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Correspondence: goetz h Kloecker University of Louisville, 529 s. Jackson street, Louisville, KY 40202, UsA Tel +1 502 562 4358 Fax +1 502 562 6811 email ghkloe01@louisville.edu; goetzkloecker@yahoo.com Background: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by c hemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology) 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC), with a response rate (RR) of 10%. This study’s hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP) in NSCLC. Methods: Patients with progressive disease (PD) after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group) score from 0 to 2 and good organ f unction. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred. Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78), 14 were female, 17 had prior radiation (not involving the target lesions), 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were 50% adenocarcinoma, 30% squamous, and 20% u nspecified. One patient had a partial response, nine had stable disease, and 14 had progressive disease. The median TTP was 61 days (9–366) and median survival 157 days (9–844). Side effects were similar to erlotinib single agent with no treatment-related mortality. There were no unexpected or increased adverse events related to digoxin. Conclusions: Digoxin did not increase the response rate of erlotinib in the treatment of p rogressive NSCLC. The TTP and survival seen in this study were similar to the published results with erlotinib alone. This combination does not warrant further clinical studies in NSCLC.

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC)