Liposomal Doxorubicin (Caelyx) in advanced pretreated Soft Tissue Sarcomas: A phase II study of the Italian Sarcoma Group (ISG)

Background: Doxorubicin remains one of the few drugs with consistent single agent activity in advanced Soft Tissue Sarcomas (STS), with a demonstrated dose-response relationship. Liposomal-encapsulated Doxorubicin (LED) has b een shown to be at least as active as free doxorubicin in experimental mode ls, and phase I and II human studies indicate that this navel strategy of d rug delivery my have less myocardial toxicity. Few clinical trials in adult STS have been published until now, with disappointing and often contrastin g results. Patients and Methods: Twenty-five consecutive patients with meas urable advanced and/or metastatic STS, previously pretreated with anthracyc line-based chemotherapy, were enrolled into the trial. LED (Caelyx) was adm inistered over I-hour intravenous infusion at the dose of 30 mg/m(2) in the first 5 patients, then at tlzefired nose of50 mgirn in the subsequent 20 p atients. Treatment was given on ambulatory basis, at 3-week intervals. Anti emetics were generally not required and only wed if indicated. Results: A t otal of 98 courses of chemotherapy were given (median 4 pel patient, range 2 to 5). Amongst the 25 evaluable patients, there were 3 partial responses (12%, 95% confidence interval 4.2% to 29.9%) lasting 3-9+ months and all oc curring in patients treated at 50 mg/m(2)/cycle. In addition 2 minor respon ses (4+ months) and 17 stable disease (2-7+ months) were observed; the rema ining 3 patients progressed while an therapy. The median delivered drug dos e-intensity was 2 2 13.3 mg/m(2)/week (range 10 to 16.6 mg/m(2)/week). Trea tment was well tolerated with no patient requiring dose reduction or therap y delay because of toxicity. Only 2 cases of WHO grade 3 toxicity occurred consisting of neutropenia and scrotal skin toxicity, respectively; no;cardi otoxicity was seen. Conclusions: This study shows that Caelyx has some acti vity in advanced anthracycline-pretreated STS, with favourable toxic profil e. From the analysis of available experiences it emerges that liposomal dox orubicin has not been tested at doses adequate to exploit the antitumor eff ects of the drug, being the reached dose-intensity being even lower than th ose deemed critical for obtaining optimal responses to fr-ee doxorubicin. W e suggest that further and better addressed studies be performed in STS, in cluding patients with less advanced,stages of disease, focused on attemptin g to delivery the drug at optimal doses.