Radiotherapy plus EGFR inhibitors: synergistic modalities

Abstract

Locally advanced (stage III or IV) squamous cell carcinoma of the head and neck (SCCHN) often requires multimodal treatment, consisting of a combination of surgery, radiation, and/or systemic therapy, namely chemotherapy or targeted agents. The expression of the epidermal growth factor receptor (EGFR) has been detected in more than 90% of all cases of SCCHN and has been correlated with decreased survival rates, resistance to radiotherapy, loco-regional treatment failure, and increased rates of distant metastases. This paper discusses several strategies aimed at targeting EGFR in combination with radiation. Until now, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted agent that has been shown to improve overall survival in combination with radiation therapy. However, considering that there are multiple mechanisms of primary and acquired resistance to EGFR inhibitors, we focused on dissecting molecular pathways of EGFR inhibition to find alternative or complementary strategies for increasing tumour responsiveness. We suggest that the combination of treatments targeting the EGFR pathway and drugs aimed at increasing immune responses represent a promising approach that deserves to be further explored.

Recent findings on the impact of ErbB receptors status on prognosis and therapy of head and neck squamous cell carcinoma

“…Nonetheless, there is a rather general consensus on the correlation between EGFR expression levels, poor prognosis and worse treatment outcomes in patients with HNSCC, while there is no definitive evidence that EGFR gene copy number and mutations may have prognostic value in this group of cancers ( 1 , 2 , 8 , 17 , 33 ). In particular, EGFR overexpression has been associated with radiotherapy resistance, loco-regional treatment failure, higher rates of metastatization, and with reduced disease-free, progression-free and overall survival in different cohorts of patients ( 8 , 17 , 77 , 78 ). Worthy of note, several authors remarked that the significance of the observed correlations is critically dependent on the assessment of EGFR protein levels in cancer tissues by means of quantitative image analysis and scoring systems, taking into account both intensity and extent of the immunostaining ( 17 , 78 ).…”

EGFR Mutations in Head and Neck Squamous Cell Carcinoma

“…For many HNSCCs, the response to a single-agent chemotherapy or monoclonal antibody alone remains dismally low mandating a multi-modal approach combining surgery, chemotherapy and/or radiation [ 46 , 47 ]. Early in vitro studies demonstrated that high concentrations of EGF slowed tumor growth, presumably through negative feedback and resulted in radiosensitization of human HNSCC cells [ 48 , 49 ].…”

“…The predictive value of EGFR has been very well established using various methodologies such as immunohistochemical analysis of tumor samples, fluorescent in situ hybridization, tissue microarray, and gene sequencing [ 69 , 70 , 71 ]. Multiple studies have shown that the overexpression of EGFR in HNSCC directly correlates with worse outcomes [ 47 , 54 , 72 , 73 , 74 ]. Meta-analyses have shown that EGFR overexpression is associated with reduced overall survival (OS), and progression-free survival (PFS), and disease-free survival (DFS) with the magnitude of these effects varying from study to study [ 75 , 76 , 77 , 78 ].…”

Current status and perspective of tumor immunotherapy for head and neck squamous cell carcinoma

“…8 Epidermal growth factor receptortargeted therapies for HNSCC Epidermal growth factor receptor (EGFR) is a prototypical receptor tyrosine kinase that is overexpressed in HNSCC and affects the proliferation, apoptosis, angiogenesis, and metastasis of tumor cells (Nair et al, 2022). Many studies have shown that the overexpression of EGFR in HNSCC directly correlates with worse outcomes (Temam et al, 2007;Agulnik, 2012;Bossi and Platini, 2017). To date, EGFR blockades are attractive targets in HNSCC patients and anti-EGFR strategies such as IgG-based monoclonal antibodies (mAbs), have shown acceptable clinical benefits.…”