Alan B. Sandler, MD

It's been an interesting time for those of us who treat patients with lung cancer. Over the past few years, non-small-cell lung cancer (NSCLC) has been a target for the numerous companies developing agents that inhibit receptors, growth factors, signaling molecules, and genes involved in tumor growth and development. The "biologic-targeted" approach to treatment is still in its infancy, but it has already given us great expectations, some surprises, some disappointments, and, ultimately, satisfaction that we now have a nonchemotherapeutic option.

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.

With best supportive care alone, patients with metastatic non–smallcelllung cancer (NSCLC) have a median survival of 4 to 5 months anda 1-year survival rate of approximately 10%. Trials carried out in the1980s and 1990s comparing chemotherapy to best supportive care reportedvariable efficacy results; however, a pivotal meta-analysis of thesedata indicated that cisplatin-based chemotherapy provided a survivalbenefit in advanced NSCLC. In the past decade newer agents such asgemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere)have all demonstrated activity in NSCLC as single agents; consequentlythese agents have been combined with cisplatin or carboplatin. Randomizedphase III trials comparing these “newer” platin-based doubletshave failed to identify an optimal platinum-based doublet therapyregimen. Though it is clear that chemotherapy is an appropriate treatmentfor many patients with lung cancer, there a sense in which the useof traditional chemotherapeutic agents has reached a therapeutic plateau.Increased understanding of cancer biology has revealed numerouspotential therapeutic strategies, including targeting the epidermalgrowth factor receptor, protein kinase C, rexinoid receptors, and theangiogenesis pathway. The Eastern Cooperative Oncology Group studyE4599 comparing paclitaxel/carboplatin with/without bevacizumab isthe first phase III randomized trial to show a survival advantage withthe addition of a molecularly targeted agent to chemotherapy in thechemotherapy-naive patient population. Future studies will involve theevaluation of additional targeted agents plus chemotherapy as well aslooking at combinations of these targeted agents alone or with chemotherapy.

There will be approximately 40,000 new cases of small-cell lung cancer this year. Prior to 1990, there were several agents with single-agent response rates of 30% to nearly 90% in the untreated small-cell lung cancer population