Gefitinib Maintenance in Stage III Non–Small-Cell Lung Cancer

Abstract

■■■ TOTHEEDITOR:Kellyetal 1 recentlyreportedinJournalofClinical Oncology that gefitinib maintenance after chemoradiotherapy and consolidation chemotherapy was associated with a significant decreaseinoverallsurvival(butonlyaslightdecreaseinprogression-free survival)comparedwithplaceboinstageIIInon‐small-celllungcancer(NSCLC).Theyofferpotentialexplanationsforthis,asdoKeedyet al 2 in an accompanying editorial. We would like to suggest an additional possible reason for this outcome. The flattening of the NSCLC dose-response curve at higher chemotherapy doses suggests that the most important factor in chemotherapy resistance is deficiency of factors required for efficacy. 3 Platinum-resistant cell lines may have decreased expression of a range of transporters that are important for cellular uptake of chemotherapy and nutrients. 4 In patients with a variety of resistant tumor types, we assessed tumor expression (by immunohistochemistry) of the copper transporter CTR1, which is also important in platinum uptake. CTR1 expression was significantly lower in tumors of patients who had received either chemotherapy or targeted therapies withintheprevious3monthsthanintumorsofpatientswithalonger interval off therapy. 5 The correlation with time from last chemotherapy or targeted therapy was stronger than the correlation with time from last cytotoxic therapy alone. This leads us to hypothesize that either chemotherapy or targeted therapy may result in a broad reduction in membrane transporters and that this, in turn, may generate broad cross resistance. This could, in part, explain why adding tyrosine kinase inhibitors to chemotherapy did not improve outcome in chemotherapy-naive advanced NSCLC patients 6 and might also predict that monoclonal antibodies (that do not require uptake across membranes) might add to chemotherapy even if small molecules did not. If correct, this would also predict that most other currentlyavailablesmallmoleculestargetingtumorcellswilladdlittle