In the pre-HAART era, several chemotherapeutic agents (bleomycin, vinblastine, vincristine and etoposide) were shown to have activity against KS in case series and small Phase II trials using different combinations and doses of these drugs [84–88]. However, liposomal anthracyclines and taxanes have become established as the backbone of current standard systemic cytotoxic therapy against KS. buy RG7204 Liposome encapsulation of anthracyclines constitutes a considerable advance in the chemotherapy of KS. The advantages of liposomal formulation include increased tumour uptake and hence favourable

pharmacokinetics and toxicity profile. The trials of liposomal anthracyclines for HIV-associated KS were undertaken in the pre-HAART era but clinicians AZD1208 research buy continue to regard them as the gold-standard first-line chemotherapy for KS. Previous manufacturing problems leading to interruptions in supply have been resolved. Both liposome encapsulated daunorubicin (DaunoXome 40 mg/m2 every 2 weeks) and the pegylated liposomal doxorubicin, which is known variously as Caelyx, Doxil or PLD (20 mg/m2 every 3 weeks) have

been shown to have good antitumour activity. A meta-analysis of 2200 patients treated in nine randomized controlled trials, including two for KS patients, demonstrated that the toxicity profile compares favourably with that of conventional anthracyclines [89]. A report of 93 patients treated at a single centre has found no evidence of cardiotoxicity even at high cumulative dosages [90] and rarely significant alopecia. However, there remains considerable myelosuppression, and occasional emesis. In addition, infusion-related hypotension and hand/foot syndrome are novel side effects seen with these liposomal formulations. Three sizeable, randomized controlled

studies have compared liposomal anthracyclines with conventional combination chemotherapy regimens and all were conducted before the introduction of HAART. A Phase III randomized comparison of DaunoXome and ABV (doxorubicin, bleomycin, vincristine) demonstrated equivalent overall response rates (partial and complete responses), time to treatment failure and survival duration [91]. Two randomized Phase III trials compared pegylated liposomal doxorubicin (PLD) with conventional combination chemotherapy, Tobramycin ABV in one study and BV (bleomycin vincristine) in the other, as first-line therapy for KS in patients not on HAART. Both found response rates were higher in the PLD arms but responses were often not sustained [92,93] (see Table 3.3 for details). The three Phase III studies may not be directly comparable. In one small randomized study of 80 patients, KS patients were randomized 3:1 to PLD (20 mg/m2) or DaunoXome (40 mg/m2) every 2 weeks for up to six cycles. Partial responses, correlating with clinical benefit, were observed in 55% patients receiving PLD and in 32% receiving DaunoXome.