title: Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial).
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  For 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.
  
  
  RESULTS
  DFPP 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.
  
  
  CONCLUSIONS
  Extracorporeal 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.
  
  
  BACKGROUND
  DRKS00000163.
authors.affiliation: Medical Practice, Altdorfstr. 10, Emmendingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eckes
authors.forename: Oliver
authors.initials: O
authors.lastname: Schmah
authors.forename: Jan W
authors.initials: JW
authors.lastname: Siebers
authors.forename: Ursula
authors.initials: U
authors.lastname: Groh
authors.forename: Stefan
authors.initials: S
authors.lastname: Zschiedrich
authors.forename: Beate
authors.initials: B
authors.lastname: Rautenberg
authors.forename: Annette
authors.initials: A
authors.lastname: Hasenburg
authors.forename: Martin
authors.initials: M
authors.lastname: Jansen
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hug
authors.forename: Karl
authors.initials: K
authors.lastname: Winkler
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pütz
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000302:isolation & purification; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000493:pharmacokinetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D010956:Plasmapheresis / Q000379:methods*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000302:isolation & purification / Q000493:pharmacokinetics; D011788:Quality of Life; D011795:Surveys and Questionnaires
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin