Clinical Phase II Study of Pegylated Liposomal Doxorubicin as Second-Line Treatment in Disseminated Melanoma

Abstract

Background: Stage IV melanoma has a poor prognosis with a median survival of 3-11 months from diagnosis of distant metastases. Response rates in first-line regimens range around 15-20%. Non-responders have a median survival around 6 months. Currently, no second-line treatment in advanced melanoma has been established. Patients and Methods: In a clinical phase II study we evaluated the efficacy of liposomal doxorubicin (Caelyx?) in 30 patients (17 m, 13 f) with progressing metastatic melanoma who had failed a previous chemotherapy. Liposomal doxorubicin was given in an outpatient setting at a dose of 50 mg/m2 i.v. on d1, d22, d43 and d64, subsequently at 40 mg/m2 at d85 before first staging and in 4-week intervals thereafter. Treatment was very well tolerated with 100 cycles given in total. Response rate, survival time, time-to-progression and toxicity were assessed. Results: Erythrodysesthesia was the most severe toxicity in 6% at CTC grade 3. Liposomal doxorubicin was of limited clinical efficacy with 21 patients progressing within the first 12 weeks. However, 7 patients were treated 3-9 months and were stable for >90 days, achieving 5 SD, 1 PR and 1 CR. Median survival after initiation of second-line treatment was 214 days (95% CI: 151-304 days) with 7 patients surviving >300 and 5 patients >400 days. Conclusions: Liposomal doxorubin as monotherapy is well tolerated but of limited clinical efficacy. Whether the survival benefit of a significant proportion of patients (20%) holds true in larger cohorts and whether the efficacy of liposomal doxorubicin can be improved by combinations without compromising the low toxicity profile needs further studies.

Current and Future Trials of Targeted Therapies in Cutaneous Melanoma

“…Nanotechnology, which is capable of encapsulating one or more therapeutic agents as a single drug in order to evaluate its efficacy in clinical trials, may be part of the possible solution to this problem [186–188]. Additionally, many nanotechnologies are shown to improve circulation time, enhanced drug uptake into tumors, avoid the reticulo-endothelial system, and minimize toxicity [186].…”

“…Currently in various stages of development are liposomes that contain chemo-therapeutic agents, antisense-ODNs, siRNA, DNA, or radioactive particles that could target the MAPK pathway [186, 188]. For instance, liposomes loaded with siRNAs targeting V600E B-RAF and AKT3 synergistically inhibited melanoma tumor growth in mice [157, 186].…”

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

“…Thus, our previous data have demonstrated that TAMs promoted B16.F10 melanoma growth via supporting melanoma angiogenesis and oxidative stress [11,29]. Notably, in other types of cancer, TAMs were shown to induce tumor cell resistance to DOX therapy [30,31], and cytotoxicity of liposomal DOX on human metastatic melanoma evaluated in several clinical studies did not induce any significant response on this cancer type [12,13,32]. Moreover, our earlier studies have demonstrated that LCL-PLP exerted antitumor action on B16.F10 melanoma in vivo via the inhibition of TAMs-mediated melanoma angiogenesis [11].…”

“…Therefore, administration of the TAMs-targeted treatment could be a promising strategy to overcome the melanoma cell resistance to the specific cytotoxic drugs. To demonstrate the role of TAMs-targeted therapy as sensitizer of melanoma cells to the antitumor agent, doxorubicin (DOX) was selected as a consequence of its inefficacy in treating human melanoma, mainly as a result of the intrinsic resistance of this cancer type to this drug [12,13]. Moreover, our recent research has gained some evidence regarding the potential of PLP to improve DOX cytotoxicity on B16.F10 murine melanoma cells in vitro via the inhibition of the proangiogenic function of TAMs [14].…”

Nanotechnology-Based Drug Delivery Systems for Melanoma Antitumoral Therapy: A Review

“…on days 1, 22, 43 and 64, subsequently at 40 mg/m 2 at day 85 before first staging and in 4-week intervals thereafter. The results demonstrated that 7 patients stay alive more than 300 days and 5 patients more than 400 days [ 278 ].…”