In two randomised controlled trials the early dropout rate due to adverse events was higher with standard combination chemotherapy than with PLD. One RCT comparing PLD with ABV chemotherapy reported early dropout rates due to adverse events of 37% for the ABV arm and 11% for PLD.61 Similarly early withdrawal because of chemotherapy-related toxicity was higher in the BV arm (27%) than the PLD arm (11%) in the second comparative RCT.62
The incidence of grade 3 neutropenia in a randomised study comparing liposomal daunorubicin and ABV chemotherapy was similar in both groups (36% versus 35% respectively).60 However, grade 4 neutropenia was more frequent as an adverse effect of liposomal daunorubicin than of ABV chemotherapy in the same randomised trial (15% versus 5%, P = 0-021).60
The most common adverse event in both arms of an RCT comparing PLD with ABV chemotherapy was leucopenia, affecting 36% of 133 patients who received PLD and 42% of 125 patients in the ABV group.61 No episodes of febrile neutropenia (neutrophils <500 x 106 cells/litre) occurred in the PLD group but 37% developed opportunistic infections and 6% experienced episodes of sepsis.61 In a further RCT 29% of 121 patients who received PLD developed grade 3 leucopenia compared with 12% in the comparative BV chemotherapy arm.62
Of 24 patients who received a cumulative dose of >500 mg/m2 of liposomal anthracycline in one randomised study, none were found to have a 20% or greater decline in their left ventricular ejection fraction (LVEF).60 Liposomal daunorubicin was discontinued in one patient whose LVEF fell from 47% to 33%. An angiogram then showed that this patient had had a complete occlusion of the left anterior descending artery. In one RCT of liposomal doxorubicin versus ABV, pre- and post-treatment estimations of LVEF were available for 47 patients who received PLD. Of these, two patients were found to have had a >20% fall in LVEF.61 One death attributable to cardiomyopathy occurred in 133 patients treated with PLD.61 It seems that, unlike conventional anthracyclines, liposomal anthracyclines are not associated with significant cumulative cardiotoxicity.
Of the patients receiving liposomal daunorubicin, 51% experienced mild nausea.60 Grade 3 nausea and vomiting was significantly more frequent with ABV than with PLD (34% versus 15%, P<0-001).61
In the randomised trial reported by Gill et al. alopecia occurred more frequently amongst the patients who received ABV chemotherapy than among those receiving liposomal daunorubicin.60 Of the ABV group, 36% experienced grade 1-2 alopecia, compared with 8% in the liposomal daunorubicin group (P< 0-0001). In another RCT comparing PLD with ABV chemotherapy, grade 3 alopecia was also more frequent in the ABV group than in those receiving a liposomal anthracycline (19% versus 1%, P<0-001).61
Peripheral neuropathy was seen in 41% of patients treated with ABV and 13% of those given liposomal daunorubicin (P<0-0001) in the study of Gill et al.60 In another randomised study, peripheral neuropathy was also less common with liposomal doxorubicin than with ABV chemotherapy (6% versus 14%, P = 0-002).61
In the only large phase III study of liposomal daunorubicin, the incidence of acute infusion reactions was 2% (2/116 patients). In an RCT of PLD, six of 133 patients (5%) experienced an acute infusion-related reaction presenting as flushing, chest pain, hypotension and back pain. Five of the six patients needed premedication for subsequent cycles but could continue on the study.61 In another study the frequency of acute infusion reactions with PLD was similar, affecting five of 121 patients (4%), but a severe anaphylactic reaction occurred in one patient.62
In the RCT of Stewart et al, five of 121 patients in the PLD arm died during the study. The cause of death for four of these patients was progression of AIDS, and the remaining patient died from progression of KS. The investigators attributed none of the deaths to the liposomal drug.62
In another RCT 24/133 patients who received PLD died, mostly as a result of complications of HIV infection, with one death resulting from cardiomyopathy.61 There was no significant difference in the death rates compared with the ABV arm of the study.61 In an RCT comparing liposomal daunorubicin with ABV chemotherapy, five of 117 patients who received PLD and five of 115 patients who received ABV chemotherapy died because of complications of HIV infection.60 Median survival in the two groups did not differ.60
A 2% (3/133 patients) incidence of palmar-plantar erythrodysaesthesia (cutaneous toxicity resulting in dry peeling red hands and feet) was reported in one trial of liposomal doxorubicin.61
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