tudy in cancer patients.
Clinical Studies
The ability of Zinecard to prevent/reduce the incidence and severity of doxorubicin-induced cardiomyopathy was demonstrated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either Zinecard or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the left ventricular ejection fraction (LVEF), utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical eva luations. Patients receiving Zinecard had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group. The difference in decline from baseline in LVEF was evident beginning with a cumulative doxorubicin dose of 150 mg/m2 and reached statistical significance in patients who received ≥400 mg/m2 of doxorubicin. In addition to eva luating the effect of Zinecard on cardiac function, the studies also assessed the effect of the addition of Zinecard on the antitumor efficacy of the chemotherapy regimens. In one study (the largest of three breast cancer studies), patients with advanced breast cancer receiving fluorouracil, doxorubicin, and cyclophosphamide (FAC) with Zinecard had a lower response rate (48% vs. 63%; p=0.007) and a shorter time to progression than patients who received FAC versus placebo, although the survival of patients who did or did not receive Zinecard with FAC was similar.
Two of the randomized breast cancer studies eva luating the efficacy and safety of FAC with either Zinecard or placebo were amended to allow patients on the placebo arm who had attained a cumulative dose of doxorubicin of 300 mg/m2 (six courses of FAC) to receive FAC with open-label Zinecard for each subsequent course. This change in design allowed examination of whether there was a cardioprotective effect of Zinecard even when it was started after substantial exposure to doxorubicin.
Retrospective historical analyses were then performed to compare the likelihood of heart failure in patients to whom Zinecard was added to the FAC regimen after they had received six (6) courses of FAC (and who then continued treatment with FAC therapy) with the heart failure rate in patients who had received six (6) courses of FAC and continued to receive this regimen without added Zinecard. These analyses showed that the risk of experiencing a cardiac event (see Table 2 for definition) at a given cumulative dose of doxorubicin above 300 mg/m2 was substantially greater in the 99 patients who did not receive Zinecard beginning with their seventh course of FAC than in the 102 patients who did receive Zinecard (See Figure 1).
Table 2 The development of cardiac events is shown by: Development of congestive heart failure, defined as having two or more of the following:
Cardiomegaly by X-ray
Basilar Rales
S3 Gallop
Paroxysmal nocturnal dyspnea and/or orthopnea and/or significant dyspnea on exertion.
Decline from baseline in LVEF by ≥10% and to below the lower limit of normal for the institution.
Decline in LVEF by ≥20% from baseline value.
Decline in LVEF to ≥5% below lower limit of normal for the institution.
Figure 1 displays the risk of developing congestive heart failure by cumulative dose of doxorubicin in patients who received Zinecard starting with their seventh course of FAC com |
