The Role of Pegylated Liposomal Doxorubicin in Ovarian Cancer: A Meta-Analysis of Randomized Clinical Trials

Abstract

Background. Recent studies suggest that carboplatin with pegylated liposomal doxorubicin (CϩPLD) is as efficacious as carboplatin with paclitaxel (CϩP) and possibly is more tolerable for ovarian cancer therapy. Pegylated liposomal doxorubicin(PLD)mayalsobeefficaciousandtolerableasmonotherapyin recurrent or platinum-resistant disease. We performed a metaanalysis of randomized trials in order to elucidate the role of PLD in ovarian cancer. Methods. We searched PubMed, Scopus, and ISI Web of Knowledge for studies comparing CϩPLD with CϩP and comparing PLD with another monotherapy. Summary hazard ratios (HRs) and relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a fixed-effects model. Results. Three trials were included in the doublet regimen analysis, and five trials were included in the monotherapy regimen analysis. CϩPLD provided superior progression-free survival (PFS) (HR, 0.87; 95% CI, 0.78 -0.96) and similar overall survival (OS; HR, 0.95; 95% CI, 0.84 -1.07) compared with CϩP. There was no evidence of improved tolerability: CϩPLD had more gastrointestinal toxicity, anemia, thrombocytopenia, cutaneous toxicity, and mucositis/stomatitis, although there was less neutropenia, neuropathy, and alopecia. PLD monotherapy had similar PFS (HR, 0.99; 95% CI, 0.89 -1.11) and OS (HR, 0.99; 95% CI, 0.88 -1.11) to other monotherapies, but it was more tolerable. There was less neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity, although cutaneous toxicity was increased. Conclusion. CϩPLD had better PFS and similar OS compared with CϩP and had a very different toxicity profile. Therapy selection could be based on patient risks for side effects. PLD is as efficacious as other monotherapies and is more tolerable. The Oncologist 2013;18:1022-1031 Implications for Practice: Carboplatin with paclitaxel (CϩP) has been the standard first-line chemotherapy regimen for ovarian cancer patients; however, two large randomized trials of carboplatin and pegylated liposomal doxorubicin (CϩPLD) versus CϩP suggest that CϩPLD is as efficacious as CϩP and possibly is more tolerable. The results of our analysis showed that CϩPLD has better progression-free survival than CϩP and similar overall survival; however, we did not find CϩPLD to be more tolerable than CϩP. The toxicity profiles were very different, and therapy selection could reasonably be based on individual patient risks of side effects. Pegylated liposomal doxorubicin (PLD) is also a treatment option for recurrent or platinum-resistant ovarian cancer, but there is no clear distinction among any of the monotherapy options in this setting. The results of our analysis showed that PLD is as efficacious as other monotherapies and is more tolerable. Consequently, it may be the preferred agent in the palliative setting. INTRODUCTIONOvarian cancer is the leading cause of death from gynecologic malignancies in the United States [1]. Standard first-line treatment includes surgical debulking and platinum-based chemotherapy, us...

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

“…In MaFIA mice, colony stimulating factor receptor 1 (Csf1r) drives expression of FK506 binding protein 1A (Fas), an inducible “suicide” gene. Since Csf1r is expressed in macrophages and not lymphocytes, this allows selective elimination of up to 90% of systemic macrophages after administration of the Fas receptor ligand, AP20187 (Clontech) [8]. Depletion of macrophages was achieved by intraperitoneal administration of AP20187 as described previously [8].…”

“…Since Csf1r is expressed in macrophages and not lymphocytes, this allows selective elimination of up to 90% of systemic macrophages after administration of the Fas receptor ligand, AP20187 (Clontech) [8]. Depletion of macrophages was achieved by intraperitoneal administration of AP20187 as described previously [8]. Mice were randomized to receive AP20187 or vehicle control (4% ethanol, 1% PEG, 1.7% Tween in water) and mice in each group were further randomized to receive PLN at 85 nmoles of phospholipids per gram body weight or equivalent volume of the vehicle (5% dextrose solution) administered via tail vein injections for two weekly doses.…”

Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy

“…Therefore, the clinical relevance of these findings is uncertain since human cancers are not always immunogenic, and liposomes always have a drug payload that may affect the immune interactions as well. Yet, these data suggest that the tumor-promoting potential of the carrier may mitigate the benefits of carrier-mediated drug delivery and could partially explain why there is often an insufficient improvement in the clinical efficacy of liposomal drugs over free drugs (4, 5, 7, 31). Clearly, more preclinical and clinical research efforts are needed to elucidate the precise mechanisms by which nanoparticles interact with immune cells, the consequences of this interaction on cancer progression, and the impact of the drug cargo as well as the tumor immunologic milieu on these carrier–immune interactions.…”

Liposome promotion of tumor growth is associated with angiogenesis and inhibition of antitumor immune responses

“…1 However, despite enhanced tumor drug delivery and decreased toxicity, patient survival rates have not improved significantly compared to free drug treatments. [2][3][4] Given that liposomes interact extensively with the immune system, 5 we theorized that carrier-mediated immune modulation may promote tumor growth and thereby diminish the efficacy of liposomal drugs. This is supported by emerging evidence that activation of the complement system by polystyrene nanoparticles can augment tumor growth.…”