EGFR INHIBITORS
Rationale and clinical basis for combining gefitinib (IRESSA, ZD1839) with radiation therapy for solid tumors

https://doi.org/10.1016/j.ijrobp.2003.09.094Get rights and content

Abstract

Purpose

The role of dysregulated epidermal growth factor receptor–tyrosine kinase (EGFR-TK) activity in promoting tumor resistance to radiation therapy is discussed, and evidence supporting the rationale for the use of gefitinib (IRESSA, ZD1839) to enhance tumor radiosensitivity is reviewed.

Methods and materials

A review of the literature regarding the role of EGFR-TK signaling in tumor response to radiation therapy was conducted, and results were summarized from preclinical and clinical studies of gefitinib in the treatment of solid tumors alone and in combination with radiation therapy.

Results

Preclinical results indicate that EGFR-TK activity in tumors can block the cytotoxic effects of radiation therapy and enhance tumor repopulation, resulting in failure of local tumor control. In xenograft tumor models, gefitinib in combination with ionizing radiation resulted in additive to synergistic growth inhibition. In randomized clinical trials, gefitinib has demonstrated efficacy with favorable tolerability as monotherapy for patients with advanced non–small-cell lung cancer or head-and-neck carcinomas who had previously received standard therapies.

Conclusions

These results indicate that there is potential for improved responses by combining gefitinib with radiation therapy in non–small-cell lung cancer, head-and-neck cancers, and other solid tumors.

Introduction

Radiation therapy plays a major role in the treatment of most common solid tumors. However, response to radiation therapy varies by individual tumor, and local control is often limited by tumor radiation resistance and the rapid proliferation of cells after radiation, resulting in tumor repopulation 1, 2. Research has led to considerable advances in understanding the molecular and cellular mechanisms underlying the resistance of solid tumors to ionizing radiation. Novel therapies have been designed to specifically inhibit the key molecules in these processes, including the epidermal growth factor receptor–tyrosine kinase (EGFR-TK) 1, 2. It is hoped that these new agents will enhance tumor sensitivity to radiation therapy and will lead to better therapeutic outcomes for patients with solid tumors.

The EGFR-TK is a particularly attractive drug target for treatment of solid tumors 1, 3. The expression of epidermal growth factor receptor (EGFR) has been linked to more aggressive tumor behavior and a worse clinical prognosis (3), and the tyrosine kinase (TK) enzyme activity of the EGFR protein is increased in many solid tumors. Signal transduction pathways turned on by EGFR-TK contribute to tumor processes such as cellular proliferation, decreased apoptosis, angiogenesis, and invasion and metastasis (3). Abnormal activity of the EGFR-TK may allow tumor cells to escape the lethality of radiation treatment and contribute to radiation resistance. Agents that inhibit EGFR-TK signaling may block this mechanism and enhance the tumor cell killing effectiveness of radiation therapy or serve as radiation sensitizers (4). Gefitinib (IRESSA, ZD1839; AstraZeneca Pharmaceuticals, LP, Wilmington, DE) is an inhibitor of EGFR-TK activity with proven antitumor efficacy as monotherapy for advanced non–small-cell lung cancer (NSCLC). Evidence will be reviewed indicating that gefitinib may act as a radiation sensitizer in a variety of solid tumors and thereby enhance the antitumor efficacy of radiation therapy.

Section snippets

EGFR-TK in solid tumors

The EGFR/ErbB1 is a member of the ErbB family of receptor TKs (5). The binding of extracellular ligands such as epidermal growth factor or transforming growth factor-α (TGF-α) causes EGFR to associate with another EGFR molecule or ErbB family member. This dimerization leads to a conformational change that activates the TK domain on the intracellular portion of the receptor, resulting in autophosphorylation of specific tyrosine residues. These phosphorylated tyrosines then bind with and activate

Advanced solid tumors

The safety and tolerability of gefitinib were investigated in several Phase I trials involving patients with tumors that are known to frequently overexpress EGFR, including NSCLC, head and neck, breast, and colorectal, among others 33, 34, 35. Almost all patients had received prior treatment with radiation therapy and/or chemotherapy. In these trials, gefitinib was found to be generally well tolerated. The most common adverse events were diarrhea, acneiform rash, nausea, asthenia, and vomiting,

Conclusions

The effectiveness of radiation therapy is limited by tumor resistance, both inherent and that induced by radiation therapy. Considerable evidence exists to suggest that EGFR plays a key role in tumor resistance to ionizing radiation itself. Agents that inhibit EGFR have been shown to counteract this resistance, thereby increasing the antitumor activity of radiation therapy.

One such agent is gefitinib (IRESSA, ZD1839), a selective EGFR-TKI. Gefitinib has been shown to inhibit tumor growth in a

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