Abstract
Anthracyclines, and doxorubicin in particular, remain a mainstay of sarcoma therapy. Despite modest activity and significant toxicities, no cytotoxic monotherapy has yet yielded superior overall survival over doxorubicin for therapy of advanced soft tissue sarcomas in a randomized trial. Similarly, combination regimens have also been unable to overcome doxorubicin in terms of overall survival. Strategies to ameliorate the most prominent side effect of doxorubicin, cardiotoxicity, are available, but their use in sarcoma patients has been limited. Aldoxorubicin is a prodrug consisting of doxorubicin with a covalent linker. It binds rapidly after intravenous infusion to cysteine-34 of human serum albumin. The drug-albumin conjugate is preferentially retained in tumor tissue, with uptake into tumoral cells. At physiologic pH, the complex is stable. Hydrolysis can occur under the acidic conditions of the endocytic lysosome, releasing doxorubicin. Doxorubicin then distributes to various cellular compartments, including Golgi, mitochondrion, and nucleus, with subsequent cytotoxic effects. Aldoxorubicin has demonstrated in vitro and in vivo activities in both cancer model systems and human xenografts. Preclinical models also support its decreased cardiac effects vs doxorubicin, although such promising results require formal comparison at efficacy equivalent doses of the two drugs. Phase I studies confirmed the tolerability of aldoxorubicin in humans. Clinical cardiotoxicity was not observed, but molecular and subclinical cardiac effects could be demonstrated. A Phase II study in treatment-naïve, advanced sarcoma patients demonstrated improved progression-free survival and response rate over doxorubicin, although no survival benefit was evident. A Phase III study of aldoxorubicin vs investigator's choice from a panel of chemotherapy regimens in the salvage setting was unable to demonstrate a benefit in progression-free or overall survival in the entire population. Progression-free survival in L-sarcomas (leiomyosarcomas and liposarcomas) was documented. While evidence of subclinical cardiac effects was seen in a small proportion of aldoxorubicin-treated patients, data from both the Phase II and III studies indicated a favorable cardiotoxicity profile vs doxorubicin. Despite the negative results from this Phase III study, the importance of anthracycline therapy in sarcoma management merits further investigation of the potential role of aldoxorubicin in this indication. Other avenues for progress include identification of sensitive histologies and biomarkers of activity, exploration of clinical niches without proven standard therapies, and exploration of alternate dosing strategies.