Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA).

BACKGROUND: Trastuzumab is successfully used for the treatment of HER2-positive breast cancer. Because of its association with cardiotoxicity, LVEF is monitored by MUGA, though this is a relatively late measure of cardiac function. Diastolic dysfunction (DD) is believed to be an early predictor of cardiac impairment. We evaluate the merit of MUGA-derived diastolic function parameters in the early detection of trastuzumab-induced cardiotoxicity (TIC). METHODS AND RESULTS: 77 trastuzumab-treated patients with normal baseline systolic and diastolic function were retrospectively selected (n = 77). All serial MUGA examinations were re-analyzed for systolic and diastolic function parameters. 36 patients (47%) developed SD and 45 patients (58%) DD during treatment. Both systolic and diastolic parameters significantly decreased. Of the patients with SD, 24 (67%) also developed DD. DD developed prior to systolic impairment in 54% of cases, in 42% vice versa, while time to occurrence did not differ significantly (P = .52). This also applied to the subgroup of advanced stage breast cancer patients (P = .1). CONCLUSIONS: Trastzumab-induced SD and DD can be detected by MUGA. An impairment of MUGA-derived diastolic parameters does not occur prior to SD and therefore cannot be used as earlier predictors of TIC.

Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report. METHODS: Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. RESULTS: The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in approximately 12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in approximately 0.4%, and leukemia occurs in approximately 0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. CONCLUSIONS: The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking.