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Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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.

SUBMITTER: Argiris A

PROVIDER: S-EPMC3368806 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.

Argiris Athanassios A Duffy Austin G AG Kummar Shivaani S Simone Nicole L NL Arai Yoshio Y Kim Seungwon W SW Rudy Susan F SF Kannabiran Vishnu R VR Yang Xinping X Jang Minyoung M Chen Zhong Z Suksta Nanette N Cooley-Zgela Theresa T Ramanand Susmita G SG Ahsan Aarif A Nyati Mukesh K MK Wright John J JJ Van Waes Carter C

Clinical cancer research : an official journal of the American Association for Cancer Research 20110712 17

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 intra ...[more]

PMID: 21750205

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Project description:BackgroundEpidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia.MethodsWe queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared.ResultsA total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068).ConclusionsIn contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Project description:To investigate the predictive capacity of early post-treatment diffusion-weighted magnetic resonance imaging (MRI) for recurrence or tumor progression in patients with no tumor residue after chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma, and, to assess the predictive capacity of pre-treatment diffusion-weighted MRI for persistent tumor residue post-CRT. A single center cohort study was performed in one French hospital. All patients with squamous cell carcinoma receiving CRT (no surgical indication) were included. Two diffusion-weighted MRI were performed: one within 8 days before CRT and one 3 months after completing CRT with determination of median tumor apparent diffusion coefficient (ADC). The primary endpoint was progression-free survival. 59 patients were included prior to CRT and 46 (78.0%) completed CRT. A post-CRT tumor residue was found in 19/46 (41.3%) patients. In univariate analysis, initial ADC was significantly lower in patients with residue post CRT (0.56 ± 0.11 versus 0.79 ± 0.13; p < 0.001). When initial ADC was dichotomized at the median, initial ADC lower than 0.7 was significantly more frequent in patients with residue post CRT (73.7% versus 11.1%, p < 0.0001). In multivariate analysis, only initial ADC lower than 0.7 was significantly associated with tumor residue (OR = 22.6; IC [4.9-103.6], p < 0.0001). Among 26 patients without tumor residue after CRT and followed up until 12 months, 6 (23.1%) presented recurrence or progression. Only univariate analysis was performed due to a small number of events. The only factor significantly associated with disease progression or early recurrence was the delta ADC (p = 0.0009). When ADC variation was dichotomized at the median, patients with ADC variation greater than 0.7 had time of disease-free survival significantly longer than patients with ADC variation lower than 0.7 (377.5 [286-402] days versus 253 [198-370], p < 0.0001). Conclusion and relevance: Diffusion-weighted MRI could be a technique that enables differentiation of patients with high potential for early recurrence for whom intensive post-CRT monitoring is mandatory. Prospective studies with more inclusions would be necessary to validate our results.

Dataset Information

Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.

Publications

Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.

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