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Open Access Research article

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

Jürgen Eckes1, Oliver Schmah2, Jan W Siebers3, Ursula Groh3, Stefan Zschiedrich4, Beate Rautenberg5, Annette Hasenburg5, Martin Jansen7, Martin J Hug6, Karl Winkler7 and Gerhard Pütz7*

Author Affiliations

1 Medical Practice, Altdorfstr. 10, Emmendingen, Germany

2 Dept. Hematology & Oncology; University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, Germany

3 Dept. Gynecology, St. Josephs Hospital Offenburg, Offenburg, Germany

4 Dept. Nephrology; University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, Germany

5 Dept. of Gynecology and Obstetrics, University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, Germany

6 Pharmacy; University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, Germany

7 Dept. Clinical Chemistry; University Medical Center Freiburg, Hugstetter Str. 55, Freiburg, Germany

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BMC Cancer 2011, 11:337  doi:10.1186/1471-2407-11-337

Published: 4 August 2011

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 (

    C
ontrolled
    A
pplication and
    R
emoval of
    L
iposomal 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.

Conclusion

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.

Trial registration

DRKS00000163