Jan Buter, MD, PhD

Targeted therapies inhibiting the epidermal growth factor receptor(EGFR) have been introduced in the treatment of patients with advancednon–small-cell lung cancer (NSCLC). Many inhibitors of theEGFR have been developed, targeting either the extracellular receptordomain with antibodies or the intracellular tyrosine kinase bindingdomain with small molecules. The tyrosine kinase inhibitor (TKI)gefitinib (Iressa) was the first targeted drug to be registered for thetreatment of NSCLC after failure of chemotherapy. Given concurrentlytogether with platinum combination chemotherapy both TKIs gefitiniband erlotinib (Tarceva) failed to increase activity. Sequential targetedtherapy after chemotherapy is currently being investigated further. Studieswith the monoclonal antibody cetuximab (Erbitux) combined withchemotherapy are ongoing. Side effects of the small molecules aremainly skin rash and diarrhea, whereas the antibodies do not give diarrhea.Selection of patients, based on molecular markers and patientcharacteristics, has become an important issue for the further developmentof these drugs, given there is activity in a relatively small group ofpatients with NSCLC. Newer drugs inhibiting more than one receptorpathway are being investigated in order to find activity in a broadergroup of patients.

Patients with locally advanced cancers have a poor prognosis when treated with radiotherapy and/or surgery alone. The appearance of distant metastases shortly after removal of the primary tumor indicates that micrometastases are already present at the time of diagnosis. We observed a favorable outcome in patients with locally advanced breast cancer treated with a prolonged regimen of neoadjuvant chemotherapy plus granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]) compared with patients receiving fewer chemotherapy cycles prior to surgery and radiotherapy. These results can partly be explained by the dose-intensive regimen used, but biologic and immunologic processes inherent to the prolonged presence of the primary tumor and its draining lymph nodes might also contribute to the beneficial outcome. The effects of the prolonged presence of the primary tumor during chemotherapy and GM-CSF administration on the antitumor immune response, and more specifically the functional properties of dendritic cells and T cells, are currently being investigated in a multicenter randomized clinical trial comparing prolonged neoadjuvant chemotherapy plus cytokines with a conventional treatment schedule. Aside from investigations concerning the immune system, other biologic processes, such as tumor angiogenesis, are being investigated at the same time. [ONCOLOGY 16(Suppl 1):32-39, 2002]