Q000096:biosynthesis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D016207:Cytokines; D011480:Protease Inhibitors; D011719:Pyrazines; D014157:Transcription Factors; D000069286:Bortezomib; D066246:ErbB Receptors; D000068818:Cetuximab