Abstract
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. 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. 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. 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.