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

Background: The high-dose sequential (HDS) regimen developed in Milan for h igh-grade lymphomas is very active, but its toxicities are still partly unk nown. We evaluated prospectively by doppler-echocardiograpy the cardiotoxic ity 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 autologo us peripheral stem-cell transplantation. Echocardiography was performed at baseline, before administration of mitoxantrone and 2, 6 and 12 months afte r transplantation. The following parameters of the left ventricular systoli c and diastolic functions were determined: end diastolic (LVD) and end syst olic (LVS) dimensions, the ejection fraction (EF), and the Doppler derived diastolic parameters: peak velocity of the early (E) and late (A) transmitr al flow, the E : A ratio, deceleration time of the E wave (DT) and isovolum etric relaxation time (IVRT). A group of 20 normal volunteers served as con trol. Results: At baseline, in comparison to controls, the patients had altered d iastolic function (diminished E : A ratio) and, although still within the n ormal range, a slightly reduced systolic function (EF). During treatment or in the course of follow-up none of the patients showed clinical signs or s ymptoms of cardiac failure, nor significant changes of systolic or diastoli c 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 remai ned constant during, and up to six months after, transplantation, decreasin g 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 fun ction and of its evolution over time were patient age and gender, with prev ious treatment with anthracyclines having a minor role. Conclusions: The HDS chemotherapy regimen produced no significant sign of c ardiotoxicity up to one year after transplantation in patients with normal baseline cardiac function and no history of cardiac disease, pretreated wit h up to 550 mg/m(2) of doxorubicin.