Liposomal Doxorubicin For Liver Cancer

By Lunbao (Jerry) Huang, Pharm.D. Candidate c/o 2013

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Over the last two decades, there has been an increasing focus on hepatocellular carcinoma (HCC, most commonly known as liver cancer).  In the United States, as of 2011, there have been an estimated 26,190 new cases and 19,590 deaths from both hepatic and intrahepatic bile duct cancer.  Defined by the National Cancer Institute (NCI) as a “primary liver cancer … that forms in the tissues of the liver,” HCC is one of the four leading causes of death worldwide.¹

Doxil^® (liposomal doxorubicin) is an anthracyclic, antineoplastic agent approved for the treatment of AIDS-related Kaposi sarcoma (after failure of or intolerance to prior systemic therapy), multiple myeloma (after failure of at least one prior therapy), and ovarian cancer (progressive or recurrent).  The liposomal injection formulation is pegylated and has some advantages over conventional intravenous doxorubicin hydrochloride.  Liposomes are microscopic lipid vesicles that contain the active ingredient inside.  A liposomal drug delivery system increases doxorubicin’s blood circulation time, increases the drug’s half-life, decreases its volume of distribution.^2,3  It also enhances drug uptake by solid tumors (including the liver and spleen), and shows an impressive reduction in cardiac toxicity in contrast to conventional doxorubicin.^2,3  Recently after Johnson & Johnson’s liposomal doxorubicin was approved by the FDA for use in the United States, there have been many articles focusing on its utility in liver cancer. ⁴

In 2002, Goldberg, et. al. demonstrated that liposomal doxorubicin might enhance the efficacy of thermal ablation of liver cancer.⁴  Doxil^®, when used before radiofrequency ablation (RFA), increased tumor lesion volume and surgical coagulation (which improves the focus of intense light energy used to destroy abnormal tissues).⁴  Thus, tumor destruction combined with radiofrequency ablation suggested that similar techniques have the possibility of improving clinical outcomes and efficacy in a variety of focal hepatic tumors.⁴

In 2009 and 2011, Poon, et. al. found benefits in using a lyso-thermosensitive version of liposomal doxorubicin (LTLD, later branded as ThermoDox^®) in conjunction with radiofrequency ablation.^5,6  The mechanism was similar to Goldberg’s finding of Doxil^® with RFA.⁴ When heated above 39.5 °C (103.1 °F), LTLD released high concentration doxorubicin directly into liver tumors, focusing its cytotoxic effect on the tumor and tumor margin only.  The studies concluded that the RFA/LTLD combination could treat Child-Pugh class A-B patients with tumors up to 7 centimeters – offering a substantial increase in potentially curable patients with HCC.

Nanoknife angiodynamics or irreversible electroporation (IRE) is an FDA-approved surgical technique used for ablation of soft tissues in specific conditions.⁷  After placing a needle into the target (but not heating the cells above 39.5°C to 100 °C), IRE sends out short but intense electric pulses from the small electrodes placed within tumor.   IRE irreversibly opens tumor cells and eventually kills off the tumor.  Generally, Doxil^® combined with IRE is a lot “safer” than ThermoDox^® with RFA, mostly due to the different temperature distribution caused by nearby, cooler blood vessels – these may “cancel-out” the temperature required to kill the tumor cells.  IRE does not have a problem in this area – IRE with liposomal doxorubicin increases the selectivity and focus on liver tumor soft tissues more than RFA with liposomal doxorubicin. With the higher selectivity of IRE, less organ proteins are denatured.

In conclusion, liposomal doxorubicin in hepatocellular carcinoma, along with IRE or RFA, shows promising effects.  However, no studies directly compare IRE with Doxil^® versus RFA with ThermoDox.^®  Current data is limited to a few patient cases.  Larger studies are needed to compare liposomal and conventional doxorubicin (versus placebo) in combination with IRE or RFA.

SOURCES:

1. Dugdale D, Chen YB, Zieve D. “Hepatocellular carcinoma (Liver Cancer).” PubMed Health. A.D.A.M. Encyclopedia, 24 Aug 2011. Web. 3 Dec 2011. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001325/
2. Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6949-53.
3. Doxil^® [Package insert] Janssen Product, New York.
4. Goldberg SN, Kamel IR, Kruskal JB, et. al. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. AJR Am J Roentgenol. 2002 Jul;179(1):93-101.
5. Poon RT, Borys N. Lyso-thermosensitive liposomal doxorubicin: an adjuvant to increase the cure rate of radiofrequency ablation in liver cancer. Future Oncol. 2011 Aug;7(8):937-45.
6. Poon RT, Borys N. Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer. Expert Opin Pharmacother. 2009 Feb;10(2):333-43.
7. <http://www.angiodynamics.com/products/nanoknife> Web. 21, Dec 2011.