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Published on 22 September 2008

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Treatment of hepatocellular carcinoma: a pharmacist’s perspective

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One treatment option for patients who have HCC is transarterial chemoembolisation. Use of drug-eluting beads to deliver doxorubicin to tumour cells is a novel alternative to the conventional approach

Shirley Todd
MSc MRPharmS

Oncology Pharmacist

Cancer Centre
University Hospital
Birmingham NHS Foundation Trust
UK

Primary liver cancer or hepatocellular carcinoma (HCC) is the most common solid-organ malignancy worldwide. Although it accounts for only 1% of all cancers diagnosed in the UK, the condition causes around 2,850 deaths a year in the UK, and the
treatment of this tumour type remains a challenge for oncologists, hepatologists and surgeons alike.[1,2]

Curative treatments available involve tumour removal by resection or transplantation. These are limited by the common late presentation with advanced disease, and transplantation additionally by issues of donor organ availability.[3] Recurrence in patients treated initially by surgical means remains a significant risk.[3,4]

Nonsurgical treatments include percutaneous ethanol injection, radiofrequency ablation and systemic chemotherapy. The most commonly used agent in systemic chemotherapy is doxorubicin, but results have been disappointing.[5] A review of published trials involving more than 600 patients reported an objective
response rate of 19% and a median survival of four months.[6] Toxicity from systemic chemotherapy is an additional problem. Another treatment option available to patients in the UK is transarterial chemoembolisation (TACE). This has a dual antitumour action. Chemotherapy, usually doxorubicin, delivered directly into the hepatic artery exerts a cytotoxic effect on the malignant cells. This is followed by occlusion of the arterial blood supply to the tumour, leading to necrosis.

Methods of transarterial chemoembolisation
At the Cancer Centre at University Hospital Birmingham NHS Foundation Trust, we have completed more than 60 TACE procedures using two different methods to deliver the cytotoxic drug to the tumour.

The first is the conventional method utilising doxorubicin
combined with iodised ethyl-esters of the fatty acids of poppyseed oil (Lipiodol Ultra Fluid) to produce a drug reservoir emulsion and possibly exert an embolic effect (this is augmented by the addition of further embolic material). This method generates a number of practical considerations for pharmacists, such as the limited stability of the final product. Safety during administration is another concern. The resultant
formulation is viscous and difficult to inject into the hepatic artery through microcatheters. The emulsion also appears to have the ability to erode apparatus used in the procedure, resulting in an increased risk of leakage of cytotoxic material. Additionally, the aseptic preparation of the formulation is intricate and time-consuming. This requires many manipulations to produce the emulsion and then separate it into multiple small syringes in an attempt to overcome some of the safety concerns during administration.

The second method employed uses polyvinylalcohol hydrogel microspheres (DC Bead), a drug delivery embolisation system also known as “drug-eluting beads”. The beads are biocompatible and allow loading and release of cationic drugs via the displacement of water from the large number of sulphonate groups.

Drug release occurs in a gradual and predictable manner, and systemic release and toxic effects are minimised compared with the conventional approach.[7] The product has been previously described in detail in this publication.[8] The microspheres represent an innovative technique for TACE, which successfully overcomes several of the preparation and administration
difficulties encountered with TACE using Lipiodol. DC Bead is CE-marked, and stability data are readily available from the manufacturer. It also appears to be a less viscous product and is therefore easier to inject.

Loading the drug onto the beads is a fairly simple procedure. The DC Bead is presented in saline solution; this is removed, and the microspheres are mixed with doxorubicin solution. Proprietary doxorubicin 2mg/ml solutions or more concentrated solutions of the reconstituted powder can be used. The bead/ doxorubicin solution is then allowed to stand until loading of the drug onto the microspheres is complete. This can take from 20 minutes up to 11 hours depending on the size of spheres used and the concentration of the doxorubicin solution to be loaded (see Table 1). Prior to use, nonionic contrast medium is added to the loaded beads to assist product delivery at the time of radiological insertion. Loaded microspheres can be stored for up to 14 days at 2-8ºC, and for seven days following the addition of a nonionic contrast. Figure 1 illustrates the loading technique used in our centre.[9]

Therapeutic outcomes of TACE
The literature indicates mixed results for the TACE procedure. Of several published randomised controlled trials involving TACE, only two show a significant survival benefit with chemoembolisation. In the first, chemoembolisation was compared against symptom control in 80 patients. Survival was demonstrated in the TACE group as 57%, 31% and 26% at one, two and three years, respectively, compared with 32%, 11% and 3% in the symptom control cohort (p=0.002).[10]

The second study compared TACE with embolisation alone or conservative treatment in 112 patients. Survival at one and two years was 82% and 63% for TACE, 75% and 50% for embolisation alone, and 63% and 27% for the control group (p=0.009 for TACE vs conservative treatment).[11] A number of other studies have failed to show a significant improvement in survival for TACE over symptom control or other treatments.[12-14] It is worth noting, however, that all the trials of TACE involved small numbers of patients with different inclusion criteria, and a range of cytotoxic agents were employed.

TACE utilising drug-eluting beads, loaded with doxorubicin, has shown promising early results in patients with HCC. Continued follow-up in one study of 71 patients showed survival at 12 months was 97.5%, and 91% at two years.[15] In another study, overall survival at one and two years was quoted as 92.5% and 88.9%, where 27 patients were treated with DC
Bead.[7] However, these studies were conducted to prove the safety and efficacy of DC Bead in the treatment of HCC and were not designed to show a survival advantage. To date there are no published results from randomised trials comparing drug-eluting beads with controls.

Drug-eluting beads
Although the use of microspheres solved some of the issues encountered when using Lipiodol and doxorubicin for the TACE procedure, they have themselves presented a number of challenges in our centre. DC Bead is a unique product, so specialist preparation techniques and training are required to ensure all manipulations result in the successful loading of beads with doxorubicin. To this end, the manufacturer worked closely with us to provide initial comprehensive onsite training.

For the size of microsphere used at our centre, it takes up to two hours for loading to occur using a 25-37.5mg/ml solution of doxorubicin, and longer still if using a proprietary 2mg/ml solution. This is a significant amount of compounding time to devote to one product. Again, close liaison with the manufacturer allowed us better access to extended stability data, and we have been able to introduce a system that allows us to load DC Bead overnight. This has helped us to improve planning and efficiency when preparing the drug-eluting beads for use in patients undergoing the TACE procedure.

[[HPE39.55]]

Future of TACE and DC Beads
The introduction of DC Bead at our centre for use in TACE procedures has solved many of the governance and risk management issues associated with using the doxorubicin/Lipiodol emulsion. However, several drawbacks remain. The loading procedure is still time-consuming. This has been improved by allowing thedrug to load overnight, but many organisational factors must come into play to allow us to complete this process in advance of the patient’s treatment. Failure in any one of these contributing factors may mean we will not have the flexibility in workload to allow the drug and microspheres to combine for the recommended period, leading to postponement of the procedure.

Promising early results using DC Bead in TACE procedures for the treatment of HCC have provoked a great deal of interest in using the product. A randomised controlled trial is due to report its outcomes before the end of 2008. This multicentre European study intends to recruit 200 patients to receive doxorubicin via TACE using either drug-eluting beads or conventional TACE using Lipiodol.[9] The primary outcomes are safety and efficacy. Randomised controlled trials designed to show a survival advantage over other treatments are, however, essential if drug-eluting beads are to become the preferred method of chemoembolisation. Additionally, the cost-effectiveness of this treatment modality will also need to be considered.

A number of other clinical trials are in the planning and recruitment stages. These also focus on safety, efficacy and chemoembolisation technique. Furthermore, following encouraging data for the use of DC Bead loaded with irinotecan to treat colorectal cancer that has metastasised to the liver, further studies are also planned in this area.[9]

Several other types of drug-eluting beads are in development. PRECISION Bead is a form of drug-eluting bead preloaded with doxorubicin intended for treating HCC. This system would have the advantage of removing the loading time of the beads from the process, although several aseptic manipulations would still be required before the system is ready for injection. Other future products include: drug-eluting beads preloaded with irinotecan, intended for treating colorectal cancer liver metastases; ibuprofen, for use in the management of postembolisation pain; and microspheres to deliver large molecules and biologicals.[9]

[[HPE39.56]]

Drug-eluting bead technology represents an exciting method of drug and biological delivery that has potential application in many therapeutic areas. The manipulation of the beads themselves represents a challenge to pharmacy aseptic units.

Acknowledgements to Biocompatibles International plc for additional information and illustrations.

References
1. Cancer Research UK. Cancerstats. London: Cancer
Research UK; 2007. Available online at:
http://info.cancerresearchuk.org/cancerstats. Accessed
26 May 2008.
2. Lau Wy. Primary hepatocellular carcinoma. In:
Blumgart LH, Fong Y, editors. Surgery of the liver and
biliary tract. London: Saunders; 2000. p. 1423-50.
3. Johnson PJ. HPB 2005;7:50-5.
4. Belghiti J, et al. Ann Surg 1991;214:114-7.
5. Simonetti Rg, et al. Ann Oncol 1997;8:117-36.
6. Nerenstone SR, et al. Cancer Treat Rev 1988;15(1):1-31.
7. Varela M, et al. J Hepatol 2007;46(3):474-81.
8. Krämer I. Hosp Pharm Eur 2006;32:35-6.
9. Biocompatibles. Biocompatibles. Farnham: Biocompatibles International plc; 2008. Available online at: www.biocompatibles.com. Accessed 26 May 2008.
10. Lo CM, et al. Hepatology 2002;35:1164-71.
11. Llovet JM, et al. Lancet 2002;359:1734-9.
12. Pelletier G, et al. J Hepatol 1990;1:181-4.
13. Groupe d’étude et de traitement du carcinome
hepatocellulaire de Paris. New Engl J Med 1995;332:1256-61.
14. Pelletier G, Ducreux M, Gay F, et al. J Hepatol
1998;29(1):129-34.
15. Malagari K, Alexopoulou E, Chatzimichail K, et al. Abdom Imaging 2007;Oct 16 [Epub ahead of print].



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