Horizon Scanning Research November 2015 & Intelligence Centre

Doxorubicin-eluting beads (DC Bead, DC Bead M1 and Radiopaque DC Bead) for

LAY SUMMARY

Hepatocellular carcinoma is the most common type of . This briefing is Most cases of hepatocellular carcinoma are caused by cirrhosis, a based on condition associated with damage and scarring to the liver. This is information available at the time often caused by excessive alcohol intake or having long term of research and a infections with hepatitis B or C. It is more common in men than women limited literature and typically affects older people. search. It is not intended to be a DC Bead consists of beads that are designed to release , a definitive statement drug, at a slow rate at the site of the cancer. This is on the safety, delivered directly to the hepatic artery, a blood vessel that supplies efficacy or blood to the liver. Studies have shown that DC Bead delivers effectiveness of the doxorubicin to the tumour without the drug spreading to healthy tissue. health technology covered and should DC Bead is already used to treat hepatocellular carcinoma in the UK. not be used for commercial purposes or NIHR HSRIC ID: 7219 (and 11780) commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Hepatocellular carcinoma (HCC): doxorubicin delivered using transarterial chemoembolisation (TACE).

TECHNOLOGY

DESCRIPTION

Doxorubicin-eluting beads (DC Bead, DC Bead M1 and radiopaque DC Bead) are used during TACE therapy for the treatment of HCC. The majority of the blood supply to the normal liver parenchyma comes from the portal vein, whereas blood flow to the tumour typically comes mainly from the hepatic artery. Furthermore, HCC tumours are generally hypervascular compared with the surrounding normal parenchymaa. TACE involves the intra-arterial injection of polyvinyl alcohol beads or particles loaded with a chemotherapeutic agent around a tumour. The blood supply to the tumour is then reduced or ceases altogether, causing it to shrink or die. The reduced blood supply also allows the chemotherapeutic agent to remain at the site of the tumour longer, exposing the tumour cells to higher levels of the chemotherapeutic and reducing the peak systemic plasma levels1. DC Bead can be loaded with a dose of up to 37.5mg doxorubicin per ml. A maximum total dose of 150mg of doxorubicin per procedure is recommended. DC Bead also comes in a smaller version, DC Bead M12,3., and a radiopaque version of DC Bead.

DC Bead has already received a CE mark and has been available in the UK since 2004. The use of doxorubicin in TACE is an established procedure for the treatment of HCC. DC Bead loaded with doxorubicin is sometimes referred to as DEBDOX, which was trademarked by Bio UK in December 2009a.

INNOVATION and/or ADVANTAGES

Doxorubicin-eluting beads offer an additional approach to TACE therapy for patients with hepatocellular cancer.

DEVELOPER

Biocompatibles UK Limited, a wholly owned subsidiary of BTG.

AVAILABILITY, LAUNCH OR MARKETING

• DC Bead was first CE Marked by Biocure Inc in 2003. The company was then taken over by Bio UK in 2004, and DC Bead is available and used in the UK. • Radiopaque DC Bead - a radiopaque embolic drug eluting bead. • DC Bead is currently registered with CE Mark as a Class IIb product.

a Company comment.

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PATIENT GROUP

BACKGROUND

HCC is a malignant tumour arising from liver cells (hepatocytes) and occurs mainly in cirrhotic livers4. It is sometimes known as hepatoma and is usually confined to the liver, although occasionally it spreads to other organs5. The liver plays an important role in the storage of nutrients, the production of bile and protein, and the breakdown of harmful and waste products6. HCC affects more men than women and the incidence increases with age6. HCC almost always develops from chronic liver disease, mainly alcoholic or viral (hepatitis B or C) and presents with cirrhosis in about 90% of casesb. Other risk factors include insulin resistance associated with non-alcoholic steatohepatitis, diabetes, and obesity7, as well as smoking, infections and alcohol consumption6.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. • NHS England. 2013/14 NHS Standard Contract for Hepatobiliary and Pancreas (Adult). A02/S/a. • NHS England. 2013/14 NHS Standard Contract for Liver Transplantation Service (Adult). A02/S(HSS)/a.

CLINICAL NEED and BURDEN OF DISEASE

Liver cancer is the 18th most commonly diagnosed cancer in the UK, accounting for 1% of all new cases of cancer8, a figure that is continuing to rise. In 2013, there were 4,387 new cases of liver cancer in England, 2,799 (64%) in males and 1,588 (36%) in females9. HCC is the main type of primary liver cancer, accounting for about 85% of cases10. Most cases of HCC are secondary to either a viral infection (hepatitis B or C) or cirrhosis11. The incidence of HCC has increased in recent years as a result of the rising prevalence of infection with hepatitis C virus and increased alcohol consumption11,12. Approximately 40-50% of HCCs in Europe can be attributed to excessive alcohol consumption13.

In 2013-14 there were 10,184 admissions for HCC (ICD-10 C22.0) in England, resulting in 61,415 bed days and 14,408 finished consultant episodes14. During 2014, there were 4,452 registered deaths from HCC in England and Wales15.

b Company comment.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. for the treatment of advanced hepatocellular carcinoma (TA189). May 2010. • NICE interventional procedure guidance. Chemosaturation via percutaneous hepatic artery perfusion and hepatic vein isolation for primary or metastatic liver cancer (IPG488). May 2014. • NICE interventional procedure guidance. Selective internal radiation therapy for primary hepatocellular carcinoma (IPG460). July 2013. • NICE interventional procedure guidance. Irreversible electroporation for treating primary liver cancer (IPG444). February 2013. • NICE interventional procedure guidance. Ex-vivo hepatic resection and reimplantation for liver cancer (IPG298). April 2009. • NICE interventional procedure guidance. Microwave ablation of hepatocellular carcinoma (IPG214). March 2007. • NICE interventional procedure guidance. Radiofrequency-assisted liver resection (IPG211). February 2007. • NICE interventional procedure guidance. Laparoscopic liver resection (IPG135). July 2005. • NICE interventional procedure guidance. Radiofrequency ablation of hepatocellular carcinoma (IPG2). July 2003.

Other Guidance

• European Society for Medical Oncology. Hepatocellular Carcinoma: ESMO-ESDO Clinical Practice Guidelines. 201216. • American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An Update. 201117.

CURRENT TREATMENT OPTIONS

For the majority of patients with HCC, treatment is palliative rather than curative. The only potentially curative options for HCC are surgery or ablation in selected patients. Treatments include: • Sorafenib – considered the standard of care for advanced HCC with well-preserved liver function by some authorities16, but is not recommended by NICE7. • Chemotherapy – doxorubicin is a commonly used chemotherapy drug and may help to shrink the size of the tumour in HCC18. Other chemotherapy drugs that may be used include , and gemcitabine18. • Chemoembolisation – TACE used with doxorubicin or cisplatin18,19. TACE is the most widely used primary treatment for HCC not amenable to curative treatment by excision or ablationc. TACE is recommended for patients with BCLCd stage B (intermediate), or those with an excellent liver function and multinodular asymptomatic tumours without macroscopic vascular invasion or extra hepatic spread, however, it cannot be used as a 16 single modality treatment to cure intermediate HCC . Studies with DEBDOX suggest

c Company comment. d Barcelona Clinic Liver Cancer (BCLC) staging system.

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there is less leakage of chemotherapy into the systemic circulation than conventional TACE, resulting in fewer side effects, with at least the same activity in randomised phase II trials16. • Hepatic resection – surgery is the most effective treatment for primary liver cancer18 and the standard treatment for HCC20. • Liver transplantation – to be eligible, the tumour size must be ≤5cm (single tumour), or a single tumour between 5-7cm for at least 6 months or two to three tumours that are <3cm18. • Radiofrequency ablation – more effective for treating small HCCs (≤5cm in diameter). In certain scenarios, it has also demonstrated clinical effectiveness equal to surgical resections19.

EFFICACY and SAFETY

Trial PRECISION V, NCT00261378, CA1008; PRECISION I; DC Bead; phase I/II. DC Bead with doxorubicin vs conventional TACE therapy; phase II. Sponsor Biocompatibles UK Ltd. Biocompatibles UK Ltd. Status Published. Published. Source of Publication21,22, trial registry23. Publication24. information Location Austria, France, Germany and Spain. Switzerland. Design Randomised, active-controlled. Non-randomised, uncontrolled. Participants n=212; aged ≥18 years; HCC not suitable n=27; patients with asymptomatic, for resection or percutaneous ablation, or untreated HCC, Child Pugh A cirrhosis patients eligible for resection or without vascular invasion or extra hepatic percutaneous ablation but the treatment spread. The pharmacokinetic profile was is unfeasible or the patient declines; no performed in 13 of the 27 patients in the prior chemotherapy, radiotherapy or DC Bead group and 5 patients were in TACE (with or without chemotherapy); the cTACE group. eligible for chemoembolisation prior to transplantation and the expected transplant waiting time exceeds 6 months; if received previous potentially curative treatment (resection and percutaneous ablation), then must demonstrate recurrence with clearly measurable disease according to RECIST or EASL (European Association for the Study of the Liver); must have bilobar disease that can be treated superselectively in a single session or both lobes able to be treated within 3 weeks; Eastern Cooperative Oncology Group performance status 0 and 1 and preserved liver function (Child Pugh Class A or B). Schedule Randomised to receive 4mL of DC Bead Patients received 2 episodes of TACE with doxorubicin at 37.5mg/mL for a total therapy using DC Bead loaded with of 150mg doxorubicin per treatment, or doxorubicin, separated by 2 months. 50-70mg/m2 to a maximum of 150mg Dose of doxorubicin ranged from doxorubicin with conventional TACE 25mg/m2 to 100mg/m2. In a subset group (cTACE). Patients received that received only cTACE, participants chemoembolisation at baseline, 2 and 4 were administered 50mg or 75mg of months for a maximum of three doxorubicin and obstruction was done procedures. with injections of gelfoam fragments

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Follow-up Follow-up up to 6 months. Follow-up up to 6 months. Primary Objective response rate according to Safety and pharmacokinetics. outcome/s RECIST and EASL. Secondary Toxicity, change in alpha foetal protein, Tumour response. outcome/s time to hospital discharge, safety, other procedures or interventions required, cardiotoxicity, local tumour response, health care resource use, patient quality of life and time to progression. Key results The DC Bead group had higher rates of During the first treatment session, 89% complete response, objective response, (24 of 27 patients) of cases achieved and disease control compared with the arterial blood flow obstruction (complete cTACE group (27% vs. 22%, 52% vs. obstruction in 21). Of the remaining 3 44%, and 63% vs. 52%, respectively). patients, 2 obtained complete obstruction Superiority hypothesis was not met (one- during the second treatment session, sided p=0.11). Objective response was whereas in the third patient, obstruction p=0.038 compared to cTACE in patients was unfinished because the HCC tumour with Child-Pugh B, ECOG 1, bilobar was fed by multiple small arteries. disease, and recurrent disease. DC Bead Obstruction was maintained in 4 of the 21 resulted in reduced serious liver toxicity patients that had achieved a total (p<0.001) and a significantly lower rate of occlusion during the first DC Bead TACE. doxorubicin-related side effects Of these 4, 3 had a second TACE (p=0.0001). session due to newly developed The mean maximum post collaterals. Based on RECIST criteria chemoembolisation alanine transaminase there were zero complete responses, and and aspartate transaminase increase in 12 partial responses (>30% reduction the DC Bead group was 50% (p<0.001) was registered in 12 patients, 44%). In and 41% (p<0.001) less than in the the remaining cases, 7 were classed as cTACE group, respectively. The mean stable disease and 5 as disease total length of hospital stay for all progression. Objective response rate procedures and serious AEs (SAEs) was increased to 66.6% (intention-to-treat); 12 ± 9 days in both treatment groups. At 26% had complete response; 41% had six months, mean levels of alpha foetal partial response. The pharmacokinetic protein were 25.62 ± 890.28IU/mL profile was performed in 13 of the DC (geometric mean ± coefficient of Bead group and 5 in the cTACE group. variance) at baseline and 16.59 ± Doxorubicin Cmax and AUC were 1237.54IU/mL at 6 months or early significantly lower in the DC Bead group withdrawal in the DC Bead group and (78.97 ± 38.3ng/mL and 662.6 ± 27.54 ± 2400.19IU/mL and 13.49 ± 417.6ng/mL min) than in the cTACE 1008.98IU/mL, respectively in the cTACE group (2341.5 ± 3951.9ng/mL and 1812.2 group. There was a small but statistically ± 1093.7ng/mL min, p=0.00002 and significant difference in mean change p=0.001, respectively). After a median from baseline in LVEF between the DC follow-up of 27.6 months, 1- and 2-year Bead and cTACE groups of 4% (95% CI, survival is 92.5% and 88.9%, 0.71–7.3; p=0.018). respectively. Adverse Treatment emergent AEs affecting the After the first TACE, 37% presented a effects (AEs) liver occurred in 16.1% of the DC Bead clinically relevant post-TACE syndrome group compared with 25% of the cTACE but did not require prolonged hospital group. Treatment emergent cardiac AEs stay; 6 (22%) patients presented with mild occurred in 4.3% of DC Bead group and fever and 4 (15%) with nausea and 7.4% of the cTACE group. SAEs included vomiting. Two patients were diagnosed 1 death due to cardiomegaly (DC Bead), with liver abscess – one was completely 1 life-threatening acute cardiac failure healed with antibiotics while the other and 1 coronary artery occlusion, (both developed progressive liver cTACE). decompensation and died at 3 months. After the second procedure (n=22), 4 patients (18%) presented with post-TACE syndrome, 7 (32%) with mild pain, and 3 (14%) with nausea and vomiting. All

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minor secondary effects disappeared within the first week. None of the patients presented alopecia, bone marrow toxicity, dyspnoea or pulmonary embolism.

ESTIMATED COST and IMPACT

COST

The cost of DC Bead is unknown. A 50mg vial (powder for reconstitution) of doxorubicin hydrochloride encapsulated in liposomes costs £456.1325. A 10mL vial (2mg/mL) of pegylated doxorubicin hydrochloride encapsulated in liposomes costs £360.2325.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 BTG Interventional Medicine. About DC Bead. http://bead.btg-im.com/products/uk-322/dcbead- 3/about-dc-bead Accessed 3 November 2015. 2 Spreafico C, Cascella T, Facciorusso A, et al. Transarterial chemoembolization for hepatocellular carcinoma with a new generation of beads: clinical-radiological outcomes and safety profile. Cardiovascular Interventional Radiology 2015;38(1):129-34. 3 Deipolyi AR, Oklu R, Al-Ansari S, et al. Safety and efficacy of 70-150 μm and 100-300 μm drug- eluting bead transarterial chemoembolization for hepatocellular carcinoma. Journal of Vascular and Interventional Radiology 2015;26(4):516-22. 4 Coon JT, Rogers G, Hewson P et al. Surveillance of cirrhosis for hepatocellular carcinoma – systemic review and economic analysis. Health Technology Assessment 2007;11:34. 5 Macmillan Cancer Support. Types of primary liver cancer. www.macmillan.org.uk/Cancerinformation/Cancertypes/Liver/Aboutlivercancer/Types.aspx Accessed 16 October 2015.

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6 Cancer Research UK. Types of primary liver cancer. http://www.cancerresearchuk.org/about- cancer/type/liver-cancer/about/types-of-primary-liver-cancer Accessed 19 October 2015. 7 National Institute for Health and Clinical Excellence. Sorafenib for the treatment of advanced hepatocellular carcinoma. Technology appraisal TA189. London: NICE; May 2010. 8 Cancer Research UK. Liver Cancer Statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/liver-cancer#heading-Zero Accessed 16 October 2015. 9 Office for National Statistics. Cancer Registration Statistics, England, 2013. www.ons.gov.uk 10 McGlynn KA. Epidemiology and natural history of hepatocellular carcinoma. Best Practice and Research Clinical Gastroenterology 2005;19:3-23. 11 Llovet JM, Burroughs A and Bruix J. Hepatocellular carcinoma. The Lancet 2003;362:1907-1917. 12 Health Protection Agency. Hepatitis C in the UK. July 2011. www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1309969906418. 13 NIHR Horizon Scanning Centre. Brivanib alaninate for hepatocellular cancer. University of Birmingham, February 2012. http://www.hsric.nihr.ac.uk/. 14 Health & Social Care Information Centre. Hospital Episode Statistics for England. Admitted Patient Care statistics, 2013-14. www.hscic.gov.uk. 15 Office for National Statistics. Death Registration Summary Tables - England and Wales, 2014. www.ons.gov.uk 16 Verslype C, Rosmorduc O and Rougier P. Hepatocellular carcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(Suppl 7):vii41-vii48. 17 Bruix J and Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022. 18 Macmillan. Primary liver cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Liver/Primarylivercancer.aspx Accessed 27 October 2015. 19 American College of Radiology. ACR appropriateness criteria: Radiologic Management of Hepatic Malignancy. https://acsearch.acr.org/docs/69379/Narrative/ Accessed 27 October 2015. 20 National Institute for Health and Clinical Excellence. Laparoscopic liver resection. Interventional procedures guidance IPG135. London: NICE; July 2005. 21 Vogl TJ, Lammer J, Lencioni R et al. Liver, gastrointestinal, and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: results from the PRECISION V randomized trial. American Journal of Roentgenology. 2011;197(4):W562-70. 22 Lammer J, Malagari K, Vogl T et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41-52. 23 ClinicalTrials.gov. Prospective randomised study of doxorubicin in the treatment of hepatocellular carcinoma by drug-eluting bead embolisation (PRECISIONV). https://clinicaltrials.gov/ct2/show/NCT00261378 Accessed 16 November 2015. 24 Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads. Efficacy and doxorubicin pharmacokinetics. Journal of Hepatology 2007;46(3):474- 481. 25 Joint Formulary Committee. British National Formulary. BNF November 2015. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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