Kinetic Targeting of pegylated liposomal Doxorubicin: a new Approach to Reduce Toxicity during Chemotherapy (CARL-trial)

Abstract

BackgroundThe therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity.MethodsFor the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response.ResultsDFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported.ConclusionExtracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike.Trial registrationDRKS00000163

Extracorporeal Elimination of Circulating Pegylated Liposomal Doxorubicin (PLD) to Enhance the Benefit of Cytostatic Therapy in Platinum-Resistant Ovarian Cancer Patients

“…Reduction of >30% in tumor size was achieved in 10 out of 12 breast cancer patients (neoadjuvant) and 1 out of 3 recurrent ovarian patients. It can be presumed that the extracorporeal elimination of PLD using double filtration plasmapheresis is a safe and efficient method to reduce the dose and regimen-limiting toxicity of PLD (50). Our so far unpublished experience with 20 apheresis cycles in metastatic ovarian cancer patients treated with PLD support these findings.…”

“…Pütz et al in Freiburg, Germany, were the first to propose the use of extracorporeal apheresis to reduce induced toxicity by nanoscale drug delivery systems (52). Both pre-clinical and clinical trials were performed to prove the efficacy and safety of DFPP in this setting, the results seem promising so far (53,50). …”

“…A single clinical trial utilizing extracorporeal elimination of liposomal chemotherapeutics to reduce toxicity has been performed so far, Eckes et al showed results of the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics) in 2011 (50). The study enrolled 15 patients with solid tumors (12 patients with breast cancer treated with PLD/vinorelbine ± herceptine in the neoadjuvant setting, and 3 patients with recurrent ovarian cancer treated with PLD).…”

“…Considering this, along with the fact that PLD concentration in tumor tissue is dependent on actual plasma concentration, it can be presumed that a higher PLD concentration is only needed to build up a relevant diffusion gradient between plasma and tumor compartment (52). The remaining drug pool probably does not have any significant anti-tumor effect after having saturated the tumor tissue, but mainly contributes to adverse effects (50,52,53). It has been shown that the accumulation in the tumor tissue is much faster than that in potential sites of adverse effects (mainly the skin) (54).…”

Extracorporeal apheresis system - A nanoparticle drugs' elimination method to enhance the benefit of cytostatic therapy in cancer patients

“…DFPP is a well-tolerated method with minimal, or generally mild, side effects Dittrich-Riediger et al, 2015). Both pre-clinical and clinical trials were performed to prove the efficacy and safety of DFPP in this setting, and the results seem promising so far (Eckes et al, 2011).…”