The high-dose sequential (Milan) chemotherapy PBSC transplantation regimen for patients with lymphoma is not cardiotoxic

Background: The high-dose sequential (HDS) regimen developed in Milan for high-grade lymphomas is very active, but its toxicities are still partly unknown. We evaluated prospectively by doppler-echocardiograpy the cardiotoxicity of this treatment. Patients and methods: Over seven weeks, 20 patients received a sequence of cyclophosphamide, methotrexate, etoposide, mitoxantrone and melphalan, each at its maximum tolerable dose, and the latter in conjunction with autologous peripheral stem-cell transplantation. Echocardiography was performed at baseline, before administration of mitoxantrone and 2, 6 and 12 months after transplantation. The following parameters of the left ventricular systolic and diastolic functions were determined: end diastolic (LVD) and end systolic (LVS) dimensions, the ejection fraction (EF), and the Doppler derived diastolic parameters: peak velocity of the early (E) and late (A) transmitral flow, the E : A ratio, deceleration time of the E wave (DT) and isovolumetric relaxation time (IVRT). A group of 20 normal volunteers served as control. Results: At baseline, in comparison to controls, the patients had altered diastolic function (diminished E : A ratio) and, although still within the normal range, a slightly reduced systolic function (EF). During treatment or in the course of follow-up none of the patients showed clinical signs or symptoms of cardiac failure, nor significant changes of systolic or diastolic parameters, apart from a transient increase in the E : A ratio after the first three chemotherapy cycles (from 1.14 to 1.37, P < 0.05). The EF remained constant during, and up to six months after, transplantation, decreasing only slightly after one year (from 62% to 59%, P < 0.05). Using analysis of covariance we showed that the major determinants of baseline cardiac function and of its evolution over time were patient age and gender, with previous treatment with anthracyclines having a minor role. Conclusions: The HDS chemotherapy regimen produced no significant sign of cardiotoxicity up to one year after transplantation in patients with normal baseline cardiac function and no history of cardiac disease, pretreated with up to 550 mg/m(2) of doxorubicin.