Neuro-Oncology Advance Access published May 13, 2016

Neuro-Oncology
Neuro-Oncology 2016; 0, 1 – 8, doi:10.1093/neuonc/now102

The cost-effectiveness of tumor-treating fields therapy in patients

with newly diagnosed glioblastoma
F. Bernard-Arnoux, M. Lamure, F. Ducray, G. Aulagner, J. Honnorat, and X. Armoiry

Université de Lyon, Claude Bernard Lyon 1, Lyon, France (F.B.-A., M.L.); Neuro-oncology Department, Hôpital Neurologique Pierre

Downloaded from http://neuro-oncology.oxfordjournals.org/ at Orta Dogu Teknik University Library (ODTU) on May 22, 2016
Wertheimer, Hospices Civils de Lyon, Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310, University of Lyon, University Claude
Bernard Lyon 1, Lyon, France (F.D., J.H.); Hospices Civils de Lyon, Groupement Hospitalier Est, Pharmacy Department/UMR CNRS 5510
MATEIS, University of Lyon, University Claude Bernard Lyon 1, Bron, France (G.A.); Hospices Civils de Lyon, Délégation à la Recherche
Clinique et à l’Innovation, Cellule Innovation/UMR CNRS 5510 MATEIS, Bron, France (X.A.)

Corresponding Author: Xavier Armoiry, PharmD, PhD, Hospices Civils de Lyon, Délégation à la recherche clinique et à l′ innovation, Cellule
Innovation/Groupement Hospitalier Est, Avenue du doyen Lépine, 69 500 Bron, France ([email protected]).

Background. There is strong concern about the costs associated with adding tumor-treating fields (TTF) therapy to standard first-
line treatment for glioblastoma (GBM). Hence, we aimed to determine the cost-effectiveness of TTF therapy for the treatment of
newly diagnosed patients with GBM.
Methods. We developed a 3-health-state Markov model. The perspective was that of the French Health Insurance, and the horizon
was lifetime. We calculated the transition probabilities from the survival parameters reported in the EF-14 trial. The main outcome
measure was incremental effectiveness expressed as life-years gained (LYG). Input costs were derived from the literature. We
calculated the incremental cost-effectiveness ratio (ICER) expressed as cost/LYG. We used 1-way deterministic and probabilistic
sensitivity analysis to evaluate the model uncertainty.
Results. In the base-case analysis, adding TTF therapy to standard of care resulted in increases of life expectancy of 4.08 months
(0.34 LYG) and E185 476 per patient. The ICER was E549 909/LYG. The discounted ICER was E596 411/LYG. Parameters with the
most influence on ICER were the cost of TTF therapy, followed equally by overall survival and progression-free survival in both
arms. The probabilistic sensitivity analysis showed a 95% confidence interval of the ICER of E447 017/LYG to E745 805/LYG
with 0% chance to be cost-effective at a threshold of E100 000/LYG.
Conclusion. The ICER of TTF therapy at first-line treatment is far beyond conventional thresholds due to the prohibitive announced
cost of the device. Strong price regulation by health authorities could make this technology more affordable and consequently
accessible to patients.

Keywords: brain tumor, cost-effectiveness analysis, glioblastoma, temozolomide, tumor-treating fields.

Glioblastoma (GBM) is the type of glioma with the highest grade protocol was shown to improve median OS from 12.1 to 14.6
of malignancy (grade IV). It represents the most frequent and months.4 During the last decade, newly tested adjuvant strate-
aggressive form of brain tumor in adults,1 with a median sur- gies such as the addition of bevacizumab5,6 have failed to dem-
vival of 3 months without treatment. GBM is characterized onstrate a benefit on OS.
by its capacity to systematically recur over time, even in pa- Based on the preliminary results of the EF-14 trial, there has
tients with complete surgical resection.2 In order to increase been a marked interest in tumor-treating fields (TTF) therapy as
progression-free survival (PFS) and overall survival (OS), different a front-line regimen. TTF therapy consists of a medical device
strategies of adjuvant therapy have been tested. To date, the that creates low-intensity and intermediate-frequency electric
standard therapy is radiotherapy combined with temozolomide fields inducing an antimitotic effect on cancer cells. This device
(TMZ).3 This therapy consists of concomitant radiotherapy and employs a transducer that is applied on a shaved scalp and
TMZ followed by TMZ alone for 6 cycles. This radiochemotherapy connected to an electric generator and battery. The electric

Received 7 January 2016; accepted 13 April 2016

# The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
For permissions, please e-mail: [email protected].

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Bernard-Arnoux et al.: Cost-effectiveness of tumor-treating fields therapy

fields cause mitotic disorder by disrupting mitotic spindle for- relapse until advancement to the death state. Death is mod-
mation during metaphases and thereby causing dielectropho- eled as the absorbing state.
retic movement on organelles during cytokinesis.7 We conducted the analysis from the perspective of the
The EF-14 trial was a phase 3 randomized, controlled trial in French Health Insurance.
which the addition of TTF therapy to the radiochemotherapy
protocol was shown to improve median PFS and median OS Transition Probabilities
by 3.1 months and 4.9 months, respectively.8 Those results
led to a new US Food and Drug Administration indication for Similarly to Messali et al.,13 we calculated the monthly transi-
first-line use in GBM. However, concerns were rapidly raised tion probabilities (values associated with the arrows in Fig. 1)
over the cost of TTF therapy, which is anticipated to be with the Declining Exponential Approximation of Life Expectan-
cies method (DEALE method)14,15 using median PFS and OS

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US$20 000/month.9 Here we aimed to determine the cost-
effectiveness of TTF therapy added to standard therapy for from the EF-14 trial. The median OSs were those reported in
newly diagnosed patients with GBM. the prespecified analysis, which evaluated only eligible patients
who received the assigned treatment.8 The DEALE method as-
sumes that patients have a constant hazard of death through-
Methods out the time and that patients’ survival describes a decreasing
exponential curve. The transition probabilities calculated ac-
Model, Population, and Treatment cordingly are presented in Table 1.
We constructed a Markov model with Tree Age Pro 2015, R1.2
(Williamstown, MA: Tree Age Software, Inc.). This type of model Direct Costs and Effectiveness
is widely used in health economic evaluations10 and has al- The healthcare resource utilization inputs for each strategy
ready been implemented for GBM.11 – 13 We used this model were derived from a literature search conducted from 2010
to measure and compare the medical cost and health out- to 2015 and focused on the management of GBM in French set-
comes for the 2 following strategies: standard of care alone tings. We identified one study in which the patterns of care and
with radiochemotherapy and addition of TTF therapy to standard associated direct costs of newly diagnosed patients with GBM
of care. The Markov decision model included 3 mutually exclu- were assessed from diagnosis to death or last follow-up
sive health states (Fig. 1): stable disease, progressive disease, date.16,17 Patients had similar baseline characteristics com-
and death. The target population was a hypothetical cohort pared with our model hypothetical cohort since a large majority
of 1000 people with the same characteristics as those in the received the radiochemotherapy protocol. In this study, costs
EF-14 trial8 (main inclusion criteria: newly diagnosed grade IV were estimated from the perspective of the French Health In-
astrocytoma, Karnofsky Performance status score ≥70). The surance and were calculated using rates from year 2014. Indi-
whole cohort was entered in the model and started the simula- rect costs had not been included. Medical and nonmedical
tion in the stable-disease state. We assumed that all patients costs included chemotherapy drugs (at front-line and at
had previously undergone radiotherapy plus TMZ. We chose a tumor recurrences), hospital stays with the Diagnosis Related
cycle length of one month and a lifetime horizon. In each Group (DRG) tariffs extracted from the French hospital informa-
cycle, patients had a given probability of staying in the same tion system, specialized medical visits for outpatient services
health state or moving to the progression state or death state. (oncologist or neurosurgeon), outpatient procedures (imaging,
Any patient could stay in only one health state at a time, and laboratory test), and medicalized transportation. The costs of
no backward transitions were permitted to stable disease. surgery and concomitant radiotherapy and TMZ were ignored
The stable-disease state describes the time of radiochemo- because the randomization occurred at the time when TMZ
therapy protocol in which patients had TMZ alone for 6 cycles or was supposed to be given alone. The cost of TMZ for the stable-
in combination with TTF therapy for up to 24 cycles, to the first disease state was calculated monthly for up to 6 cycles. Other
relapse. The progression state represents the time from the first direct medical costs were assumed to be provided equally
throughout the stable and progressive-disease states for both
strategies. Chemotherapy hospital stays were included only in
the progressive state as this state corresponded to the admin-
istration of intravenous chemotherapies after relapse. Total
costs for this study were divided by the mean duration of

Table 1. Transition probabilities for the Markov model

Monthly Transition Probabilities

State Transition TMZ Alone TTF Therapy + TMZ

Stable disease to progression 0.15910 0.09301

Stable disease to death 0.04346 0.03325
Progression to death 0.05800 0.05041

Fig. 1. The Markov model Abbreviations: TMZ, temozolomide; TTF, tumor-treating fields

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survival (reported at 20.1 months) to obtain monthly costs ex- Input costs are summarized in Table 2.
cept costs for chemotherapies at relapse, which were divided Our effectiveness outcome was life expectancy after each
by the time from relapse to death or last follow-up date cycle. Hence, the effectiveness input was one month regardless
(found at 7.9 months). if patients were in the stable or progressive state, and zero for
For TTF therapy, we considered the utilization of Optune the death state. We did not use quality adjusted-life-year
(Novocure Inc.). To date, there is no regulated tariff for this (QALY) because of the lack of relevant published data on
medical device, but the cost reported by the company is health-state utilities associated with GBM.
E21 000 per month (corresponding to the provision of the de-
vice plus additional support). Similarly to the EF-14 trial, this
cost was included in the stable-disease state for a maximum Analysis

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of 24 months. Patients could be kept on TTF therapy up to We calculated the incremental cost-effectiveness ratio (ICER)
the second relapse. Knowing that the time to first progression expressed as monetary costs per life-years gained (LYG). We
was 7.1 months and that the median duration of TTF therapy applied a 4% annual discount rate to costs and outcomes ac-
was 9 months, we assumed that the device was used an aver- cording to French national guidelines.10 Our threshold limit
age of 2 months in progressive disease (eg, until the second re- was arbitrarily chosen at E100 000/LYG. We performed
lapse). Hence, we input the cost of TTF therapy only for the first 1-way deterministic sensitivity analysis for all parameters in
2 cycles in the progressive state. order to assess the impact that a fixed change in each param-
The costs related to chemotherapies (drugs and hospitaliza- eter has on the ICER. We applied+20% on costs,+50% on
tions) at recurrence were applied monthly and equally among discount rate, and+2 weeks on median PFS and OS. Since
progressive-disease state cycles in the conventional strategy. we anticipated finding a high ICER, we also conducted a
For the TTF group, these costs were applied from the third threshold sensitivity analysis in which the range of cost of
cycle in the progressive state (eg, the first 2 cycles being for a TTF therapy varied between E2000 and E21 000/month.
month of TTF therapy). This was aimed at exploring the cost of TTF therapy that

Table 2. Input monthly costs for both strategies in Eurosa

Stable Disease Progression

Months 1 –6 Months 7 –24 Subsequent Months Months 1 –2 Subsequent Months

TMZ alone strategy

Costs other than drugs
Chemotherapy hospital stays 0 0 0 390 390
Other hospital staysb 1133 1133 1133 1133 1133
Transports 315 315 315 315 315
Imaging 50 50 50 50 50
Medical visits 25 25 25 25 25
Biologic exams 9 9 9 9 9
Drugs costs
Adjuvant TMZ 789 0 0 0 0
Chemotherapy at reccurencec 0 0 0 1650 1650
TOTAL 2321 1532 1532 3572 3572
TTF therapy strategy
Costs other than drugs and devices
Chemotherapy hospital stays 0 0 0 0 390
Other hospital staysb 1133 1133 1133 1133 1133
Transports 315 315 315 315 315
Imaging 50 50 50 50 50
Medical visits 25 25 25 25 25
Biologic exams 9 9 9 9 9
Drugs and devices costs (E)
Adjuvant TMZ 789 0 0 0 0
TTF therapy 21 000 21 000 0 21 000 0
Chemotherapy at reccurencec 0 0 0 0 1650
TOTAL 23 321 22 532 1532 22 532 3572

Abbreviations: TMZ, temozolomide; TTF, tumor-treating fields.

a
Except for the cost of TTF therapy, all monthly costs were derived from a French cohort study after conversion of total costs to monthly costs.
b
Other hospital stays include long-term care, home care,and rehabilitation.
c
Includes TMZ and other chemotherapies commonly used (eg, bevacizumab).

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could reach a more acceptable ICER. Finally, we conducted a Sensitivity Analysis

probabilistic sensitivity analysis using a second-order Monte
One-way sensitivity analyses on the ICER were represented in a
Carlo analysis with symmetric triangular distributions for
tornado diagram based on assumptions previously described
each parameter. The principle of triangular distribution is to
(Fig. 2). The parameters with the most influence on the ICER
apply for each parameter a likeliest, minimum, and maximum
were the cost of TTF therapy, followed by OS and PFS in both
value. The likeliest values corresponded to those that were
arms. The diagram shows that the variation of each parameter
applied for the base-case analysis. The ranges for sensitivity
in every case exceeds the threshold limit (E100 000/LYG). The
analyses (minimum-maximum) that we applied were the
threshold sensitivity analysis on the cost of TTF therapy showed
same as those in the one-way sensitivity analyses. The mul-
that at a cost of E10 000/month, the ICER would be E292 353/
tivariate probabilistic analysis was performed running 1000
LYG. At a cost of E2000/month (price discounted by approxi-

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patients in 10 000 Monte Carlo iterations.
mately 90%), the ICER would be E71 220/LYG. At a monthly
cost of E3000, the ICER would fall below the threshold of
E100 000/LYG (E98 862/LYG). The probabilistic sensitivity anal-
Results
ysis is represented by a Monte Carlo diagram in Fig. 3. The 95%
Base Case confidence interval of the ICER was estimated at E447 017/LYG
to E745 805/LYG. At a threshold of E100 000/LYG, the probabil-
The base-case analysis showed a life expectancy of 22.08
ity of TTF therapy being cost-effective is 0% (Fig. 4). Fig. 4 also
months in the TTF therapy strategy and 18 months in the con-
shows the probability of TTF being cost-effective for other
ventional strategy (incremental effectiveness: 4.08 life-
threshold limits than E100 000/LYG.
months gained or 0.34 LYG). The total costs of TTF therapy
and conventional therapy strategies were E243 141 and
E57 665, respectively (incremental cost: E185 476). This
Discussion
analysis resulted in an ICER of E549 909/LYG. After applying
a 4% annual rate discount, the ICER was estimated at We evaluated the cost-effectiveness of adding TTF therapy to
E596 411/LYG (incremental cost: E180 431; incremental ef- standard of care using a 3-health-state Markov model. The
fectiveness: 0.3 LYG). model had the same illustrative structure compared with

Fig. 2. Tornado diagram (calculated with discounted incremental cost-effectiveness ratio (ICER) expressed as E/life-years gained [LYG]). One-way
sensitivity analysis in a tornado diagram. Variations on variables were +2 weeks for survival parameters, +20% for cost, and +50% discount rate.

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Fig. 3. Monte Carlo diagram (calculated with discounted incremental cost-effectiveness ratio [ICER] expressed as E/life-years gained [LYG]). ICER
scatterplots per year with a willingness- to- pay (WTP) equal to E100 000/LYG. Abbreviations: TMZ, temozolomide; TTF, tumor-treating fields.

Fig. 4. Cost effectiveness acceptability curve (calculated with discounted incremental cost-effectiveness ratio [ICER] expressed as E/life-years
gained [LYG]). The willingness-to-pay corresponds to a given threshold ICER expressed as E/LYG. Abbreviations: TMZ, temozolomide; TTF,
tumor-treating fields.

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other recently published studies on GBM.11,13 Our effectiveness Conversely, the high ICER for TTF therapy is mainly due to a
results are consistent with those reported in the EF-14 trial (for dramatic increase in cost and not a lack of effectiveness in
the TTF group, life expectancy was 22.08 months in our model terms of OS improvement. As shown in the tornado diagram,
and median OS of 20.5 months in the trial; for the TMZ alone the cost of TTF therapy was the parameter with the highest in-
group, life expectancy was 18 months in our model and median fluence on ICER. In France, cost-effectiveness evaluation does
OS of 15.6 months in the trial), leading to a comparable incre- not have a key role in decision-making for reimbursement of
mental effectiveness (4.08 months in our model and 4.9 health technologies since reimbursement is mainly decided
months in the trial). on the basis of clinical effectiveness. However, assuming that
The slight difference can be explained by the fact that life a positive opinion is provided for reimbursement, it is almost
expectancy and median survival are mathematically different. certain that pricing negotiation with the manufacturer would

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Indeed, life expectancy corresponds to the arithmetic mean of not lead to an agreement and consequently restrict the access
the actual survival times of all individuals, whereas median sur- to patients. In countries where cost-effectiveness is a major
vival is the length of time from the randomization in which half component of decision-making, such as the United Kingdom,
of the patients in a group of patients are still alive. the ICER would be far beyond the conventional threshold and
The results are also consistent for evaluation of costs. In the would lead to a non-recommendation of the technology. Con-
conventional strategy (TMZ alone starting from the second stage sequently, the likelihood of having the technology refunded by
of the radiochemotherapy protocol), total undiscounted costs sickness funds is very small, although it is the first treatment for
were estimated at E57 665. This excludes costs of surgery and GBM to demonstrate a clinically significant benefit to OS since
concomitant radiotherapy and TMZ. The costs were similar to 2005. Very little is known about factors that might explain the
those reported in a French pharmacoepidemiologic study16 in anticipated cost of the technology. Health economic evalua-
which total costs from diagnosis to death were E70 201 includ- tions have been extensively applied to anticancer therapies. Re-
ing E18 500 for surgery and concomitant radiotherapy-TMZ. Fur- cently, the ICER of cetuximab versus bevacizumab as first-line
thermore, the incremental undiscounted cost of E185 476 treatment for metastatic colorectal cancer (mCRC) was esti-
obtained in our model is consistent with the utilization of TTF mated at US$97 223/LYG.21 In another study, the ICUR of bev-
therapy at a cost of E21 000/month for 9 months. acizumab in addition to chemotherapy in first- and second-line
Following the emergence of costly strategies for the treat- treatment for mCRC was estimated at US$571 240/QALY and
ment of GBM, a growing body of literature on cost-effectiveness US$364 083/QALY, respectively.22 A high level of ICUR was
studies has been published over the last years. Two were aimed also found for bevacizumab added to chemotherapy in ad-
at assessing cost-effectiveness of fluorescence-guided surgery vanced non – small cell lung cancer (incremental QALYs: 0.13;
with 5-ALA18,19 compared with conventional surgery and re- incremental cost: US$72 000; ICUR: US$ 560 000/QALY).23 Re-
ported ICERs of E6700/LYG and E4550/additional complete re- cently approved therapies for advanced melanoma such ipili-
section achieved, respectively. Others have evaluated the mumab and nivolumab have dramatically changed the
cost-effectiveness of TMZ as adjuvant therapy.13,20 In the eco- management of the disease, but these drugs are very expen-
nomic evaluation conducted with the trial validating the radio- sive (approximately E60 000 – 80 000/patient). However, the
chemotherapy protocol, the incremental cost of TMZ was associated incremental effectiveness is notable, which leads
E9402, and the incremental effectiveness was 0.252 LYG, lead- to more acceptable ICERs/ICURs. Barzey et al.24 estimated
ing to an ICER of E37 361/LYG.20 More recently, Messali et al.13 that ipilimumab as second-line treatment for advanced mela-
reported an ICER of US$8 875/QALY for TMZ used at the same noma had an ICER of US$78 218/LYG (incremental effective-
disease stage. There is also a growing concern on cost issues ness: 1.88 LYG; incremental cost: US$146 716) versus best
with bevacizumab for both front-line and late stage of supportive care. More recently, Bohensky et al.25 found that
GBM.11,16 the ICER of nivolumab compared with ipilimumab for the treat-
This study is, to our knowledge, the first to report the cost- ment of Braf wild-type advanced melanoma in Australia was
effectiveness of TTF therapy added to standard of care in newly AUD$48 851/LYG (incremental effectiveness: 1.58 LYG; incre-
diagnosed GBM patients. We found an ICER of E596 411/LYG, mental cost:AUD$77 119). Based on these examples, ICERs
which is far beyond conventional thresholds even if we take higher than E500 000/LYG are rarely encountered.
rare diseases into account. Although cost-effectiveness and With a cost of E21 000 per month and a median of 9
cost-utility studies are conceptually different (the first evalu- months of treatment, TTF therapy would be one of the most ex-
ates an ICER and uses outcome measures such as life expec- pensive treatments using a medical device. A price halved by 2
tancy; the second evaluates an incremental cost-utility ratio would still exceed conventional benchmarks (E292 353/LYG). A
[ICUR] and uses QALY as an outcome measure), one can remark decrease of monthly price to E3000 per month would lead to a
that the ICER of TTF therapy has a similar magnitude as the more acceptable ICER.
ICUR of bevacizumab for first-line treatment (US$439 764/ To our knowledge, no data from the EF-14 trial are currently
QALY).11 However, the factors explaining such substantial available to compare the clinical outcome of patients who con-
ICER/ICUR are different. The addition of bevacizumab to stan- tinued TTF therapy after the first progression with those who
dard of care induces a significant incremental cost but, most discontinued after the first progression. Hence, the impact on
importantly, it has null incremental effectiveness (no improve- the ICER of early TTF therapy discontinuation after the first pro-
ment of median OS) and a very modest increase of QALYs. Con- gression cannot be measured.
sequently, regardless of any cost matters, the use of Our study has several limitations. First, we conducted a cost-
bevacizumab as front-line therapy appears to be unjustified effectiveness evaluation and not a cost-utility study using
because it has no impact on patient survival. QALYs as the outcome measure. To our knowledge, there is

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only one study by Garside et al.26 that reported estimates of

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