Journal of Medical Economics

ISSN: 1369-6998 (Print) 1941-837X (Online) Journal homepage: https://www.tandfonline.com/loi/ijme20

A cost analysis of SIR-Spheres yttrium-90 resin

microspheres versus tyrosine kinase inhibitors
in the treatment of unresectable hepatocellular
carcinoma in France, Italy, Spain and the UK

Richard Pollock, Fabien Colaone, Laura Guardiola, Suki Shergill & Victoria K
Brennan

To cite this article: Richard Pollock, Fabien Colaone, Laura Guardiola, Suki Shergill & Victoria
K Brennan (2020): A cost analysis of SIR-Spheres yttrium-90 resin microspheres versus tyrosine
kinase inhibitors in the treatment of unresectable hepatocellular carcinoma in France, Italy, Spain
and the UK, Journal of Medical Economics, DOI: 10.1080/13696998.2020.1731213

To link to this article: https://doi.org/10.1080/13696998.2020.1731213

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 A cost analysis of SIR-Spheres yttrium-90 resin microspheres versus tyrosine
kinase inhibitors in the treatment of unresectable hepatocellular carcinoma
in France, Italy, Spain and the UK

Richard Pollock1, Fabien Colaone2, Laura Guardiola2, Suki Shergill2, Victoria K Brennan2

1. Covalence Research Ltd, London, UK

2. Sirtex Medical United Kingdom Ltd, London, UK

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Corresponding author

Richard Pollock

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Covalence Research Ltd

51 Hayes Grove, London, United Kingdom, SE22 8DF

pollock@covalence-research.com
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ABSTRACT

BACKGROUND AND AIMS

A wide range of treatment options are available for hepatocellular carcinoma (HCC), including
systemic treatment with tyrosine kinase inhibitors (TKIs) such as sorafenib and lenvatinib,
immunotherapies, locoregional therapies such as selective internal radiation therapy (SIRT), and
treatments with curative intent such as resection, radiofrequency ablation and liver transplantation.
Given the substantial economic burden associated with HCC treatment, the aim of the present
analysis was to establish the cost of using SIRT with SIR-Spheres yttrium-90 (Y-90) resin microspheres
versus TKIs from healthcare payer perspectives in France, Italy, Spain and the United Kingdom (UK).

METHODS

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A cost model was developed to capture the costs of initial systemic treatment with sorafenib (95%)

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or lenvatinib (5%) versus SIRT in patients with HCC in Barcelona Clinic Liver Cancer (BCLC) stages B

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and C. A nested Markov model was utilized to model transitions between progression-free survival
(PFS), progression, and death, in addition to transitions between subsequent treatment lines. Cost

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and resource use data were identified from published sources in each of the four countries.

RESULTS
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Relative to TKIs, SIRT with SIR-Spheres Y-90 resin microspheres were found to be cost saving in all
four country settings, with the additional costs of the microspheres and the SIRT procedure being
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more than offset by reductions in drug and drug administration costs, and treatment of adverse
events. Across the four country settings, total cost savings with SIR-Spheres Y-90 resin microspheres
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fell within the range 5.4–24.9%, and SIRT resulted in more patients ultimately receiving treatments
with curative intent (4.6% versus 1.4% of eligible patients).
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CONCLUSIONS
SIR-Spheres Y-90 resin microspheres resulted in cost savings relative to TKIs in the treatment of
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unresectable HCC in all four country settings, while increasing the proportion of patients who
become eligible for treatments with curative intent.
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Keywords: Hepatocellular carcinoma; costs and cost analysis; yttrium; brachytherapy; United
Kingdom; Italy; France; Spain

Running title: Cost of Radioembolization in HCC

JEL classification codes: C51; C63; I10

MANUSCRIPT

BACKGROUND AND AIMS

World Health Organization (WHO) data for 2018 reported liver cancer to be the sixth most common
cancer by worldwide number of incident cases, and the fourth most common cause of cancer-
related death, with an estimated 841,080 new cases (representing 4.7% of all incident cancers) and
781,631 deaths (representing 8.2% of all cancer deaths) in 2018.1 Worldwide, the age-standardized
incidence of liver cancer was 2.8 times higher in men than in women.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer,2 and current
treatment guidelines recommend that all patients with HCC be evaluated for potentially curative

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therapies, which include resection, transplantation and, in the case of smaller lesions, ablative

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therapies such as radiofrequency or cryoablation.3 In patients who are not candidates for treatments

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with curative intent, locoregional therapies should be considered as a treatment option, potentially
as part of a strategy to downstage patients to treatments that do have a curative intent.

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In 2007, the SHARP randomized controlled trial (RCT) demonstrated the superior efficacy of tyrosine
kinase inhibitor (TKI) sorafenib (Nexavar®; Bayer AG, Leverkusen, Germany) versus placebo in
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patients with advanced HCC in patients who had not received prior systemic therapy, with median
overall survival (OS) of 10.7 versus 7.9 months (p<0.001).4 Based on the SHARP data, sorafenib
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became and remains the preferred systemic treatment option in patients with unresectable HCC.
Findings of the REFLECT trial were published in 2018, and showed lenvatinib (Lenvima®; Eisai GmbH,
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Frankfurt am Main, Germany), a multireceptor TKI, to be non-inferior to sorafenib in terms of OS

(13.6 months versus 12.3 months, hazard ratio 0.92).5
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As the number of systemic treatment options for unresectable HCC has increased, the evidence base
supporting the use of locoregional therapies has also grown. The SorAfenib versus
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Radioembolisation in Advanced Hepatocellular carcinoma (SARAH) trial was a phase III, open-label
RCT in locally advanced or inoperable HCC designed to directly compare the efficacy and safety of
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SIRT with SIR-Spheres® Y-90 resin microspheres versus sorafenib.6 While SARAH showed no
difference in median OS (9.9 vs. 9.9 months in patients who ultimately received treatment, p=0.92).
In spite of the finding of no difference in the primary endpoint incidence of all adverse events was
56% lower with SIR-Spheres Y-90 resin microspheres than sorafenib (p<0.001), objective response
rate was 19.0% with SIR-Spheres Y-90 resin microspheres compared with 11.6% in patients treated
with sorafenib, and patient quality of life was significantly higher as measured by the EORTC QLQ-
C30 questionnaire.7 Furthermore, progression in the liver as the first site was significantly lower with
SIR-Spheres Y-90 resin microspheres than sorafenib (hazard ratio 0.72, 95% confidence interval
0.56–0.93, p=0·0143). The SIRveNIB trial, conducted in the Asia-Pacific region, similarly found no
significant differences in OS between SIRT with SIR-Spheres Y-90 resin microspheres and sorafenib
(11.3 months with SIRT compared with 10.4 months with sorafenib in the population who ultimately
received treatment in each arm, p=0.27).7

In second-line treatment for patients who had progressed on or were intolerant to sorafenib, trials
of brivanib, everolimus, ramucirumab, tivantinib, and ADI-PEG 20 had failed to show any benefits
over placebo, until the phase III randomized RESORCE trial showed positive results for regorafenib in
patients with disease progression on sorafenib, with a median OS of 10.6 versus 7.8 months
(p<0.0001). The CELESTIAL trial of cabozantinib also then demonstrated improvements in OS relative
to placebo in patients with HCC previously treated with sorafenib.8

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Given the potential for improved quality of life and an increased proportion of patients ultimately

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becoming eligible for receiving treatments with curative intent after SIRT, the aim of the present
study was to evaluate the cost of using SIRT with SIR-Spheres Y-90 resin microspheres as first-line

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therapy in patients with unresectable HCC compared with TKIs sorafenib or lenvatinib. The focus was
on a population of patients with BCLC stage B not eligible for treatment with TACE, and eligible
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patients with BCLC stage C HCC from the perspective of national healthcare payers in four European
countries: France, Italy, Spain, and the UK (specifically patients covered by the NHS in England).
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METHODS
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MODEL DEVELOPMENT

A cost model was developed in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) to
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simultaneously model disease progression and progression from first-line treatment to second- and
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third-line treatments and best supportive care (BSC). The model was structured as a nested Markov
model, with the top-level Markov model incorporating states of progression-free survival (PFS), post-
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progression survival (PPS), and death, and nested models within the PFS and PPS states capturing
transitions between subsequent treatments (Figure 1).

Transitions between the PFS, PPS and death states were modeled using a partitioned survival, area-
under-the-curve (AUC) cohort simulation approach. Kaplan-Meier data for PFS and overall survival
(OS) were obtained from the per-protocol population in the SARAH RCT and used to fit parametric
curves, which then informed the top-level transition probabilities between the PFS, PPS and death
states.7 Exponential, generalized gamma, Gompertz, log logistic, lognormal and Weibull fits to the
PFS and OS curves were evaluated using the Akaike information criterion (AIC) and Bayesian
information criterion (BIC), with the lowest scoring (i.e. best fitting) models for PFS and OS selected
for use in the base case analysis.9,10 Where the model with the lowest AIC was different from the
model with the lowest BIC, the lowest sum of AIC and BIC was used to determine the best model fit.

The model reported costs divided across seven categories: implantable device costs (covering the
cost of the SIR-Spheres Y-90 resin microspheres), hospital care and intervention room costs
(covering the costs of the SIRT work-up and treatment), drug costs, adverse event costs, follow-up
and drug administration costs, curative intent treatment costs, and end of life care costs. In addition
to costs, the model also reported the proportion of patients ultimately undergoing treatments with
curative intent, the evolution of the use of treatments with curative intent over the time horizon of
the analysis, and mean life expectancy in years.

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SCENARIOS, TIME HORIZON, DISCOUNTING AND ANALYSIS PERSPECTIVE

In all four country-specific analyses, all patients eligible for inclusion started in the PFS state on an

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initial HCC treatment in the two scenarios: sorafenib (95%) or lenvatinib (5%) in the “without SIRT”

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scenario, and SIRT with SIR-Spheres Y-90 resin microspheres (100%) in the “with SIRT” scenario. The
95:5 split between sorafenib and lenvatinib in the “without SIRT” arm was based on expert clinical
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opinion. Analyses were conducted over a 3-year time horizon from the perspective of the national
healthcare payer in each of the respective countries.The national healthcare payer perspective was
adopted in line with guidelines or consensus from the relevant authorities in each country: the
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Haute Autorité de Santé (HAS) in France, the Agenzia Italiana del Farmaco (AIFA) in Italy, the
National Institute of Clinical Excellence (NICE) in the UK, and the Interministerial Committee for
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Pricing (ICP) in Spain.11,12,13 No discounting was applied in line with best practice budget impact
modeling guidelines from the International Society for Pharmacoeconomics and Outcomes Research;
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while the objectives and audience of a budget impact model and a short-term cost model may be
different, the omission of discounting results in a simple sum of the predicted costs over a 3-year
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budget period rather than capturing the time preference-adjusted net present value of any future
expenditure. 14
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TREATMENT FOLLOWING PROGRESSION

After initial treatment with SIRT or after progression with sorafenib or lenvatinib, the PPS state
incorporated a nested Markov model to capture transitions between subsequent systemic
treatments or best supportive care (BSC). After SIRT, second-line treatments included BSC,
lenvatinib, sorafenib or, within the PFS state, treatments with curative intent (radiofrequency
ablation, resection, or liver transplantation). Second-line treatments after sorafenib included BSC,
regorafenib or treatments with curative intent as available after SIRT (Figure 2 and Figure 3). The
distribution between second-line treatments in each case was informed by data from the SARAH
RCT, with an adjustment for use of post-SIRT lenvatinib (which received marketing authorization
after treatment assignment in SARAH was complete) based on the assumption of 5% uptake.

Following SIRT (or technical issues arising during SIRT work-up), 42.5% of patients were assumed to
receive BSC; 4.6% were assumed to undergo treatment with curative intent based on data from
SARAH; and the remaining 52.9% of patients (including all patients deemed ineligible for SIRT due to
technical contraindications observed during the SIRT work-up) were assumed to receive treatment
with lenvatinib (5%) or sorafenib (95%). Of the 4.6% of patients receiving treatments with curative
intent after SIRT, 54.3% received tumor ablation, 28.3% received hepatic resection, and the
remaining 17.4% received a liver transplant, in line with subsequent treatments received by patients

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in the SIRT arm of the SARAH RCT.6 Patients experiencing progression with second-line lenvatinib

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were subsequently assumed to receive BSC, while patients experiencing progression after second-

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line sorafenib were assumed to receive either BSC or regorafenib.

Following first-line sorafenib or lenvatinib treatment, 1.4% of patients were assumed to receive

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treatment with curative intent, again based on subsequent treatments observed in the SARAH trial.
Of the 1.4%, 64.3% were assumed to receive tumor ablation, and the remaining 35.7% were
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assumed to receive a liver transplant.6

The per-cycle probability of treatment switching was based on data from pivotal trials of the
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respective agents (Appendix Table 1).15,16 Transition probabilities were derived from the median time
on treatment from the respective trials using the following formula where Ti denotes the median
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time on treatment i, pij represents the proportion of patients on treatment i who subsequently
receive treatment j, and k represents a constant time unit conversion from the median time on
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treatment units to model cycle length:

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RESOURCE USE
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In patients receiving SIRT with SIR-Spheres Y-90 resin microspheres, 8.3% of patients were assumed
to require a repeat work-up procedure, while 11.4% of patients would not ultimately receive SIRT
due to technical contraindications in line with data from a study into work-up issues associated with
SIRT (Figure 2).17 Of those patients receiving SIRT, 7.1% were assumed to receive a repeat treatment,
based on expert opinion in the French setting. The expert opinion was in close alignment with the
325-patient ENRY study of SIRT in patients with HCC, in which 93.2% of patients received one SIRT
treatment and the majority (141/147 or 95.9%) of whole-liver treatments were performed in a single
session.18

Incidence of 28 adverse events was assumed to be the same across all four country settings and was
captured based on data from the SARAH RCT, across five categories: constitutional symptoms,
dermatological events, gastrointestinal disorders, liver disorders, and laboratory test abnormalities.

COUNTRY-SPECIFIC DATA

Country-specific data on the annual incidence of primary liver cancer in each country were obtained
from the World Health Organization International Agency for Research on Cancer (WHO IARC).19 The
annual number of new cases of primary liver cancer was then derived by multiplying by national
population sizes as obtained from the Institut national de la statistique et des études économiques,

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the Istituto Nazionale di Statistica, the Instituto Nacional de Estadística, and the Office for National
Statistics, in France, Italy, Spain, and the UK respectively.20,21,22,23 As the WHO IARC data pertains to

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all primary liver cancer, a multiplier of 0.75 was applied to derive the HCC incidence rate by

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excluding cholangiocarcinomas, hepatoblastomas, sarcomas, poorly-specified carcinomas, and other
hepatic malignancies in line with data from the Surveillance, Epidemiology, and End Results (SEER)
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registry (Appendix Figure 2).24

The proportions of patients diagnosed in BCLC stages B and C were derived from country-specific
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sources where available. In France, data were derived from the CHANGH study, which enrolled 1,207
patients across 103 hepato-gastroenterology units in French hospitals in 2008-2009, of which 894
were ultimately included in the analysis.25 Across all 894 patients, 5.5% were diagnosed in BCLC
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stage B, and 46.8% in BCLC stage C. These proportions were then applied to an estimate of the
number of incident HCC patients in France (Appendix Figure 2). In Italy, data from the ITA.LI.CA
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database were employed based on a 2015 publication by Giannini and colleagues.26 Of 600 patients
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with HCC included in the analysis, 23.2% were diagnosed at BCLC stage B and 23.0% were diagnosed
at BCLC stage C.22 Where country-specific data on BCLC stage at diagnosis could not be identified
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(Spain and the UK), data from 2,261 patients in Europe were obtained from the HCC BRIDGE study,
in which 11.2% of patients were diagnosed at BCLC stage B, and 51.2% of patients were diagnosed at
BCLC stage C.27 In all country settings, it was assumed that one third of patients in BCLC stage C
would be eligible for treatment with SIRT (Appendix Figure 2).

Cost data in each country setting were collected from relevant national sources and inflated to 2018
local currency values where necessary using the healthcare component of the local inflation indices.
For the French analysis, costs were derived from multiple sources, with hospital-based costs being
based on data from the Étude Nationale des Coûts (National Cost Study; ENC), and from
Classification Commune des Actes Médicaux (CCAM), Nomenclature des Actes de Biologie Médicale
(NABM), and Nomenclature Générale des Actes Professionnels (NGAP) tariffs. Costs associated with
treatments with curative intent were based on a 2017 cost-effectiveness analysis of early detection
and curative treatments for HCC in France.28 Costs of grade 1 and 2 adverse events in France were
based primarily on a multicountry analysis of adverse event costs in patients with metastatic renal
cell carcinoma, supplemented with an NGAP GP appointment fee where no specific data were
available.29 Costs of grade 3 and 4 adverse events were based on a combination of the ENC and data
collected during the SARAH trial.

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In the Italian setting, two recently-published studies of locoregional therapies for HCC in Italy were

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used to inform the cost collection exercise, and unit costs were cross-checked against health

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economic studies of metastatic melanoma in Italy published by Wehler et al. and Vouk et al. in 2016
and 2018, respectively.30,31,32,33 Drug costs in the Italian setting were taken from the Gazzetta

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Ufficiale either at the time of the approval or the most recent ex-factory price update for sorafenib,
lenvatinib and regorafenib.34,35,36 Grade 1 and 2 adverse events in Italy were costed based on the
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assumption of a single GP interaction for each event, while grade 3 and 4 events were costed based
on a combination of DRGs, and data from the studies of adverse events in patients receiving
treatment for metastatic melanoma.26
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In Spain, drug costs were taken from the Agencia Española de Medicamentos y Productos Sanitarios,
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while costs of nurse interactions, imaging procedures, clinical examinations, and treatments with
curative intent were based on tariffs for the Basque Country published by Osakidetza.37 The cost of
death was based on a 2014 study of patients with metastatic colorectal cancer by Pericay et al.
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assuming 20 days of hospital-based palliative care in 65% of patients.38

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In the UK, drug costs were sourced from the British National Formulary, while costs of interactions
with nurses, general practitioners and podiatry services were based on data from the Personal Social
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Services Research Unit (PSSRU) Unit Costs of Health & Social Care 2018 report.39,40 All UK hospital-
based treatments and diagnostics were calculated based on HRG-coded data from the 2017-18
National Schedule of Reference Costs.41 The cost of death in the UK was based on the social care
component of care costs in the last twelve months of life from the PSSRU report.36 In all four country
settings, the costs associated with SIRT with SIR-Spheres Y-90 resin microspheres were based on
diagnosis-related groups (DRGs), or healthcare resource groups (HRGs) in the case of the UK analysis.
SENSITIVITY ANALYSIS

A series of one-way sensitivity analyses were conducted in which the sensitivity of model outcomes
to changes in individual model parameters was investigated. Sensitivity analyses conducted included
eliminating transitions to treatments with curative intent; removing costs of all adverse events, then
grade 1/2, and grade 3/4 events separately; switching to data from the SARAH trial to inform the
proportion of patients deemed ineligible for SIRT after the work-up; and switching to data from the
SIRveNIB and SARAH RCTs (as opposed to expert opinion) to inform the proportion of patients in
whom repeat SIRT treatments were performed. In the SARAH RCT, 18.8% of patients were not
ultimately eligible for SIRT due to a combination of high (>20%) lung shunt fraction (LSF),
gastrointestinal uptake of 99mTc macroaggregated albumin during work-up, and/or advanced disease.

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In SIRveNIB and SARAH, 2.3% and 37% of patients respectively received at least one repeat

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treatment, compared with the 7.1% assumed in the present base case on the basis of expert opinion

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in France. Finally, two analyses were conducted in which patients who went on to receive any
systemic therapy after SIR-Spheres Y-90 resin microspheres were assumed to receive lenvatinib in

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10% and 20% of cases (with the remainder receiving sorafenib), compared to 5% in the base case
analysis.
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RESULTS

Overall survival and progression-free survival analysis

AIC and BIC criteria identified the generalized gamma models to be the best fit to the SIR-Spheres Y-
90 resin microspheres Kaplan-Meier data from the SARAH trial for both OS and PFS, while lognormal
models were the best fit to the sorafenib OS and PFS data (Appendix Table 2 and Appendix Figure 1).

Base case analyses

Relative to the scenario without SIRT, the cost analysis projected savings with SIR-Spheres Y-90 resin
microspheres in all four country settings (Table 2 and Figure 3). Cost savings in the scenario with SIRT
were 7.7% in the UK, 11.7% in France, 5.4% in Italy, and 26.5% in Spain, relative to the scenario

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without SIRT. Initial treatment with SIR-Spheres Y-90 resin microspheres was also projected to result

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in an increase in the proportion of patients ultimately eligible to undergo treatments with curative

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intent from 1.4% in the scenario without SIRT to 4.6% in the scenario with SIRT (Figure 4),
corresponding to 71 additional patients treated with curative intent across the four countries. Of the

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patients not receiving treatments with curative intent, fewer patients in the SIRT arm also ultimately
received regorafenib, which was modeled as the “last line” of therapy before BSC (Figure 5). The
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model projected that life expectancy would be 1.176 years with SIR-Spheres versus 1.168 years with
sorafenib, representing a negligible increase of 0.009 years.
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Across all four country settings, the largest modeled category of expenditure was drug costs in the
scenario without SIRT, and the cost of the SIR-Spheres Y-90 resin microspheres in the scenario with
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SIRT. The contributions of the other modeled cost categories varied between countries, but drug
costs and SIRT work-up and procedure costs were substantial contributors to costs in the “with SIRT”
arm in all country settings. Regardless of the differences between the cost categorizations, the
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overall costs per patient were closely aligned across the UK, French and Italian settings, with only the
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Spanish analysis reporting higher costs overall, driven predominantly by the higher costs associated
with treating grade 3 and 4 adverse events.
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Sensitivity analyses

One-way sensitivity analyses showed the model to be relatively insensitive to changes in the
parameters investigated (Table 2). One notable exception was the exclusion of adverse event costs
in the Spanish setting, which reduced the cost in the scenario without SIRT by 25% and the cost in
the scenario with SIRT by 22%. Further analysis showed that the change in cost was driven
predominantly by the exclusion of the grade 3 and 4 events. Changes in costs arising from omitting
treatments with curative intent from the analysis were mixed; in the analyses, patients who would
otherwise have undergone radiofrequency ablation, resection or liver transplant were instead
treated with sorafenib and, as such, the analysis is reflective of the relative costs of treating with
curative intent versus sorafenib treatment. The analysis in which 37% of patients received
subsequent SIRT treatments showed that the scenario with SIRT would still be cost saving in the
French and Spanish settings, but would be fractionally more expensive than the “without SIRT” in
the Italian and UK settings, where costs would be anticipated to be 3.5% (EUR 1,257) and 2.7% (GBP
973) higher per treated patient, respectively.

DISCUSSION

The analysis showed SIRT with SIR-Spheres Y-90 resin microspheres to be cost saving relative to the
TKIs sorafenib or lenvatinib in the treatment of unresectable HCC across four European countries in

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patients with HCC in BCLC stages B and C. with SIR-Spheres Y-90 resin microspheres was also
projected to increase the proportion of patients eligible for treatments with curative intent. Across

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all four countries, the largest expenditure per patient was on implantable device costs in the “with

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SIRT” scenario, and drug costs in the “without SIRT” scenario.

The present analysis has a number of strengths; it represents a comprehensive effort to model
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realistic progressions of patients with BCLC B or C HCC through multiple treatment lines, and the
analyses were based on an extensive, multi-country cost collection exercise, capturing drug and
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administration costs; follow-up costs, including nurse visits, clinical exams, CT scans, podiatry
services; laboratory test costs; 28 adverse events; costs of SIRT work-up and procedure, including
dosimetry and technical issues and repeat treatments; cost of SIR-Spheres Y-90 resin microspheres;
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and palliative care and end-of-life costs. Furthermore, certain aspects of the base case analysis were
conservative with respect to the scenario with SIRT, notably using higher rates of retreatment with
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SIRT (thereby incurring higher costs) than those reported in SIRveNIB, and using lower rates of drop-
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out from SIRT work-up to treatment than those reported in SARAH (thereby resulting in more
patients ultimately receiving SIRT).
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The modeling of progression through subsequent treatment lines used a novel approach in which
transitions between the PFS, PPS and death states were captured using a conventional partitioned
survival AUC cohort model, while a nested Markov process drove transitions between subsequent
treatments based on transition probabilities derived from point estimates of the median time on
treatment with sorafenib, lenvatinib, and regorafenib. Developing realistic models of treatment
switching can be particularly challenging in oncology where treatments may be poorly-tolerated or
only efficacious over relatively short time periods. Modeling survival in populations in which
substantial proportions of control arm patients have switched treatment can be particularly
challenging in intent-to-treat (ITT)-based analyses, potentially resulting in a significant
underestimation of efficacy. Techniques such as rank-preserving structural failure time models,
iterative parameter estimation, and inverse probability of censoring weights are well-established
methods of correcting for these effects, but all rely on access to patient-level data and none directly
address the effects of switching onto non-investigational treatments or of patients receiving multiple
lines of treatment.42,43,44

Given the objective of capturing the costs of subsequent treatment with lenvatinib, regorafenib, and
treatments with curative intent in the present analysis, a patient-level data-based modeling
approach employing survival correction was not feasible, and the nested Markov model employed
represents a pragmatic solution for modeling the use of newer agents within partitioned survival

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models based on data from trials predating the use of the newer treatment(s). Transitions between

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the PFS, PPS, and death states were still based on data from the SARAH trial and OS may therefore

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have been underestimated, but the approach nevertheless appears to provide a reasonable estimate
of the proportion of patients receiving second- and third-line therapies over time. The use of fixed

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per-cycle transition probabilities to capture treatment discontinuation in the present analysis could
be the subject of future improvements to the methodology, in which time-dependent probabilities
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could be modeled based on, for instance, conditional Poisson, negative binomial, or other discrete
probability distributions.
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The analysis also had a number of limitations that should be considered when interpreting the
findings. Challenges arose in accurately costing adverse events across the four country settings,
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primarily due a lack of data on the cost of adverse events specifically in patients with HCC. For
instance, the French and Italian analyses relied on adverse event cost data from studies in patients
with metastatic renal cell carcinoma and melanoma, respectively. While the costs of treating the
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same treatment-emergent adverse events would not be expected to materially differ between types
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of cancer, the provenance of the adverse event cost data should be taken into account, especially
given the incremental cost differences that were driven by different adverse event costs across the
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four country settings.

When interpreting any cost analysis, it is worth considering the broader implications. By definition,
budget impact analyses focus exclusively on financial flows, without considering differences
between the scenarios in terms of effectiveness. In the present analysis, the SIRT scenario was cost
saving across all four country settings. In the context of cost-effectiveness, this would restrict
analysis outcomes to the two lower quadrants of the cost-effectiveness plane and questions on the
relative effectiveness of the combined scenarios are therefore reduced to whether the scenario with
SIRT would result in equivalent or better outcomes, or whether it would worsen patient outcomes.
The SARAH trial was designed to establish whether SIR-Spheres Y-90 resin microspheres improved
OS relative to sorafenib, specifically being 80% powered to detect a 4-month increase in OS with
SIR-Spheres Y-90 resin microspheres versus sorafenib with a bilateral alpha risk of 5%.45 The trial
may not therefore have been sufficiently powered to detect differences in the trial’s secondary
endpoints and the interpretation of differences secondary endpoints can therefore be challenging.
Nevertheless, the SARAH trial reported that SIRT with SIR-Spheres Y-90 resin microspheres improved
objective response rates and quality of life and increased the proportion of patients subsequently
receiving potentially curative therapy, suggesting that SIRT with SIR-Spheres Y-90 resin microspheres
may therefore dominate sorafenib in a cost-effectiveness analysis based on the SARAH data.

A final potential limitation of the analysis is the speed at which the HCC treatment landscape is

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evolving. Results from the IMbrave150 study have recently been presented, showing that

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combination therapy with programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and vascular

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endothelial growth factor (VEGF) inhibitor bevacizumab significantly improves OS and PFS in patients
with unresectable HCC relative to sorafenib.46 The combination of atezolizumab and bevacizumab is

us
not yet approved or reimbursed for the treatment of HCC in any of the countries evaluated in the
present analysis, but its potential future approval and uptake should be considered. Cabozantinib, a
an
kinase inhibitor, has also recently been approved for the treatment of HCC in patients who have
already received sorafenib by the Food and Drug Administration (FDA) and European Medicines
Agencies (EMA).47,48 The cabozantinib approvals were based on the CELESTIAL trial, which showed
M

significantly longer OS and PFS than placebo in this patient group.49 However, despite the EMA
approval, the reimbursement status for cabozantinib in the treatment of HCC in Europe is
ed

heterogeneous, with the marketing authorization holder (Ipsen Pharma) not yet having provided
evidence submissions to NICE in the UK, AIFA in Italy, or the Ministerio de Sanidad y Consumo in
pt

Spain. As with atezolizumab and bevacizumab, the cost implications of the future addition of
ce

cabozantinib to the second-line HCC armamentarium should therefore also be considered.

CONCLUSION
Ac

The SARAH RCT demonstrated that, relative to sorafenib, SIRT with SIR-Spheres Y-90 resin
microspheres results in improved objective response rates, a higher proportion of patients
ultimately undergoing treatments with curative intent, and improvements in quality of life according
to the EORTC QLQ-C30 questionnaire. In addition to these benefits, the present analysis
demonstrated that SIRT with SIR-Spheres Y-90 resin microspheres would result in cost savings
relative to systemic treatment with TKIs in eligible patients across four different country settings in
Europe. SIRT was projected to be cost saving even with the analysis capturing the substantial costs of
curative treatments in a higher proportion of patients with SIRT than with TKIs. SIRT with SIR-
Spheres Y-90 resin microspheres therefore represents both an efficacious and financially prudent
treatment option in patients with unresectable HCC.

TRANSPARENCY

DECLARATION OF FUNDING

Development of the cost model, execution of the cost analyses, and preparation of the manuscript
were funded by consultancy fees paid from Sirtex Medical United Kingdom Ltd to Covalence
Research Ltd.

t
ip
DECLARATION OF FINANCIAL/OTHER INTERESTS

cr
RFP is a director and shareholder of Covalence Research Ltd, which received consultancy fees from
Sirtex Medical United Kingdom Ltd, a subsidiary of Sirtex Medical Ltd (the manufacturer of SIR-

us
Spheres Y-90 resin microspheres), to develop the cost model, conduct the analysis and prepare the
manuscript. SS is a director and full-time employee of Sirtex Medical United Kingdom Ltd. VKB, FC,
an
and LG are full-time employees of Sirtex Medical United Kingdom Ltd.

JME peer reviewers on this manuscript have received an honorarium from JME for their review
M

work, but have no other relevant financial relationships to disclose.

AUTHOR CONTRIBUTIONS
ed

FC, SS, and VKB conceived of the analysis. RFP developed the cost model. FC, LG, RFP, SS, and VKB
pt

contributed to country-specific data collection exercises. RFP prepared the first draft of the
manuscript. FC, LG, SS, and VKB proof-read and critically reviewed the manuscript for intellectual
ce

content and accuracy. RFP revised the manuscript and formatted the final manuscript for journal
submission.
Ac

ACKNOWLEDGEMENTS

No assistance in the preparation of this article is to be declared.

PREVIOUS PRESENTATIONS

A French analysis based on an early version of the cost model (excluding the curative treatment
options) was presented at ASHEcon 2019, June 23-26, Washington DC, USA.
TABLES AND FIGURES

Figure 1 Nested Markov model structure illustrating the top-line transitions from
progression-free survival to post-progression survival and death, and nested
transitions between treatment lines

Progression-free survival Post-progression survival

SIR-Spheres Sorafenib Regorafenib

BSC
Treatments with curative intent Dead

Tumor ablation Resection

t
Lenvatinib

ip
Liver transplant

cr
Figure 2
us
Treatment algorithm following initial treatment with selective internal radiation
an
therapy
M

Repeat work-up SIRT work-up

8.3% (83) 100% (1,000)
Work-up

SIRT
ed

Repeat treatment SIRT treatment Technical or dosimetry issue

7.1% (63) 88.6% (886) 11.4% (114)
Treatment
pt

Subsequent systemic Liver-targeted treatment

BSC after SIRT
treatment with curative intent
ce

42.5% (377)
52.9% (583) 4.1% (41)
Second line
after SIRT

Lenvatinib Sorafenib Tumour ablation Resection Liver transplant

Ac

5.0% (29) 95.0% (554) 54.3% (22) 28.3% (12) 17.4% (7)

Third line BSC after BSC after

Regorafenib
lenvatinib sorafenib
after SIRT 100% (29) 53.3% (295)
46.7% (259)

Best supportive care 95.9% (959) No further tumour treatment 4.1% (41)

Abbreviations: BSC, best supportive care; SIRT, selective internal radiation therapy.
Figure 3 Treatment algorithm following initial treatment with sorafenib

Sorafenib
Sorafenib 100.0% (1,000)

BSC after Liver-targeted treatment

Regorafenib
sorafenib with curative intent
46.7% (467)
51.9% (519) 1.4% (14)
Second line
after sorafenib

Tumour ablation Resection Liver transplant

64.3% (9) 0.0% (0) 35.7% (5)

Best supportive care 98.6% (986) No further tumour treatment 1.4% (14)

t
ip
Abbreviations: BSC, best supportive care.

cr
us
an
M
ed
pt
ce
Ac
Table 1 Country-level results of the base case cost analyses of SIRT with SIR-Spheres Y-90
resin microspheres versus tyrosine kinase inhibitors in France, Italy, Spain and the
UK

France Italy Spain UK

Patients 699 629 497 465
Without With Without With Without With Without With
SIRT SIRT SIRT SIRT SIRT SIRT SIRT SIRT
(EUR) (EUR) (EUR) (EUR) (EUR) (EUR) (GBP) (GBP)
Implantabl 0 8,005,18 0 7,158,06 0 5,663,15 0 6,309,91
e device 4 5 9 5
costs

t
Drug costs 17,077,6 4,361,50 17,330,5 4,381,01 14,968,0 3,852,98 13,812,1 3,577,03

ip
88 6 17 6 58 0 30 6
Hospital 0 3,129,87 0 5,135,86 0 1,854,08 0 3,001,84

cr
care and 7 1 7 7
interventio

us
n room
costs
Adverse 3,817,36 2,528,13 2,405,18 1,647,41 5,896,90 3,784,57 1,025,42 698,771
an
event costs 9 7 4 8 7 7 7
Follow-up 1,162,71 672,906 378,835 329,497 2,413,56 1,637,86 433,386 265,097
M

and drug 7 5 9
administra
tion costs
ed

Curative 433,826 735,578 521,813 786,716 282,048 509,481 138,359 257,140

intent
treatment
pt

costs
End of life 3,822,77 3,801,53 1,895,09 1,884,56 1,611,96 1,603,00 1,645,61 1,636,46
ce

costs 8 8 2 2 0 3 1 8
Total 26,314,3 23,234,7 22,531,4 21,323,1 25,172,5 18,905,1 17,054,9 15,746,2
78 26 40 36 37 57 14 74
Ac

Abbreviations: EUR, 2018 Euros; GBP, 2018 pounds sterling; SIRT, selective internal radiation therapy; UK, United Kingdom.
Figure 4 Cost analyses of SIRT with SIR-Spheres Y-90 resin microspheres versus tyrosine
kinase inhibitors in France, Italy, Spain and the UK showing average costs per
patient eligible for treatment with SIR-Spheres Y-90 resin microspheres

t
ip
cr
us
an
Abbreviations: EUR, 2018 Euros; GBP, 2018 pounds sterling; SIRT, selective internal radiation therapy; UK, United Kingdom.
M
ed
pt
ce
Ac
Figure 5 Proportion of patients with hepatocellular carcinoma ultimately receiving
treatments with curative intent after SIR-Spheres Y-90 resin microspheres and
tyrosine kinase inhibitors

5.0%
4.5%
4.0% 0.8%

3.5%
3.0% 1.3%
2.5%
2.0%
1.5%
2.4% 0.5%
1.0%

t
0.5% 0.9%

ip
0.0%
With Y-90 resin Without Y-90 resin
microspheres microspheres

cr
Ablation Resection Transplantation

Figure 6
us
Proportions of patients alive and having received regorafenib treatment over the
duration of the analysis
an
18%
Proportion of patients alive and having

16%
M
received regorafenib treatment

14%

12%
ed

10%

8%
pt

6%

4%
ce

2%

0%
Ac

0 3 6 9 12 15 18 21 24 27 30 33 36 39
Time (model cycles)

With SIRT Without SIRT

Abbreviations: SIRT, selective internal radiation therapy.

Table 2 One-way sensitivity analysis results

France Italy Spain UK

Without With Without With Without With Without With
SIRT SIRT SIRT SIRT SIRT SIRT SIRT SIRT
(EUR) (EUR) (EUR) (EUR) (EUR) (EUR) (GBP) (GBP)
Base case 37,632 33,228 35,842 33,920 50,614 38,012 36,646 33,834
No treatments
with curative 37,129 32,870 35,142 33,372 50,208 38,028 36,491 34,014
intent
No adverse event
32,173 29,612 32,016 31,300 38,757 30,403 34,442 32,332
costs

t
Grade 1/2

ip
adverse event 32,486 29,823 32,229 31,448 40,455 31,590 34,791 32,576
costs only

cr
Grade 3/4
adverse event 37,318 33,017 35,630 33,772 48,916 36,826 36,297 33,590
costs only
SIRT technical or
dosimetry issue 37,632 32,981 35,842 33,715 us50,614 37,904 36,646 33,445
an
data from SARAH
SIRT retreatment
data from 37,632 32,730 35,842 33,410 50,614 37,502 36,646 33,226
M

SIRveNIB
Additional SIRT
treatment in 37% 37,632 36,330 35,842 37,099 50,614 41,191 36,646 37,619
ed

of patients
10% of post-SIRT
pt

systemic
37,632 33,597 35,842 34,316 50,614 38,389 36,646 34,016
treatment with
lenvatinib
ce

20% of post-SIRT
systemic
37,632 34,334 35,842 35,106 50,614 39,143 36,646 34,382
Ac

treatment with
lenvatinib
Abbreviations: EUR, 2018 Euros; GBP, 2018 pounds sterling; SIRT, selective internal radiation therapy with SIR-Spheres Y-90 resin
microspheres; UK, United Kingdom.
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