Mechanisms of Disease: Radiosensitization by Epidermal Growth
The epidermal growth factor receptor (EGFR) inhibitors are among the most intensely studied new molecular therapeutic agents. Although response rates have been somewhat disappointing when EGFR inhibitors are used as single-agent therapy for advanced disease, these inhibitors may be more effective as chemo- and radiosensitizers. The first phase III randomized trial evaluating EGFR inhibitors as radiosensitizers in patients with locally advanced head and neck cancer was strongly positive, indicating significant potential of this class of agents to improve outcome with radiotherapy. However, optimal implementation of EGFR inhibitors as radiosensitizers depends, in part, on a better understanding of the mechanisms of radiosensitization. Preclinical studies provide important observations with regard to potential mechanisms. The phenotypic cellular changes associated with EGFR inhibition are impressively consistent between different model systems, with almost all studies showing that EGFR inhibitors affect proliferation, angiogenesis, and cell survival. Whether EGFR inhibitors influence response to radiation directly, or whether the improved response is a result of additive effects of the two modalities, remains unclear. However, cell-cycle arrest, endothelial cell sensitivity, and apoptotic potential are all important factors in radiation response of epithelial tumors. Furthermore, less-studied effects of EGFR inhibitors on DNA repair suggest that modulation of DNA damage response to cytotoxic injury might result in radio- or chemosensitization. This review will explore potential mechanisms of radiosensitization by EGFR inhibitors.

During the past decade, intense research has initiated a new era of cancer treatment, that of molecular therapeutics. Among the most intensely studied new agents are the epidermal growth factor receptor (EGFR) inhibitors, which target one or more of four EGFR family members of transmembrane tyrosine kinase receptors that functionally transmit extracellular cues to intracellular signal transduction pathways that mediate growth, differentiation, and survival.

EGFR inhibitors are an attractive class of molecularly targeted agents for several reasons. First, EGFR is deregulated in a substantial proportion of human malignancies, including head and neck, lung, brain, breast, colorectal, and prostate cancer, creating a fairly broad platform of potential application. Second, activation of signal transduction pathways by the EGFR family is central to many malignant processes. Third, EGFR overexpression is associated with a poor prognosis and worse response to therapy in many tumor types. Promising preclinical studies have prompted the development of clinical trials testing the tolerability and efficacy of various EGFR inhibitors ( Table 1 ), both as single-agent therapy, and in combination with conventional cytotoxic therapy. Although enthusiasm has carried an unprecedented pace of development and approval of new anti-cancer agents, the clinical results are modest. Perhaps more than ever before, we appreciate the heterogeneity of tumors and the complex interplay of diverse mechanisms driving the pathophysiology of cancer.

Response rates have been lower than anticipated in trials testing the efficacy of EGFR inhibitors as single-agent therapy in the advanced disease setting. Single-agent EGFR-inhibitor treatment may be more effective in earlier stage disease or in the adjuvant setting, and clinical trials have been proposed to test this hypothesis. However, the trials showing the greatest benefit have been those testing EGFR inhibitors in combination with conventional cytotoxic therapy.

The clearest benefit of EGFR-inhibitor treatment to date is noted when it is combined with radiotherapy to treat locally advanced head and neck cancer. A phase III trial compared the efficacy of standard radiotherapy to standard radiotherapy plus an anti-EGFR antibody, cetuximab (Erbitux®, ImClone Systems, Inc, Somerville, NJ, USA). The tumors of 424 patients with Stage III or IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were stratified by T stage, nodal status, and performance score. The patients were then randomly assigned to receive radiotherapy alone or radiotherapy plus weekly, concurrent cetuximab. Radiotherapy was delivered using one of three fractionation regimens (stratified): once daily (2 Gy × 35 fractions over 7 weeks); twice daily (1.2 Gy × 60–64 fractions over 5–5.5 weeks); or concomitant boost (1.8 Gy × 30 fractions with a second daily fraction of 1.5 Gy for the last 12 treatment days over 6 weeks). Concurrent chemotherapy was not allowed. Two-year local control was 56% in the radiotherapy plus cetuximab arm versus 48% in the radiotherapy-alone arm, with median duration of local control of 36 months and 19 months, respectively (P = 0.02). Remarkably, overall survival was also significantly enhanced with the combined therapy: 3-year survival was 57% in the radiotherapy plus cetuximab arm versus 44% in the radiotherapy-alone arm, with median survival of 54 months and 28 months, respectively (P = 0.02). The improvement in outcome was associated with an increase in acute skin, but not mucosal, toxicity. Although the results of this trial do not necessarily define the appropriateness of addition of cetuximab to the current standard of chemoradiotherapy for head and neck cancer, they prove that EGFR inhibitors can effectively radiosensitize at least a subset of head and neck cancers.

Many preclinical data support the hypothesis that EGFR inhibitors would effectively radiosensitize head and neck cancers. First, EGFR over-expressing head and neck cancer cell lines and xenografts were observed to be radioresistant compared with cell lines or xenografts expressing normal levels of EGFR, suggesting that EGFR overexpression results in radioresistance. In addition, there are positive correlations between EGFR overexpression and locoregional failure in cells from patients with head and neck cancers treated with radiotherapy. Second, preclinical studies showed that head and neck cancer cell lines and xenografts were radiosensitized by EGFR inhibitors. Third, phase I/II clinical trials demonstrate excellent local control with EGFR inhibitors plus radiotherapy compared with radiotherapy controls, with only modest enhancement of radiation-related toxicity. The results of the recent phase III radiosensitization trial showed that the addition of an EGFR inhibitor to standard radiotherapy improved local control, which translated into almost a doubling of median survival, and significantly improved overall survival at 2 and 3 years.

These results validate the importance of EGFR signaling in radiation response of head and neck cancer, and indicate that EGFR inhibitors are effective radiosensitizers in certain settings. However, many important questions remain unanswered. How do we identify tumors that are radioresistant by virtue of EGFR signaling, and are thus likely to be radiosensitized by EGFR inhibitors? How can we tell whether EGFR inhibitors effectively inhibit the key pathways driving EGFR-mediated radioresistance? Considering tumor instability and heterogeneity, how can we optimize the simultaneous targeting of pathways involved in radiation response using combinations of different targeting agents? A better understanding of the mechanisms underlying EGFR-mediated radiation response will help answer these questions.