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Economic evaluation of contrast-enhanced liver MRI in the characterisation of suspected liver lesions 17 MARCH 2016 ISPOR-AC CONTEMPORARY ECONOMIC MODELLING – STATE OF THE ART

Sopany Saing, Phil Haywood, Stephen Goodall

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CONTEXT

• Making a funding decision – MSAC on behalf of RANZCR

• Diagnostic imaging – use in clinical practice and impact on the patient

• Lack of direct evidence

• Improved clinical outcomes for the patient will require behavioural change by clinicians.

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ECONOMIC RESEARCH QUESTION

• In patients with known extrahepatic malignancy with suspected or possible liver metastasis, what is the cost-effectiveness of contrast enhanced MRI in lesion characterisation compared to contrast enhanced CT scan?

Population:

• known extrahepatic malignancy who are being considered by a specialist for hepatic therapies

• previous liver imaging from staging – pathology indeterminate

• use of hepatobiliary specific contrast agent

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ECONOMIC LITERATURE REVIEW

Reference Study type

MRI contrast used Comparators Total cost

Total Effectiveness (LYS, QALYs, Other)

Mann, 2001 CA manganese (Teslascan®) CE-CT

MRI cost saving due to avoided unneccessary nontherapeutic operation NA

Schultz, 1999 CA SPIO (Feridex®) CE-CT

Cost savings of USD$1,901 per patient in the study due to biopsies and laparotomies avoided NA

Zech, 2009 CA (Primovist®) ECCM-MRI vs. CT

CT cheapest in Germany and Italy, PVMIR cheapest in Sweden NA

Yip, 2014 CEA Gd or (Primovist®) CT + PET

Upfront: USD$4368 Sequential: USD$3947 Hybrid: USD$3850

Average time to decision (weeks) - Upfront: 3.00 Sequential: 4.09 and Hybrid: 2.74

Annemans, 2008 CEA

SPIO (Resovist®) CE-CT

MRI: €18,416 and CT: €16,972 (MRI cheaper)

LYs - MRI: 2.878 and CT:3.011 (MRI less)

Westwood, 2013 CUA

Gd,Primovist® and SPIO

CE-US and CE-CT CT < CEUS < MRI

Base case has same LY and QALYs

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LIVER METASTASIS

• Metastasis in the liver are common due to the liver’s dual blood supply

• Liver metastasis are reported to be 20 - 50 x more common than primary liver cancers.

• Treatment algorithms:

Curative options: tumours are resected Non-curative options: unresectable disease (due to the size and number

of tumours present), chemotherapy or palliative care.

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WHY COLORECTAL CARCINOMA?

Primary cancer

Incidence of primary cancer in Australia (AIHW) (2012-13)

Incidence of liver metastasis (base case)

Estimated incidence of primary cancer with liver metastasis

Estimated proportion of primary cancer with liver metastasis

Colorectal 24,786 33% 8179 62%

Breast 25,117 0.60% 151 1%

Pancreas 6,020 46% 2769 21%

Neurendocrine 5,260 32.70% 1720 13%

Oesophagus (and stomach) 4,341 10.00% 434 3%

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• Colorectal carcinoma is the leading cause of liver metastasis

CLINICAL PRACTICE ALGORITHM FOR MRI OF THE LIVER

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Comparators Proposed service

Patients with extrahepatic cancer with suspected liver metastasis

Pathology indeterminate

No pathology or unresectable disease

Pathology confirmed

CT Intraoperative US Biopsy

Pathology indeterminate

Diagnosis confirmed

Treatment as appropriate

Further imaging or diagnostic

Diagnosis confirmed

Pathology indeterminate

MRI with contrast

Cease investigation

MRI VS. CT

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MRI CT Method magnetic fields a series of x-rays Time taken patients are to lie within the

machine for 10-15 minutes, little movement as possible, anaesthetic or sedation may be required.

less than a minute, less sensitive to patient movement

Radiation exposure

no exposure exposure to ionising radiation

Limitations contraindications (e.g, an implanted pacemaker, metal implants).

allows patients with metal implants

Availability fewer machines many machines

MRI CT

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CONTRAST MRI

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CONTRAST AGENT FOR MRI

gadoxetic acid* gadobenate dimeglumine Brand name Primovist® MultiHance®

Type Hepatobiliary-specific Intracellular agent

Proposed MBS price $300 $44.80

Hepatic uptake 50% 3-5%

Delay for hepatobiliary phase images

20 min (no additional session required)

90 min (additional session required)

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Contrast agents for liver MRI: Intracellular vs. Extracellular Hepatobiliary specific intracellular vs. other intracellular.

*disodium gadoxetate. Price provided in proposal.

DIAGNOSTIC ACCURACY

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Source: Duncan J, Scarfe A, Garrod T, Riitano D, Vreugdenburg T, Ma N Cameron A, Saing S, Goodall S (2015). Magnetic resonance imaging (MRI) of liver lesions. MSAC Application 1372, Assessment Report. Commonwealth of Australia, Canberra, ACT

Sensitivity of CE-MRI compared with CT for CRC liver metastases

CLINICAL EVIDENCE - SUMMARY

Comparator Diagnostic accuracy - sensitivity

Diagnostic accuracy - specificity

Observed patient benefit from clinical trials

Safety outcomes

CE-CT CE-MRI superior

CE-MRI equivalent

CE-MRI equivalent based on similar accuracy

CE-MRI equivalent and avoids radiation exposure risk

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DECISION TREE: EXTRAHEPATIC MALIGNANCY WITH SUSPECTED LIVER METASTASES

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MODEL ASSUMPTIONS - STRUCTURAL

• Costs and benefits are not captured beyond 12 months due to the absence of long-term clinical data (conservative).

• Impact on early health care resource use.

• An additional specialist visit within the year to monitor primary cancer.

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MODEL ASSUMPTION - CLINICAL

Improved diagnosis leads to earlier detection of resectable liver metastasis.

metastases - receive appropriate treatment (curative or non-curative)

no metastases - watch and wait strategy

Incorrect diagnosis - (cost of an MRI for patients who receive a false positive or false negative test).

false negative = reduced (50%) chance of having a curable metastasis compared to a true positive. Impact of delayed treatment and severity of health state. Same survival but utility decrement applied

false positive = unnecessary surgery (costs and utility of unnecessary surgery)

These are tested in a scenario analysis.

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COSTS: MRI AND CT TEST

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Resource Cost Total cost Reference

CE-MRI

Proposed MRI item $425.00 Estimated as 85% of proposed fee

Proposed MRI co-payment $75.00 Estimated as 15% of proposed fee

$500.00

General anaesthetic and sedation $2.49 Weighted average of MBS itemsa

Hepatobiliary specific contrast Primovist® $255 Estimated as 85% of unreimbursed fee

Hepatobiliary specific contrast Primovist® co-payment $45.00 Estimated as 15% of unreimbursed fee

Total additional MRI cost $302.49 Contrast, general anaesthetic/sedation [$7.66, $1,115.85]

Total (MBS fee + contrast) $802.49

CE-CT

MBS benefit (includes contrast) $264.88 MBS items 56401, 56407, 56441, 56447

MBS co-payment $29.37 Department of Health for 2013-2014

$294.25 [$110.71, $336.03] a(weighted average of MBS items 17610, 17615, 17620, 17625) + (weighted average of MBS items 17640, 17645, 17650, 17655) + MBS 21922

COSTS: TREATMENT

Description Base Low High Source

Costs

Cost of surgery if TP $7,794.20 $3,897.10 $28,751.85 AR-DRG

Cost of surgery if FN $6,713.25 $3,356.62 $24,764.37 PBS, MBS and Kardamanidis, 2007

Cost of non-curative if TP $8,621.49 $4,310.74 $31,712.15 AR-DRG, and MRI

Cost of non-curative if FN $7,515.74 $190.28 $27,724.66 PBS, MBS, Kardamanidis, 2007 and MRI

Cost of no metastases if FP $802.49 $20.32 $2,960.29 Cost of MRI

Cost of no metastases if TP $0.00 $0.00 $0.00 Assumption

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Assumed lower and upper estimates by calculating the inverse of the gamma cumulative distribution. Gamma distribution applied to costs for PSA.

MODEL PARAMETERS – PROBABILITIES

Description Base Low High Source Probabilities Prevalence of liver metastasis 0.4 0.2 0.8 Westwood, 2013 and Saunders, 2002 MRI sensitivity 0.94 0.91 0.96 Pooled from clinical literature MRI specificity 0.97 0.97 0.97 Scharitzer, 2013 CT sensitivity 0.77 0.67 0.84 Pooled from clinical literature CT specificity 0.97 0.95 1 Scharitzer, 2013 Probability of curable disease TP 0.2 0.1 0.4

Kanas, 2012 and expert opinion Probability of curable disease FN 0.1 0.05 0.2 Survival Survival of curative liver metastasis 0.75 0.71 0.79

Westwood, 2013 Survival of non-curative liver metastasis 0.57 0.40 0.67 Survival of no metastasis 0.97 0.96 0.97

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95% confidence intervals for diagnostic accuracy as reported in literature. Beta distribution applied to probabilities for PSA.

MODEL PARAMATERS - UTILITIES

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Description Base Low High Distribution Source Utility Utility of metastases curative TP 0.78 0.27 1

Beta Wiering, 2011 Utility of metastases non-curative TP 0.67 0 1 Disutility for delayed surgery FN 0.3 0.46 0.46

Gamma Wiering, 2011 and Westwood, 2013 Disutility for delayed palliative care FN 0.2 0.36 0.36

Utility of unnecessary surgery FP 0.74 0.47 1 Langenhoff 2006 Utility of no metastasis TN 0.85 0.58 1 Beta Ramsey, 2000

RESULTS: BASE CASE

Cost Benefit ICER Additional case detected* MRI $4,063 0.48 - CT $3,566 0.41 - Incremental outcomes $497 0.07 $6,929 QALY MRI $3,740 0.66 - CT $3,311 0.65 - Incremental outcomes $429 0.01 $40,548

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*Based on a simplified decision tree (ignoring curative and non-curative treatments options after diagnosis)

RESULTS: SCENARIO ANALYSIS

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Cost QALY ICER (cost per QALY gained) Sensitivity analysis All receive MultiHance® (gadobentate dimeglumine contrast) and therefore MBS item 63491 is claimed MRI $3,474 0.66 - CT $3,282 0.65 - Incremental outcomes $192 0.01 $29,404 No unnecessary surgical treatment for FP same as TN MRI $3,339 0.66 - CT $3,118 0.65 - Incremental outcomes $220 0.01 $44,827 Probability of curable metastasis same for TP and FN MRI $3,742 0.66 - CT $3,321 0.65 - Incremental outcomes $421 0.01 $42,448

RESULTS: ONE-WAY SENSITIVITY

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RESULTS: PROBABILISTIC SENSITIVITY

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RESULTS • Compared to current practice (CE-CT), the cost effectiveness of CE-MRI

is $40,548 per QALY gained.

• Model is short term and only captures early health care resource use.

• Evidence of potential benefits associated with CE-MRI for the diagnosis of liver metastases in patients with identified colorectal carcinoma. CE-MRI can be recommended as cost effective provided that improved diagnostic accuracy results in earlier, curative disease management.

• Main drivers of the model:

• cost of the MRI contrast agent used ($44 vs. $300 per patient)

• cost of non-curative treatment,

• prevalence of liver metastases,

• diagnostic accuracy of CE-CT

• and the utility decrement for delayed non-curative care

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LIMITATIONS

• Modelling assumption – linked evidence

• Generalisability of results to other primary cancers

• Lack of long-term clinical data linking test results to longer term outcomes, no recurrence of metastasis

• Patients who do have their liver metastasis diagnosed and treated still have colorectal cancer

• Neo-adjuvant therapy has not been modelled

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DISCUSSION

• CE-MRI can be recommended as cost effective provided that improved diagnostic accuracy results in earlier, curative, disease management.

• Unclear if an improvement in diagnostic accuracy will necessarily translate into improved clinical outcomes for the patient. This may be due to the requirement of behavioural change by clinicians.

• Utilisation is uncertain

• additive vs. substitution

• in patients where there may be few benefits

• Value of information regardless of change in clinical management?

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ACKNOWLEDGEMENT

• ASERNIPS (Royal Australasian College of Surgeons):

Joanna Duncan, Anje Scarfe, Tamsin Garrod, Dagmara Riitano, Tom Vreudgenburg, Ning Ma and Alun Cameron • Department of Health on behalf of the Medical Services Advisory

Committee (MSAC)

• Clinical feedback:

Royal Australian and New Zealand College of Radiologists, radiologist (Dr Frank Voyvodic), oncologist (Dr Tim Price) and liver surgeon (Professor Guy Maddern)

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QUESTIONS?

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THANK YOU.

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