Pre-publication history

Background: Digitoxin, in concentrations therapeutic for treatment of cardiac disease, induces apoptosis in different human malignant cell lines in vitro. Our intention with the present study was to investigate if patients on digitoxin for cardiac disease have different cancer incidence compared to the general population. Methods: Computer stored data on digitoxin concentrations in plasma in 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the expected cancer cases for the common types of cancer. Results: The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased incidence of cancer already before start on digitoxin. Thus, the increased cancer incidence among digitoxin users is explained by factors mutual for the occurrence of both cancer and cardiovascular disease and not to the actual use of digitoxin. Smoking is one evident risk factor for both lung cancer, as well as some other cancers, and cardiovascular disease. More intriguingly is that leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before start on digitoxin. This indicate that yet unknown risk factors exists for cardiovascular disease and lymphoproliferative cancer. An internal analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion: The morbidity and mortality is high in the population on digitoxin due to high age and cardiac disease and these factors disturb efforts to isolate an eventual anti-cancer effect of digitoxin in this setting. Still, the results indicate an anti-cancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anti-cancer agents.