ONCOLOGY Vol 20 No 5_Suppl_2

As inhibitors of the epidermal growth factor receptor (EGFR) become an increasingly common therapeutic option in cancer, appropriate management of their associated toxicities emerges as a critical part of treatment. Cutaneous manifestations, probably linked to the function of the EGFR in epithelial development, are the most common adverse reactions to EGFR inhibition. The key manifestations are follicular eruptions, nail disorders, xerosis, and desquamation. Growing attention continues to be devoted to the analysis of these events, particularly given their potential role as markers of responsiveness to treatment. However, to date, there are few evidence-based guidelines for the appropriate management of these dermatologic events. Multidisciplinary collaboration between oncologists and dermatologists will be required to improve our understanding and optimize the characterization of these skin toxicities, and to design effective management approaches.

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms.

Since initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers. Two main classes of anticancer agents affect the EGFR: those targeting the extracellular ligand-binding domain and those that block the intracellular tyrosine kinase (TK) domain. Cetuximab (Erbitux) is a mouse/human chimeric monoclonal antibody that targets the ligand-binding domain of the EGFR, whereas erlotinib (Tarceva) and gefitinib (Iressa) are small-molecule TK inhibitors. Common toxicities of agents targeting the EGFR differ from those associated with traditional chemotherapy. Given the common pathway through which these agents work, some adverse events are similar. Many patients treated with these agents develop an acne-like rash on the face and upper body, most likely related to keratinocyte alterations and hair follicle proliferation and maturation. Although clinical manifestation of this reaction closely resembles acne vulgaris, the histology is more similar to infectious folliculitis. Other adverse events appear to be related to a drug class or individual agent. For example, interstitial lung disease is a rare but potentially fatal reaction that has been reported with gefitinib. Hypomagnesemia reported in association with cetuximab may be related to EGFR blockade in the kidney. Anaphylactic or anaphylactoid infusion reactions are also seen with cetuximab, as with other monoclonal antibodies.

Dermatologic events are considered the most relevant elements of the toxicity profile of epidermal growth factor receptor (EGFR) inhibitors. However, some nondermatologic adverse events can also be common. Although these toxicities are rarely severe, they may have fatal outcomes if not managed appropriately. For example, gefitinib (Iressa) and erlotinib (Tarceva) (and more rarely, cetuximab [Erbitux]) are associated with a risk of interstitial lung disease, while the administration of cetuximab may be associated with infusion reactions. Preparedness to assess patients at risk and to manage symptoms promptly and effectively can greatly reduce any potential risks. As a result, anti-EGFR therapies are generally well tolerated. As anti-EGFR agents are integrated into standard regimens or combined with novel treatments, familiarity with their safety profiles will become increasingly important. This article reviews the key nondermatologic adverse events associated with cetuximab, gefitinib, and erlotinib, and summarizes the most important management recommendations.