Diagnosis and staging of patients with ovarian cancer

Diagnosis and staging of patients with ovarian cancer National Clinical Guideline No. 20

Annex 1: Systematic review of cost effectiveness

Published by:The Department of HealthBlock 1, Miesian Plaza, 50 – 58 Lower Baggot Street, Dublin 2 , D02 XW14

Tel: +353 (01) 6354000www.health.gov.ie

ISSN 2009-6259.© Department of Health, August 2019.

Systematic review of cost-effectiveness – Diagnosis and staging of patients with ovarian cancer

August 2018

This research was funded by the Health Research Board HRB-CICER-2016-1871.

Diagnosis and staging of patients with ovarian cancer – Systematic review of cost-effectiveness

Health Research Board – Collaboration in Ireland for Clinical Effectiveness Reviews

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About HRB-CICER

In 2016, the Department of Health requested that the Health Research Board (HRB) fund an

evidence synthesis service called HRB-CICER (Collaboration in Ireland for Clinical

Effectiveness Reviews) to support the activities of the ministerial appointed National Clinical

Effectiveness Committee (NCEC). Following a competitive process, the Health Information

and Quality Authority (HIQA) was awarded the contract for the five-year period from 2017

to 2022. The HRB-CICER team comprises a dedicated multidisciplinary research team

supported by staff from the Health Technology Assessment (HTA) team in HIQA and the HRB

Centre for Primary Care Research at the Royal College of Surgeons in Ireland (RCSI), as well

as national and international clinical and methodological experts.

With regard to clinical guidelines, the role of the HRB-CICER team is to independently review

evidence and provide scientific support for the development, by guideline development

groups, of National Clinical Guidelines for the NCEC. The HRB-CICER team undertakes

systematic reviews of the clinical effectiveness and cost-effectiveness of interventions

included in the guidelines as well as estimating the budget impact of implementing the

guidelines. The HRB-CICER team also works closely with the guideline development groups;

provides tailored training sessions; assists in the development of clinical questions and

search strategies; performs systematic reviews of international clinical guidelines and

supports the assessment of their suitability for adaption to Ireland; and supports the

development of evidence-based recommendations informed by the evidence produced by

HRB-CICER within the National Clinical Guidelines.

Membership of the evaluation team The members of the HRB-CICER, HIQA and National Cancer Control Programme (NCCP)

evaluation team were Mr Paul Carty, Ms Louise Murphy, Dr Niamh Kilgallen, Dr Helena Gibbons,

Ms Michelle O’Neill, Dr Patricia Harrington, Ms Catherine Duffy, Dr Eve O’Toole, Professor Susan

Smith and Dr Máirín Ryan.

How to cite this report: Carty, P, Murphy, L, Kilgallen, N, Gibbons, H, O’Neill, M, Harrington, P, Duffy, C, O’Toole, E,

Smith, S, Ryan, M. Diagnosis and staging of ovarian cancer – Systematic review of cost-

effectiveness. Dublin: HRB-CICER, HIQA, 2018.

http://www.hrbcentreprimarycare.ie/

http://www.hrbcentreprimarycare.ie/



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Table of contents

1. Background .................................................................................................................. 6

1.1 Description of the condition ................................................................................................ 6

1.2 Description of the intervention ........................................................................................... 6

1.3 Purpose of this systematic review ....................................................................................... 7

2. Methods ....................................................................................................................... 8

2.1 Review questions ................................................................................................................. 8

2.1.1 Diagnosis ........................................................................................................................... 9

2.1.2 Staging ............................................................................................................................. 11

2.1.3 Relapse ............................................................................................................................ 12

2.1.4 Pathology ........................................................................................................................ 13

2.1.5 Genetics/Hereditary cancer ............................................................................................ 15

2.2 Types of studies ................................................................................................................. 17

2.3 Types of participants .......................................................................................................... 17

2.4 Types of outcome measures .............................................................................................. 18

2.5 Search methods for identification of studies .................................................................... 18

2.6 Exclusion criteria ................................................................................................................ 19

2.7 Data collection and analysis ............................................................................................... 19

3. Results........................................................................................................................ 20

3.1 Overview of results ............................................................................................................ 20

3.2 Methodological quality and transferability of evidence ................................................... 21

3.3 Summary of included studies ............................................................................................. 22

4. Discussion .................................................................................................................. 37

4.1 Conclusion .......................................................................................................................... 40

5. References .................................................................................................................. 42

Appendix 1: Search terms ............................................................................................... 44

Appendix 2: Grey literature search ................................................................................. 47

Appendix 3: Excluded studies ......................................................................................... 48

Appendix 4: Quality assessment and transferability of evidence ..................................... 55



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List of abbreviations that appear in this report CT Computed tomography

DARE Database of Abstracts of Reviews of Effects

ED Emergency department

HRB-CICER Health Research Board – Collaboration in Ireland for Clinical Effectiveness Reviews

HRQoL Health-related quality of life

HSE Health Service Executive

HTA Health technology assessment

ICER Incremental cost-effectiveness ratio

ICU Intensive care unit

IOTA International Ovarian Tumour Analysis

MRI Magnetic resonance imaging

NCCP National Cancer Control Programme

NCEC National Clinical Effectiveness Committee

NCG National clinical guideline

NHS EED National Health Service Economic Evaluation Database

PARP Poly (ADP-ribose) polymerase

PET Positron emission tomography

PICOS Population, intervention, comparator, outcome, study design

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

QALY Quality-adjusted life year



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1. Background

Under the National Cancer Strategy 2017-2026,(1) the National Cancer Control Programme

(NCCP) has a mandate to develop national clinical guidelines (NCGs) for cancer care in

Ireland, in line with National Clinical Effectiveness Committee (NCEC) standards. Under the

strategy, an NCG has been developed for the diagnosis and staging of patients with ovarian

carcinoma.

1.1 Description of the condition

Ovarian cancer is used to describe closely related cancers that begin in the cells of the ovary,

fallopian tube and peritoneum. Early ovarian carcinoma can be difficult to diagnose and

later stages become difficult to treat. It may become fatal by spreading within the pelvis and

abdomen. Therefore, early detection of ovarian carcinoma is critical to successful

treatment.(2)

In Ireland, ovarian carcinoma is one of the top five causes of cancer death in women and

accounts for approximately 6.6% of all female cancer deaths.(2) The median age of ovarian

carcinoma diagnosis is 65–69 years, while 15% of women are diagnosed before the age of

50. Five-year net survival has been estimated by the National Cancer Registry to be 35%.(2)

There is also extensive clinical literature documenting clinical prediction of ovarian cancer in

primary care and its challenges.(3)

In 2018, the European Cancer Information System (formerly the European Cancer

Observatory) estimated that, based on the old European Standard Population, the age-

adjusted incidence rate was 16.1 per 100,000 women in Ireland. This compares with an

average incidence of 11.8 per 100,000 women across the EU.(4) The estimated age-adjusted

mortality rate for Irish women with ovarian carcinoma of 9.7 per 100,000 is also high

compared with the EU average of 7.1 per 100,000.(4)

Risk factors for developing ovarian cancer include positive family history, nulliparity,

hormone replacement therapy, being taller and heavier, tobacco smoking and exposure to

asbestos. Presentation and diagnosis at late stage reduces the possibility for curative

treatment and may contribute to the relatively high cancer mortality rate in Ireland in

comparison with the EU average.(2)

1.2 Description of the intervention

Long-term survival rates for patients are considerably better when cancers are diagnosed at

stages I and II rather than stages III and IV.(1) However, the vague symptoms experienced by

women who have ovarian carcinoma present a challenge to early diagnosis. The purpose of

this NCG is to improve the quality, safety and cost-effectiveness of ovarian cancer care in



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Ireland by providing guidance and standards for the diagnosis and staging of ovarian cancer.

This NCG is of particular importance for women in whom ovarian cancer is suspected.

The clinical questions underpinning the NCG relate to the reliability, usefulness and accuracy

of diagnostic tests and technologies that have the ability to guide patient treatment. These

technologies include ultrasound, magnetic resonance imaging (MRI), computed tomography

(CT), positron emission tomography-computed tomography (PET-CT), biopsy histology,

immunohistochemistry antibody panels, detection of germline or somatic mutations and

mismatch repair protein analysis.

1.3 Purpose of this systematic review

Due to variation in clinical practice and the high cost of diagnostic assessments, the

recommendations in this NCG have the potential for significant financial and resource

impact. The purpose of this systematic review was to identify and evaluate economic

evidence to inform the clinical recommendations of this NCG.

Review of the cost-effectiveness of health technologies enables guideline developers to

explicitly consider how best to maximise health outcomes and minimise costs within the

healthcare system by evaluating the effectiveness of a technology relative to its cost. Within

this framework, clinical effectiveness refers to the clinical benefits (better health outcomes)

derived from an intervention. As this NCG provides recommendations on the diagnosis and

staging of patients, effectiveness refers to the early detection of patients with ovarian

cancer which leads to clinical benefits in terms of the prevention or improvement of adverse

outcomes. As such, the cost-effectiveness of the health technologies (such as PET-CT)

included within this review is determined by the clinical benefits (from receiving treatment)

associated with early diagnosis relative to the associated costs of diagnostic assessment.



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2. Methods

A systematic review was undertaken to assess the available cost-effectiveness evidence

across a range of interventions relating to diagnosis and staging of ovarian cancer, including

ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), positron

emission tomography-computed tomography (PET-CT), biopsy histology,

immunohistochemistry antibody panels, genetic testing and genetic counselling.

In general, it is considered best practice to develop the economic review questions in

conjunction with the clinical review questions and to conduct the literature searches in

tandem. Reviewing the evidence in this manner is more efficient and allows for explicit

consideration of the economic evidence during formulation of the clinical

recommendations. For this review, preliminary clinical recommendations had already been

developed. Hence, the economic review questions were formulated on the basis of these

draft clinical recommendations. In this regard, the review aimed to identify economic

evidence that would inform and support the finalised recommendations. Although this

approach is not considered ideal, it reflects a pragmatic approach to considering economic

evidence during guideline development.

In accordance with national health technology assessment (HTA) guidelines, the costs from

previous economic evaluations were adjusted and are presented in 2017 euro.(5, 6) Cost

calculations were undertaken by one reviewer and quality assured by a second reviewer.

Costs were not updated where the cost year was either not clearly reported or was

inconsistent in the original publication.

The reporting of this systematic review adheres to the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA) criteria.(7) The review also follows national

guidelines for the retrieval and interpretation of economic literature.(8) The proposed

methodology for the systematic review was outlined in a protocol and registered on

PROSPERO.(9)

2.1 Review questions

This systematic review was developed to answer nine review questions. Each review

question was formulated in line with the PICOS (population, intervention, comparator,

outcome, study design) framework presented in Tables 1 to 9.

The economic review questions were developed using both the clinical review questions and

draft recommendations. These are presented before each economic review question in

order to clearly demonstrate the progression from clinical question to clinical

recommendation and, finally, to economic review question.



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2.1.1 Diagnosis

Clinical question 2.2.1:

In patients with suspected ovarian carcinoma, what ultrasound features are

suspicious for malignancy and require further investigation?

Clinical recommendation(s):

In patients with suspected ovarian carcinoma, a combination of transabdominal and

transvaginal ultrasound should be performed and interpreted using the IOTA

(International Ovarian Tumour Analysis) simple rules in conjunction with clinical

assessment.

Economic review question 1:

In patients with suspected ovarian carcinoma, is combined transvaginal and

transabdominal ultrasound cost-effective when compared with transabdominal

ultrasound alone?

Table 1: PICOS for review question 1

Population Patients with suspected ovarian carcinoma or adnexal mass

Intervention Combined transabdominal and transvaginal ultrasound

Comparator Transabdominal ultrasound only

Outcomes Any relevant measures of costs and benefits

Study design Full economic evaluation studies (cost-effectiveness analysis, cost-utility

analysis and cost-benefit analysis), cost analysis and comparative resource

use studies


In patients with an indeterminate ovarian mass on ultrasound, what is the utility of

CT, MRI and PET-CT, for confirmation of malignancy?


In patients with an indeterminate ovarian mass, MRI is the recommended imaging

modality if the MRI findings will affect patient management.


On the basis of cost-effectiveness, what is the preferred imaging modality (CT, MRI

or PET-CT) to confirm malignancy in women diagnosed with an indeterminate

ovarian mass detected by ultrasound?



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Population Patients with an indeterminate ovarian mass on ultrasound

Intervention Diagnosis by MRI with/without diffusion-weighted imaging

Comparator Diagnosis by CT or PET-CT




use studies

Key: CT — computed tomography; MRI — magnetic resonance imaging; PET — positron emission

tomography.



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2.1.2 Staging


In patients with an ovarian carcinoma, what is the utility of CT, MRI and PET-CT, for

staging ovarian carcinoma?


CT thorax, abdomen and pelvis with oral intravenous contrast is recommended for

the staging of ovarian cancer.

If the CT is indeterminate, patients should be discussed at a multidisciplinary team

meeting.


On the basis of cost-effectiveness, what is the preferred imaging modality (CT, MRI

or PET-CT) for staging women with ovarian carcinoma?


Population Women with ovarian carcinoma

Intervention Staging by MRI or PET-CT

Comparator Staging by CT


Study design Full economic evaluation studies (cost-effectiveness analysis, cost-

utility analysis and cost-benefit analysis), cost analysis and comparative

resource use studies


tomography.



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2.1.3 Relapse


In women who have a suspected relapse of ovarian carcinoma, what is the utility of

PET-CT and CT for re-staging?


For patients with a high suspicion of relapse of ovarian cancer, either clinically or

biochemically, CT thorax, abdomen and pelvis is recommended as the first line

imaging test.

For patients with a high suspicion of relapse of ovarian cancer either clinically or

biochemically, if the CT abdomen pelvis does not demonstrate recurrence, PET-CT

should be considered, following discussion at a multidisciplinary team meeting.


In women who have had a relapse of ovarian carcinoma, what is the cost-

effectiveness of PET-CT versus CT for re-staging?


Population Women who have a relapse of ovarian carcinoma

Intervention PET-CT to restage

Comparator CT to restage (with/without MRI as an adjunct)




use studies


tomography.



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2.1.4 Pathology


In women with a suspected tubo-ovarian carcinoma, how does biopsy histology

compare with fluid cytology for the definitive diagnosis and sub-typing of

suspected tubo-ovarian carcinoma?


Diagnosis of tubo-ovarian cancer is recommended by histological examination of

tissue sample and should allow for subtyping by morphology and

immunohistochemistry. If this is not possible, a cytological specimen may suffice.

Decisions on treatment based on cytology specimens should only be undertaken

after correlation with clinical, radiological, pathological and cytological findings in

the multidisciplinary team setting.


What is the cost-effectiveness of biopsy histology compared with fluid cytology

for the definitive diagnosis and sub-typing of suspected tubal/ovarian/peritoneal

carcinoma?


Population Women with suspected tubo-ovarian carcinoma

Intervention Biopsy histology to confirm diagnosis and subtype

Comparator Fluid cytology to confirm diagnosis and subtype



analysis and cost-benefit analysis), cost analysis and comparative

resource use studies



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In women with a suspected tubo-ovarian carcinoma, what immunohistochemistry

antibody panels should be considered for diagnosis and subtyping of tubo-ovarian

carcinoma?


Immunohistochemical panels should be appropriate to definitively sub-type tubo-

ovarian carcinoma while excluding metastatic disease and non-epithelial

malignancies. If complex immunohistochemistry marker testing is required, this

should be performed at a specialist accredited laboratory.


What are the costs of the preferred immunohistochemistry antibody panels for

diagnosis and subtyping of women with suspected tubo-ovarian carcinoma?


Population Women with suspected tubo-ovarian carcinoma

Intervention Immunohistochemistry antibody panels containing any or a

combination of the following immunohistochemical markers:

WT1

P53

PAX8

P16

Estrogen receptor

Progesterone receptor

BER EP4

Keratin 7

Keratin 20

CDX2

Keratin 5 and 6

Calretinin

Napsin A

CA 19.9

GCDFP 15

Mammoglobin

GATA3

CEA

CA125

TTF1

HNF1B

Comparator -

Outcomes Any relevant measures of costs

Study design Cost analysis



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2.1.5 Genetics/Hereditary cancer


Which women with tubo-ovarian carcinoma should be offered genetic testing to

diagnose familial cancer syndromes and/or to guide patient management?


All patients with tubo-ovarian carcinoma should be offered germline mutation

testing appropriate to sub-type. Specifically, testing of all high-grade non-mucinous

carcinomas for BRCA gene mutations is recommended.

All tubo-ovarian carcinoma patients with a genetic test which shows either a

pathogenic variant or a variant of uncertain significance should be offered post-test

counselling. If the patient has a significant cancer family history, even if BRCA1/2

testing is normal, a referral to genetic services is advised.


In women with non-mucinous tubo-ovarian carcinoma, is universal genetic testing

cost-effective compared with genetic testing of subpopulations for diagnosing

familial cancer syndromes and/or guiding patient management?


Population Women with non-mucinous tubo-ovarian carcinoma

Intervention Universal genetic testing

Comparator Genetic testing of at-risk subpopulations identified by scoring systems

(such as the Manchester scoring system)




resource use studies.


In women with non-mucinous tubo-ovarian carcinoma that receive a positive

diagnosis following genetic testing, is it cost-effective to offer post-test counselling?


Population Women with non-mucinous tubo-ovarian carcinoma that receive a

positive diagnosis following genetic testing



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Intervention Post-test counselling

Comparator Pre-test counselling or a combination of pre- and post-test counselling







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Which women with tubo-ovarian carcinoma should be considered for mismatch

repair (MMR) protein analysis to diagnose familial cancer syndromes and/or to guide

patient management?

Clinical recommendation:

The tumours of all women with a diagnosis of endometrioid or clear cell carcinoma

regardless of age should undergo mismatch repair (MMR) protein testing by

immunohistochemistry.


In women with a diagnosis of endometrioid or clear cell carcinoma, is universal

mismatch repair protein testing cost-effective versus other testing strategies to

identify familial cancer syndromes and/or to guide patient management?


Population All women with a diagnosis of endometrioid or clear cell carcinoma

Intervention Universal mismatch repair protein testing

Comparator No testing or an alternative testing strategy (such as by age or family

history)



analysis and cost-benefit analysis), cost analysis and comparative


2.2 Types of studies

The review aimed to identify health economic studies such as economic evaluations (cost-

effectiveness analysis, cost-utility analysis, cost-minimisation analysis and cost-benefit

analysis) and comparative resource use studies.

2.3 Types of participants

The population of interest was women (aged 18 and above) with diagnosed or suspected

tubo-ovarian cancer.



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2.4 Types of outcome measures

A non-exhaustive list of economic outcome measures applicable to this review is outlined

below.

Economic evaluations

Cost-utility and/or cost-effectiveness analysis:

incremental cost-effectiveness ratio (ICER)

cost per unit of effect (such as cost per life year gained) or effects per unit cost (for

example, life year gained per euro spent)

quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) or health/life

years equivalent

incremental net monetary benefit.

Cost-benefit and/or cost-minimisation analysis:

net monetary benefit

incremental costs.

Other economic outcome measures

Costs and resource use:

direct (for example, cost of treatment including chemotherapy medications) and

indirect medical costs (e.g. out-of-pocket patient expenses)

length of stay (hospital or ICU/HDU)

inpatient admissions

intensive care unit (ICU)/high dependency unit (HDU)/emergency department (ED)

admissions

implementation costs (for example, training and education)

escalation costs

service utilisation costs

cost savings or offsets.

2.5 Search methods for identification of studies

On 12 June 2018, electronic searches were conducted in Medline, Embase and the Cochrane

Library (which includes the Database of Systematic Reviews, the Database of Abstracts of

Reviews of Effects (DARE), the Health Technology Assessment (HTA) Database and the

National Health Service Economic Evaluation Database (NHS EED)) using a search string

adapted from the clinical searches conducted by Brendan Leen, Regional Librarian, Health

Service Executive (HSE) South (see Appendix 1). A grey literature search was also conducted

via Google Scholar and national and HTA electronic sources (see Appendix 2).



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2.6 Exclusion criteria

The following exclusion criteria were applied:

studies that were published before January 2011

studies which were not available in English

conference papers and abstracts where the full paper was unobtainable.

2.7 Data collection and analysis

Selection of studies

Citations were screened by two reviewers (one from HRB-CICER and one from the National

Cancer Control Programme (NCCP)) to eliminate clearly irrelevant studies based on the title

and abstract of the citation. The full text of the remaining citations were independently

reviewed by two reviewers (one from HRB-CICER and one from the NCCP) as per the

inclusion criteria, with disagreements resolved through discussion.

Data extraction and management

Data extraction was performed independently by two people (one from HRB-CICER and one

from the NCCP) with disagreement resolved through discussion.

Assessment of quality and transferability in included studies

Risk of bias was assessed using the Consensus on Health Economic Criteria (CHEC)-list

quality appraisal tool.(10) The studies were evaluated for transferability and applicability to

the Irish setting using the International Society for Pharmacoeconomics (ISPOR)

questionnaire.(11) Both questionnaires were completed independently by two people (one

from HRB-CICER and one from the NCCP), with disagreement resolved through discussion.

Data synthesis

A narrative synthesis of the results was provided due to the heterogeneity of the economic

studies.



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3. Results

3.1 Overview of results

The search of listed databases and grey literature sources identified a total of 3,019

citations. Following removal of duplicates, the title and abstract of 2,733 citations were

screened independently by two reviewers. Following independent screening, a total of 109

full text articles were assessed for eligibility. Of these, 105 papers were excluded according

to the inclusion and exclusion criteria and four studies were identified for inclusion in this

review. A further two studies were identified for inclusion following examination of the

reference lists of the previously identified papers. The PRISMA flow chart (outlining the

search, screening and selection of economic studies) is presented in Figure 3.1.

Figure 3.1: PRISMA flow chart of economic article selection for the systematic review



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The main reasons for exclusion were unavailability of a full text article (for example

conference abstract only) (n=45), ineligibility of the intervention or comparator (n=34), the

patient population (n=3), or the study design was not relevant for the review ((n=23), for

example no economic analysis). Systematic reviews were excluded as per the protocol, with

their reference lists searched to identify relevant studies. A list of excluded studies is

presented in Appendix 3.

Of the six studies identified for inclusion in this systematic review, one paper addressed

economic review question 4,(12) and five papers addressed economic review question 7.(13-17)

Four studies were identified from UK, one study was conducted in the US and one study was

conducted in Italy. The summary characteristics of the included studies is presented in Table

3.1. No economic studies were identified in relation to economic review questions 1, 2, 3, 5,

6, 8 and 9.

Table 3.1: Characteristics of included studies

Study (year) Country Type of analysis Intervention Review

question

Mansueto et al.

(2009)(12)

Italy CEA PET-CT 4

Eccleston et al.

(2017)(13)

UK CEA BRCA testing &

genetic counselling

7

George et al.

(2016)(14)

UK Cost analysis BRCA testing

pathway

7

Kwon et al.

(2010)(17)

USA CEA BRCA testing 7

Plaskocinska et al.

(2016)(15)


pathway

7

Slade et al.

(2016)(16)


pathway

7

Key: CEA — cost-effectiveness analysis; PET-CT — positron emission tomography-computed tomography.

3.2 Methodological quality and transferability of evidence

The included studies were assessed using the CHEC-list(10) and International Society for

Pharmacoeconomics (ISPOR)(11) questionnaires to determine their quality, relevance and

credibility. Relevance was assessed on the grounds of the study population, characteristics

of the intervention, outcomes measured and the overall study context. Common issues

across studies included the design of the model, methods for dealing with uncertainty,

reporting of key information, and uncertainty regarding the face validity of the model due to

the absence of internal and external validation. The credibility of the results was considered



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using criteria related to the design, validation and analysis methods, the quality of the data

used, as well as how the results were reported and interpreted and whether the authors

had any conflicts of interest. The included studies were generally considered to be of low to

moderate quality. Reporting was generally adequate and considered to be fair and

balanced. As the questionnaires are designed for application to full economic evaluations,

many of the questions were not applicable to the costing studies.

Studies were judged to be subject to a high risk of bias where the authors failed to clearly

report key information such as the perspective of the analysis and the modelled time

horizon. The quality and transferability of each study is discussed individually in Section 3.3.

The results of the quality, relevance and credibility are presented in Figure 1 and Figure 2 of

Appendix 4.

3.3 Summary of included studies

3.3.1 Economic review question 4: In women who have had a relapse of ovarian

carcinoma, what is the cost-effectiveness of PET-CT versus CT for re-staging?

One economic evaluation, by Mansueto et al. (2009),(12) was retrieved in this systematic

review which addressed economic review question 4. A summary of the characteristics,

methods and results of the study by Mansueto et al.(12) is presented in Table 3.2.

The study comprised a cost-effectiveness analysis (CEA) from the third-party payer

perspective in Italy, with unit costs reported in 2006 euros. The CEA evaluated three

strategies for the early detection of recurrence of ovarian cancer. These were:

1. CT only — management choice based on the sole knowledge of contrast enhanced

CT

2. PET-CT for negative CT (strategy A) — management choice based on both contrast

enhanced CT and on PET-CT in patients with a negative finding at contrast enhanced

CT

3. PET-CT for all (strategy B) — management choice based on both contrast enhanced

CT and PET-CT in all patients.

The analysis incorporated the clinical data from an uncontrolled retrospective study of 32

patients reported by Mangili et al.(18) The costs of the three diagnostic strategies ranged

from €71,323 (€91,785) (CT only) to €94,663 (€121,821) (PET-CT for negative CT). Mansueto

et al.(12) found that strategy B (PET-CT for all) was cost-effective with an incremental cost-

effectiveness ratio (ICER) of €227 (€292) per case of surgery avoided when compared with

CT only. Strategy A (PET-CT for negative CT) was both more costly and less effective (the

number of surgical procedures was higher) than the reference strategy (CT only) and thus

excluded by extended dominance.



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There were a number of limitations to the analysis. Firstly, it failed to account for the health-

related quality of life (HRQoL) that patients experience in each given health state. The

absence of a HRQoL measure in the analysis prevents the calculation of the incremental

quality-adjusted life years (QALYs) gained. Therefore, it is difficult to directly compare the

cost-effectiveness results of the study versus that of other health technologies. This is

because the results cannot be applied to the implicit willingness-to-pay threshold (€45,000

per QALY gained) employed in Ireland. Secondly, the study failed to specify the time horizon

over which the analysis was conducted. Therefore, we cannot be certain that all relevant

outcomes and costs are included within the analysis. Discounting of costs and health gains

was also not reported. According to Irish guidelines for economic evaluation, discounting

should be applied to costs and health gains at a 5% rate in CEA. Finally, the analysis was

based on the findings of a small group of patients (n=32) and thus may be subject to bias.



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Table 3.2: Summary of characteristics, methods and results for economic review question 4

Author, country

(year)

Population and

Interventions Analysis details Costs Clinical outcomes

Analysis of

uncertainty Results

Mansueto, Italy

(2009)(12)

Population:

Patients with

suspected

ovarian cancer

recurrence

(mean age: 57.3

years; range: 39–

75 years)

Interventions:

1. CT only

2. PET-CT for

negative CT

(strategy A)

3. PET-CT for all

(strategy B).

Analysis type:

Decision tree

(CEA)

Perspective:

Third party payer

Time horizon:

Not reported

Discount rate:

Not applied

Currency and

cost year:

2006 Euros

Cost

components:

CT and PET-CT,

blood exam,

surgery with

complications,

and surgery

without

complications.

Surgery avoided,

number of

patients that

displayed a

change in the

number of

lesions, and

changes in the

number of

positive cases.

One-way and

multivariate

sensitivity

analysis.

The ICER for strategy B ranged from €91 to €379 in the one-way sensitivity analysis and from €50 and €433 in the

multivariate

sensitivity

analysis.

Total costs (for 32

patients):

CT only: €71,323 (mean cost per patient of €2,229). Strategy A: €94,663 (mean cost per patient of €2,958). Strategy B: €93,093 (mean cost per patient of €2,909).

Total surgical procedures (for 32 patients): CT only: 15 Strategy A: 20 Strategy B: 12

ICER:

Strategy B: €227 per

case of surgery

avoided versus CT

only. Key: CEA — cost-effectiveness analysis; CT — computed tomography; ICER — incremental cost-effectiveness ratio; PET — positron emission tomography.



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3.3.2 Economic review question 7: In women with non-mucinous tubo-ovarian carcinoma,

is universal genetic testing cost-effective compared with genetic testing of subpopulations

for diagnosing familial cancer syndromes and/or guiding patient management?

Five studies were identified in this systematic review that addressed economic review

question 7. This included two economic evaluations(13, 17) and three costing studies.(14-16) A

summary of the characteristics, methods and results of the two economic evaluations is

presented in Table 3.3.

Eccleston et al. (2017)(13) developed a patient-level simulation to compare universal

germline BRCA testing and genetic counselling in women with epithelial ovarian cancer and

testing of first and second degree relatives of BRCA mutation-positive individuals compared

to no testing in the UK. The study comprised a cost-utility analysis (CUA) conducted from the

perspective of the National Health Service (NHS) across a 50 year time horizon. Discounting

of costs and benefits was applied at a lower rate of 3.5% than the 5% recommended by Irish

national guidelines for economic evaluation.(6) The authors reported an ICER of £4,339 (95%

CI: £1,593-£11,764) per QALY gained for universal testing compared with no testing. This

was considered cost-effective at the £20,000 per QALY gained willingness-to-pay threshold

employed in the UK. Eccleston et al.(13) suggested that, because the benefits of targeted

therapies (such as poly (ADP-ribose) polymerase (PARP) inhibitors) were not modelled in the

CUA, universal testing may be more cost-effective than their analysis indicates. In their

model, only the relatives of index cases benefitted from BRCA testing. This is a conservative

assumption that assumes that all patients are diagnosed at a late stage, thus preventing

risk-reducing surgery.

Although the analysis was considered to be of good quality and relevant to the Irish context

(see Appendix 4), a number of limitations were noted. Firstly, overall survival and

progression-free survival were not included in the analysis, with the costs and benefits of

treatment considered only for standard first-line chemotherapy. Secondly, the results may

be somewhat biased in favour of testing because the negative impact of risk-reducing

surgery on patients’ morbidity and mortality were not considered in the model. Thirdly, the

authors did not report the cost year for unit costs used in the analysis, which makes the

study difficult to interpret in terms of transferability. Fourthly, the authors reported the

ICER on the basis of the non-probabilistic results but applied 95% confidence intervals from

the probabilistic sensitivity analysis. This is not best practice as the ICER should have been

estimated from the probabilistic results (£5,282 per QALY gained). Finally, a potential

conflict of interest, due to the presence of industry funding, was noted.

Kwon et al.(17) developed a Markov model to evaluate the cost-effectiveness of four

strategies for genetic testing of women with ovarian cancer in the USA taking in to account

potential benefits for first degree relatives. These were:

1. No BRCA mutation testing



Page 26 of 56

2. BRCA testing only if Ashkenazi Jewish ancestry, a personal history of breast cancer,

or a family history of breast and/or ovarian cancer, according to an Education

Committee Statement from the Society of Gynecologic Oncologists (SGO criteria)

3. BRCA testing only if invasive serous cancer (test serous)

4. BRCA testing if any invasive, non-mucinous epithelial ovarian cancer (test all).

This CUA adopted a societal perspective across a lifetime horizon. Discounting of costs and

benefits was applied at a lower rate of 3% than the 5% recommended by Irish national

guidelines for economic evaluation.(6) Genetic testing according to the SGO criteria (that is,

women with ovarian cancer who have a personal history of breast cancer, a family history of

breast/ovarian cancer, or of Ashkenazi Jewish ancestry) was found to be cost-effective with

an ICER of $32,670 (€34,981) per QALY gained (at a willingness-to-pay threshold of $50,000

per QALY gained) compared with no testing. The cost-effectiveness of this strategy was

primarily influenced by the prevention of cancers among first degree relatives by

undergoing risk-reducing surgery.

The authors found that BRCA testing of index cases with invasive serous cancers only had an

ICER of $131,113 (€140,390) per QALY gained versus testing with the SGO criteria. BRCA

testing all index cases (test all) had an ICER of $151,429 (€162,143) per QALY gained versus

testing those with invasive serous cancers only. Neither of these strategies would be

considered cost-effective when applied to the implicit willingness-to-pay threshold of

$50,000 per QALY gained employed by the authors.

There were a number of significant limitations identified. Firstly, the analysis did not model

the costs and benefits of treatment options following genetic testing, which may impact the

cost-effectiveness of genetic testing in the long term. Secondly, HRB-CICER assumed that

the analysis adopted a lifetime horizon and that costs were reported in 2008 US dollars

(because the analysis considered the average lifetime cost in 2008), but neither of these

points were explicitly reported by the authors. This complicates interpretation of

transferability to the Irish context. Finally, although a Monte Carlo simulation was

mentioned in the results, the robustness of the model’s outcomes did not appear to be

tested by a probabilistic sensitivity analysis.



Page 27 of 56

Table 3.3: Summary of characteristics, methods and results of full economic evaluations addressing economic review question 7

Author, country

(year)

Population and


Analysis of

uncertainty Results

Eccleston, UK

(2017)(13)

Population:

All women with

epithelial ovarian

cancer in UK

Intervention:

Universal

germline BRCA

testing and

genetic

counselling of the

women and first

and second

degree relatives

if mutation-

positive

Comparator:

No testing

Analysis type:

Patient-level

simulation (CUA)

Perspective:

UK health service

(NHS)

Time horizon:

50 year

Discount rate:

3.5%

Currency and

cost year:

UK pounds, cost

year not reported

Cost

components:

BRCA testing,

genetic

counselling,

cancer

surveillance, RRS,

HRT, cancer

treatment, and

palliative care

Number of

deaths, number

of ovarian cancer

cases, number of

breast cancer

cases, and QALYs

DSA and PSA

PSA showed that

the expected

ICER was £5,282

per QALY gained

(95% CI: £1,593–

£11,764).

The probability of

BRCA testing

being cost-

effective was

99.9% at the

£20,000 per QALY

gained threshold.

BRCA testing was

always more

effective than no

testing.

Total costs (for

7,284):

Incremental cost: £3

million (total cost =

£9.6 million)

QALYs:

Incremental QALYs

gained: 706

ICER:

£4,339 per QALY

gained (95% CI:

£1,593–£11,764)

Kwon, USA

(2010)(17)

Population:

Women with

ovarian cancer

and first degree

Analysis type:

Markov model

(CUA)

Currency & cost

year:

2008 US dollars

(but cost year not

Average life

expectancy and

QALYs.

One- and two-

way sensitivity

analysis.

Costs:

No testing: $2,637

SGO criteria: $,3680

Test serous: $4,968



Page 28 of 56

Author, country

(year)

Population and


Analysis of

uncertainty Results

relatives

Interventions:

1. No BRCA

mutation testing

2. BRCA testing

only if Ashkenazi

Jewish ancestry,

a personal

history of breast

cancer, or a

family history of

breast and or

ovarian cancer,

according to an

Education

Committee

Statement from

the SGO (SGO

criteria)

3. BRCA testing

only if invasive

serous cancer

(test serous)

4. BRCA testing if

any invasive,

Perspective:

Societal

Time horizon:

Lifetime (but not

explicitly stated)

Discount rate:

3%

explicitly stated)

Cost

components:

Initial and follow-

up consultations,

mastectomy,

breast

reconstruction

with latissimus

flap, partial

mastectomy with

axillary node

dissection,

laparoscopic BSO,

pathologist

examination,

genetic

counselling, BRCA

mutation direct

sequencing, DNA

interpretation

and reporting,

single site testing,

hospital costs,

Test all: $6,084

QALYs:

No testing: 16.6171

SGO criteria:

16.6490

Test serous:

16.6589

Test all: 16.6662

ICERs:

SGO criteria:

$32,670 per QALY

gained versus no

testing.

Test serous:

$131,113 per QALY

gained versus SGO

criteria.

Test all: $151,429

per QALY gained

versus testing only

those with invasive

serous cancers.



Page 29 of 56

Author, country

(year)

Population and


Analysis of

uncertainty Results

non-mucinous

epithelial ovarian

cancer (test all).

prophylactic

mastectomy with

reconstruction

and BSO, and

patient

opportunity costs

for 6 weeks.

Key: BSO — bilateral salpingo-oophorectomy; CEA — cost-effectiveness analysis; CUA — cost-utility analysis; DSA — deterministic sensitivity analysis; HRT — hormone

replacement therapy; ICER — incremental cost-effectiveness ratio; NHS — National Health Service; PSA — probabilistic sensitivity analysis; QALY — quality-adjusted life

year; RRS — risk-reducing surgery; SGO — Society of Gynaecologic Oncologists.



Page 30 of 56

Three cost analyses that addressed economic review question 7 were identified in this

systematic review.(14-16) A summary of the characteristics, methods and results of these

studies is presented in Table 3.4.

Plaskocinska et al.(15) conducted a cost consequence analysis in which they undertook a

micro-costing exercise of a universal BRCA testing pathway without pre-test genetic

counselling versus the current treatment pathway (in which testing is based on family

history and women are offered pre- and post-test genetic counselling) for women diagnosed

with high-grade serous or endometrioid epithelial ovarian cancer within the previous 12

months in the UK. The analysis adopted the perspective of the clinical genetics service (in

which only direct costs are considered) and mapped the costs from referral for genetic

testing to diagnostic test outcome, with costs reported in 2015 UK pounds. There was an

average incremental patient pathway cost of £3,027 (€3,616) for universal BRCA testing

versus the current treatment pathway due to the greater number of genetic tests

undertaken. The key cost driver in the universal BRCA testing pathway was the cost of

genetic testing, whereas the provision of diagnostic testing was the main cost driver in the

current pathway. The non-genetic test-related costs accounted for only 22% of the total

costs in the universal BRCA testing pathway versus 62% in the current pathway. The cost

offset is due to genetic counselling being offered to all women before testing in the current

pathway.

Study participants also completed self-report questionnaires to assess the psychological

impact and acceptability of genetic testing. The psychological impact was measured using

the Depression Anxiety Stress Scales (DASS-21) and Impact of Event Scale (IES)

questionnaires. IES and DASS-21 scores were significantly lower than equivalent scores in

response to cancer diagnosis (Wilcoxon signed rank tests Z score range = -6.174 to -8.852;

all p<0.001). This demonstrated that undergoing genetic testing did not cause further stress

beyond that already incurred as a result of the cancer diagnosis itself. Acceptability was

measured using 12 study-specific questions with a possible score range from one to six. The

authors reported high levels of acceptability of testing with patients feeling that the test

gave them a better understanding of their family’s risk (mean = 5.31, standard deviation =

1.26, n=173). However, variation was reported in relation to the ease with which patients

decided to undergo genetic testing (mean = 2.05, standard deviation = 1.8, n=172).

Plaskocinska et al.(15) concluded that testing should be offered to all women with epithelial

ovarian cancer under 70 years of age as mutation prevalence would be above the current

threshold of 10% used for eligibility for testing breast cancer families in the UK. They

estimated that this could be cost-saving by reducing the number of tests by around 37% but

would miss 6% of mutations. Additionally, they estimated that no mutations would be

missed if a criterion was applied whereby those aged over 70 with a previous history of

breast cancer or a family history (first-degree relative) of breast or ovarian cancer were

tested. The study was determined to be of moderate quality due to methodological



Page 31 of 56

limitations. The authors also excluded the cost of clinical management, which is likely to be

a key cost driver in the patient pathway.

Slade et al.(16) conducted a micro-costing study of 28 possible pathways from referral to

management with alternative strategies for BRCA testing and management of women with

breast and/or ovarian cancer in the UK. The pathways were summarised as follows:

Pathways 1 to 10 represented patients that were diagnosed with breast and or

ovarian cancer and referred to the genetic cancer service. The main differences

between these pathways were whether a patient was eligible for BRCA testing,

whether the patient underwent BRCA testing, and the subsequent patient

management based on the patient’s BRCA test and family history.

Pathways 11 to 28 represented patients that were not diagnosed with breast or

ovarian cancer but were referred to the genetic cancer service. The main differences

between these pathways were whether a relative of the patient had already

undergone BRCA testing, whether the patient or relative were eligible for BRCA

testing, and the subsequent patient management based on the patient’s BRCA test

and family.

Subsequent patient management options were as follows:

Unaffected BRCA carrier management — according to family history

Population surveillance — mammography every three years from 50 to 70 years of

age

Moderate risk surveillance — annual mammography from 40 to 50 years of age

Higher risk surveillance — annual mammography from 40 to 50 years of age and 18

monthly mammograms from 50 to 60 years of age

Affected BRCA carrier management — annual mammography from 40 to 70 years of

age and annual MRI from 30 to 50 years of age)

Mutation carriers are eligible for risk-reducing surgery, bilateral mastectomy and/or

bilateral salpingo-oophorectomy.

The analysis adopted the perspective of the healthcare provider. A discounting rate of 3.5%

was applied to the costs of surveillance and hormone replacement therapy, which is lower

than the 5% recommended by Irish national guidelines for economic evaluation.(6)

Furthermore, costs were reported in 2013 UK pounds. The costs of the pathways ranged

from £377 (€471) (pathway 16, 24 and 28) to £13,553 (€16,954) (pathway 17). The least

expensive pathways consisted of unaffected individuals from a family where:

previous testing did not identify a BRCA mutation

no relative is available for BRCA testing

no BRCA testing is recommended.



Page 32 of 56

The lower costs reflected the absence of BRCA testing and the smaller subsequent

management costs. Slade et al. reported that the pathway costs were primarily driven by

the patient management, particularly in terms of those identified as carrying a BRCA

mutation. The most expensive pathway comprised a relative of an unaffected individual

(that has presented) undergoing BRCA testing where both individuals are mutation positive,

which reflects the management costs incurred by both individuals. The study was judged to

be of moderate quality. However, it was noted that the time horizon of the analysis was not

reported, which makes it unclear if all relevant long-term costs have been considered.

George et al.(14) conducted a cost comparison of BRCA testing pathways extrapolated from

the findings of a sample (n=207) of women with ovarian cancer in the UK. The study

compared a mainstream pathway, where all women with mutations automatically received

a genetic counselling appointment within 3–4 weeks from the test initiation, with the

traditional BRCA testing pathway, where standard practice is for potentially eligible patients

to be referred to a genetics team for discussions before and after testing. The data and costs

of each pathway were extracted from the study by Slade et al.(16) The authors found that the

introduction of the mainstream pathway led to an incremental annual cost saving of

£2,655,565 due to a decrease of genetics appointments from approximately 13,000 (as

according to George et al.,(14) approximately 6,500 new patients are diagnosed with non-

mucinous ovarian cancer annually in the UK) to approximately 1,000 per year as only

women with a mutation receive a follow-up genetic counselling appointment.

The study by George et al.(14) was determined to be of low quality due to a number of

significant methodological issues. The authors did not report the perspective, time horizon

nor cost year used in the analysis. Additionally, there was no evidence of methods to deal

with uncertainty in the analysis. Finally, it is important to note that the recommendation in

this guideline is for women with variants of uncertain significance as well as pathogenic

variants to be offered post-test counselling. Variants of uncertain significance were not

accounted for in the study by George et al.,(14) which limits its transferability to the Irish

context.



Page 33 of 56

Table 3.4: Summary of characteristics, methods and results of included cost studies for economic review question 7

Author, country

(year)

Population and


Analysis of

uncertainty Results

George, UK(14)

(2016)

Population:

Women with

ovarian cancer

(n=207)

Intervention:

BRCA testing

pathway where

all women with

mutations

automatically

receive a

genetics

appointment

within 3–4 weeks

from the test

initiation

(mainstream

pathway)

Comparator:

Traditional BRCA

testing pathway

(all eligible

patients referred

Analysis type:

Cost comparison

Perspective:

Not reported

Time horizon:

Not reported

Discount rate:

NA

Currency and

cost year:

UK pounds, cost

year not reported

Cost

components:

Pathway data and

costs sourced

from Slade et al.

(2016)(16)

NA None Cost for 6,500

patients in

traditional pathway:

£2,987,855.

Cost of

approximately 1,000

patients in

mainstream

pathway: £332,290.

Annual cost saving

of the mainstream

pathway:

£2,655,565.



Page 34 of 56

Author, country

(year)

Population and


Analysis of

uncertainty Results

to genetics team

pre- and post-

test)

Plaskocinska, UK

(2016)(15)

Population:

Women aged 18

years or over

diagnosed with

high-grade

serous or

endometrioid

epithelial ovarian

cancer within the

previous 12

months.

Intervention:

Universal BRCA

testing without

pre-test genetic

counselling

(GTEOC pathway)

Comparator:

Current

treatment

Analysis type:

Cost

consequence

analysis

Perspective:

Clinical genetics

service

Time horizon:

Not reported

Discount rate:

NA

Cost currency

and year:

2015 UK pounds

Cost

components:

Full treatment

pathway from

referral for

genetic testing to

diagnostic test

outcome

Psychological

impact of genetic

testing was

captured via the

IES and DASS-21

questionnaires.

Acceptability of

genetic testing

was captured in

12-point

questionnaires.

One way

sensitivity

analysis.

Changing the cost

of the genetic

test and

implementing an

age cut-off of 70

years had large

effects on the

budget.

Costs:

Overall budget:

£253,617 (GTEOC)

vs £142,702

(current)

Average patient

pathway cost per

BRCA mutation

positive: £14,919

(GTEOC) versus

£11,892 (current)

Average patient

pathway cost for

each test offered:

£1,093 (GTEOC)

versus £2,265

(current)

Average patient

pathway cost per

patient without



Page 35 of 56

Author, country

(year)

Population and


Analysis of

uncertainty Results

pathway genetic testing:

£243 (GTEOC)

versus £383

(current).

Slade, UK

(2016)(16)

Population:

Women with

breast and/or

ovarian cancer

Intervention:

28 possible

pathways for

BRCA testing

depending on the

diagnosis of

breast and/or

ovarian cancer,

eligibility and

presentation for

testing, and

family history of

testing.

Analysis type:

Cost analysis

(micro-costing)

Perspective:

Healthcare

provider (NHS)

Time horizon:

Not reported

Discount rate:

3.5% applied to

costs of

surveillance and

HRT

Cost currency

and year:

2013 UK pounds

Cost

components:

Full pathway

from referral to

management

NA One way

sensitivity

analysis on some

elements of

resource use and

costs. This

included varying

the method of

consultation, the

cost of the test

and removal of

the London

weighting on

staff time, and

alternating the

clinical team

member involved

in the patient

pathway.

Varying the cost

Costs:

Overall pathway

costs ranged from

£377 (pathway 16,

24 and 28) to

£13,553 (pathway

17). Average cost

per pathway:

£2,227 (weighted

average = £1761*).

Average cost per

person: £1,898 for

those affected with

breast or ovarian

cancer (weighted

average = £2,084*)

versus £2,411 for

those unaffected

(weighted average =

£1,561*). Average



Page 36 of 56

Author, country

(year)

Population and


Analysis of

uncertainty Results

of the test had

the greatest

impact on total

service costs.

cost per BRCA

mutation identified:

£8,070 (weighted

average = £6,657*)

Average cost per full

BRCA test: £4,462

(weighted average =

£3,212*) versus

£3,118 (weighted

average = £3,300*)

when performing a

predictive BRCA test

for a known

mutation.

Average cost of

BRCA testing in a

relative of

unaffected

presenting patient:

£5,376 (weighted

average = £4,445*). Key: DASS — Depression Anxiety Stress Scales; GTEOC — Genetic Testing in Epithelial Ovarian Cancer; HRT — hormone replacement therapy; IES — Impact of Event

Scale; NA — not applicable; NHS — National Health Service.

* Weighted according to clinical audit data of the number of patients at first appointment that followed each pathway from September 2009 to February 2010).



Page 37 of 56

4. Discussion

Due to variation in clinical practice and the high cost of diagnostic assessments, the

recommendations in this national clinical guideline (NCG) for the diagnosis and staging of

patients with ovarian cancer have the potential for significant financial impact. The purpose

of this review was to identify and evaluate relevant economic evidence to inform the clinical

recommendations of this NCG. The clinical recommendations of the NCG relate to the utility

(reliability/usefulness) and accuracy of diagnostic tests and technologies that have the

ability to guide patient treatment. These technologies include ultrasound, magnetic

resonance imaging (MRI), computed tomography (CT), positron emission tomography-

computed tomography (PET-CT), biopsy histology, immunohistochemistry antibody panels,

detection of germline or somatic mutations and mismatch repair protein analysis. Review of

the cost-effectiveness of health technologies enables the guideline developers to explicitly

consider how best to maximise health outcomes and minimise costs within the healthcare

system by evaluating the effectiveness of a technology relative to its cost. There is no

willingness-to-pay threshold for non-pharmaceutical health technologies in Ireland.

However, an implicit threshold of €45,000 per QALY gained is often applied for

interpretation of cost-effectiveness.

While cost analyses can be useful to inform financial implications of policymaking, they are

often not directly transferable due to variation in patient pathways between jurisdictions.

They can also form an inadequate basis for reimbursement decisions as they do not reflect

whether a health technology represents value-for-money. Similarly, cost-effectiveness

analyses may differ across jurisdictions in terms of the modelled costs and benefits,

discounting, outcomes, and perspectives. Hence, in the absence of country-specific analysis

it can be difficult to determine the generalisability of international economic evidence.

No economic studies were identified in relation to economic review questions 1, 2, 3, 5, 6, 8

and 9. These review questions were in relation to the cost and/or cost-effectiveness of the

following:

combined transabdominal and transvaginal ultrasound versus transabdominal

ultrasound only in patients with suspected ovarian cancer

diagnosis by MRI versus diagnosis by PET-CT or CT in patients with an indeterminate

ovarian mass on ultrasound

staging by MRI or PET-CT versus staging by CT in women with ovarian cancer

biopsy histology versus fluid cytology to confirm diagnosis and subtype in women

with suspected tubo-ovarian cancer

immunohistochemistry antibody panels for diagnosis and subtyping of women with

suspected tubo-ovarian cancer



Page 38 of 56

post-test genetic counselling versus pre-test genetic counselling or a combination of

pre- and post-test genetic counselling in women with non-mucinous tubo-ovarian

cancer

universal mismatch repair protein analysis versus no testing or another testing

strategy in women with a diagnosis of endometrioid or clear cell carcinoma.

One economic evaluation by Mansueto et al.(12) was identified in relation to economic

review question 4, which sought to determine the cost-effectiveness of PET-CT versus CT for

restaging in women who have had a relapse of ovarian cancer. Mansueto et al.(12) found that

PET-CT for all women with a suspected recurrence of ovarian cancer was the most cost-

effective strategy with an incremental cost-effectiveness ratio (ICER) of €227 (€292) per case

of surgery avoided compared with CT only. They also found that PET-CT for negative CT was

more costly and less effective than CT only. However, the generalisability of these findings

are restricted by the methodological limitations of the study. Consistent with the findings of

other reviews, this systematic review revealed that there is a paucity of evidence

surrounding the cost-effectiveness of PET-CT for diagnosing the recurrence of ovarian

cancer.(19) With increasing application of medical imaging, there is a growing need for

economic analyses to inform decision-makers on the cost-effectiveness of these

technologies.

Two economic evaluations were identified in this systematic review that addressed

economic review question 7. Eccleston et al.(13) found that universal BRCA testing in women

with epithelial ovarian cancer was cost-effective with an ICER of £4,339 per QALY gained

compared with no testing in women with epithelial ovarian cancer in the UK. The findings of

this study were considered to be of good quality and transferable to the Irish context.

However, the strategy modelled by Eccleston et al.(13) included testing of first and second

degree relatives. Accordingly, the benefits which accrued to the intervention were in those

who received genetic testing based on family history and the study excluded benefits in the

index women who are diagnosed with ovarian cancer assuming that they are diagnosed at

too late a stage to benefit from risk reducing surgery. As this guideline’s scope is targeted to

index women only and neither explicitly recommends for or against genetic testing based on

family history, the applicability of Eccleston et al.’s findings to the Irish context should be

interpreted with caution. Kwon et al.(17) found that BRCA testing in women with ovarian

cancer who have a personal history of breast cancer, a family history of breast and/or

ovarian cancer, or of Ashkenazi Jewish ancestry was cost-effective in the US with an ICER of

$32,670 (€34,981) per QALY gained versus no testing. The cost-effectiveness of this strategy

was mainly driven by the prevention of cancers among first degree relatives by undergoing

risk-reducing surgery. They also found an ICER of $151,429 (€162,143) per QALY gained for

BRCA testing for all women with non-mucinous epithelial ovarian cancer versus testing

those with invasive serous cancers only. This ICER would not be considered cost-effective in



Page 39 of 56

Ireland. However, this study was subject to significant methodological limitations and again

the modelled strategies included routine testing of first degree relatives of the index women

A notable limitation of the studies identified in this systematic review is that they did not

model the costs and benefits of treatment with PARP (poly (ADP-ribose) polymerase)

enzyme inhibitors. Inclusion of PARP inhibitors in cost-effectiveness analysis, in terms of

costs and benefits, could impact the cost-effectiveness of diagnostic strategies.(20) BRCA

testing currently enables treatment with PARP inhibitors in women with ovarian cancer. The

treatment of patients with PARP inhibitors is an evolving field with newer agents becoming

licensed to treat this patient cohort irrespective of BRCA status. The requirement for BRCA

germline testing to determine eligibility for treatment with a PARP inhibitor may change in

the future.

Three cost analyses were identified that addressed economic review question 7 in this

systematic review. Plaskocinska et al.(15) found an average incremental patient pathway cost

of £3,027 (€3,616) for universal BRCA testing without pre-test genetic counselling versus

usual care in the UK which comprised testing based on family history where women were

offered pre- and post-test genetic counselling. On the basis of their analysis (which included

examination of the acceptability and psychological impact of this pathway), the authors

concluded that BRCA testing should be offered to all women with epithelial ovarian cancer

under 70 years of age. Slade et al.(16) found that the costs of 28 alternative pathways relating

to breast and ovarian cancer and BRCA testing ranged from £377 (€471) to £13,553

(€16,954). The pathway costs were primarily driven by the management of patients,

particularly in terms of those identified as carrying a BRCA mutation. The least expensive

pathways reflected the absence of BRCA testing and the smaller subsequent management

costs. The most expensive pathway reflected the cost of BRCA testing and the subsequent

high management costs incurred. Finally, George et al.(14) found that the introduction of a

mainstream pathway (where all women with mutations automatically received a genetics

appointment within 3–4 weeks from the test initiation) led to an incremental annual cost

saving of £2,655,565 due to a decrease of genetics appointments from approximately

13,000 to approximately 1,000 per year. However, this study was deemed to be of low

quality, and the findings should be interpreted with caution.

A 2016 systematic review by D’Andrea et al.(21) found nine economic evaluations of BRCA

testing in breast and ovarian cancer target populations. The review and studies identified by

D’Andrea et al.(21) were excluded from this systematic review (apart from the study by Kwon

et al.(17) which was included following handsearching) because they did not meet the

inclusion criteria (see Section 2 for the inclusion criteria and Appendix 4 for the list of

excluded studies). However, their findings are of relevance. Four main strategies were

identified by the authors:



Page 40 of 56

population-based (comprehensive or targeted) genetic screening of individuals

without cancer

family history-based (testing individuals without cancer but with a family history

suggestive of BRCA mutation) genetic screening

familial mutation-based (testing individuals without cancer but with a known familial

BRCA mutation) genetic screening

cancer-based (individuals with BRCA-related cancers) genetic screening.

D’Andrea et al.(21) concluded that population-based genetic screening is not cost-effective,

while family history- and cancer-based testing strategies are likely to be cost-effective,

although further cost-effectiveness analyses are required to consolidate this conclusion.

Importantly, unlike genetic testing for hereditary colorectal cancer (that is, Lynch

syndrome),(22) the review found no evidence to support BRCA testing in newly diagnosed

cases of ovarian cancer followed by cascade testing of relatives. Similar to the findings of

the cost analyses in this systematic review, they found that the cost-effectiveness of genetic

testing strategies was highly sensitive to the price of the genetic test.

There are two important limitations to our systematic review. Firstly, the search strategy

used to identify relevant literature applied a time filter that restricted results to 2011

onwards. Studies prior to 2011 were identified by handsearching of relevant papers,

however, identification in this manner is not systematic. This approach was adopted in

accordance with the search strategy underpinning the clinical evidence supporting this NCG.

Secondly, the clinical and economic evidence reviews were performed sequentially.

Therefore, the economic review comprised the formulation of refined review questions

based on the clinical findings. Formulation of more broadly defined review questions from

the outset of guideline development would likely identify a larger quantity of relevant

literature. However, the sequential nature of the review ensures that, where available, the

recommendations are informed by economic evidence.

4.1 Conclusion

There is a lack of high quality economic evidence in relation to the costs and cost-

effectiveness of technologies for the diagnosis and staging of ovarian cancer. Of the nine

review questions in this systematic review, economic evidence was unavailable for seven.

One low quality economic study was identified that considered PET-CT for restaging of

patients with a suspected relapse of ovarian cancer. The study compared whole body

contrast enhanced CT only, PET-CT and PET-CT following a negative CT. PET-CT for all

women with a suspected recurrence of ovarian cancer was the most cost-effective strategy,

and this was both less costly and more effective than PET-CT following a negative CT. The

guideline recommendation that PET-CT should be considered only for patients with a high

suspicion of relapse of ovarian cancer if CT thorax, abdomen and pelvis does not



Page 41 of 56

demonstrate recurrence, differs to the pathway included in this low quality economic study

which means that the results are not directly transferable. Therefore, the cost-effectiveness

of this recommendation is unknown.

There is no published literature on the cost-effectiveness of genetic testing in Ireland. Based

on the limited international literature identified in this systematic review — four economic

studies were from the UK and one was from the US —the international economic evidence

is contradictory in its findings and may not be applicable to the Irish context given that

genetic testing of relatives of the index case is not explicitly recommended in this guideline.

Further cost-effectiveness analyses are required to determine the cost-effectiveness of

technologies for the diagnosis and staging of ovarian cancer. Additionally, Irish context-

specific analyses of the cost-effectiveness of the following are required:

1. PET-CT for re-staging of patients with suspected relapse of ovarian cancer

2. universal genetic testing in women with non-mucinous tubo-ovarian cancer.



Page 42 of 56

5. References

1. Department of Health, 2017. National Cancer Strategy 2017 - 2016. 2. National Cancer Registry, 2017. Cancer in Ireland 1994-2015 with estimates for 2015-

2017: Annual Report of the National Cancer Registry. NCR, Cork, Ireland. 3. Grewal K, Hamilton W, Sharp D. Ovarian cancer prediction: development of a scoring

system for primary care. BJOG : an international journal of obstetrics and gynaecology. 2013;120(8):1016-9.

4. ECIS - European Cancer Information System. [Available from: https://ecis.jrc.ec.europa.eu/]. 2018.

5. Health Information and Quality Authority. Guidelines for the Retrieval and Interpretation of Economic Evaluations of Health Technologies in Ireland. [Available from: https://www.hiqa.ie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Lit.pdf]. 2014.

6. Health Information and Quality Authority, 2018. Guidelines for the Economic Evaluation of Health Technologies in Ireland. [Available from: https://wwwhiqaie/sites/default/files/2018-01/HIQA_Economic_Guidelines_2018pdf].

7. Hill K, Goldstein RS, Guyatt GH, Blouin M, Tan WC, Davis LL, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ. 2010;182(7):673-8.

8. Health Information and Quality Authority. Guidelines for the Retrieval and Interpretation of Economic Evaluations of Health Technologies in Ireland. [Available from: https://wwwhiqaie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Litpdf]. 2014.

9. PROSPERO CRD42018104527. [Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018104527].

10. Evers S, Goossens M, De Vet H, van Tulder M, A. A. Criteria list for assessment of methodological quality of economic evaluations: Consensus on Health Economic Criteria. International Journal of Technology Assessment in Health Care. 2005;21(2):240-5.

11. Caro JJ, Eddy DM, Kan H, Kaltz C, Patel B, Eldessouki R, et al. Questionnaire to Assess Relevance and Credibility of Modeling Studies for Informing Health Care Decision Making: An ISPOR-AMCP-NPC Good Practice Task Force Report. Value in Health. 2014(17 ):174-82.

12. Mansueto M, Grimaldi A, Mangili G, Picchio M, Giovacchini G, Vigano R, et al. Positron emission tomography/computed tomography introduction in the clinical management of patients with suspected recurrence of ovarian cancer: a cost-effectiveness analysis. Eur J Cancer Care (Engl). 2009;18(6):612-9.

13. Eccleston A, Bentley A, Dyer M, Strydom A, Vereecken W, George A, et al. A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2017;20(4):567-76.

14. George A, Riddell D, Seal S, Talukdar S, Mahamdallie S, Ruark E, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Scientific reports. 2016;6:29506.

https://ecis.jrc.ec.europa.eu/%5d

https://www.hiqa.ie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Lit.pdf%5d

https://www.hiqa.ie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Lit.pdf%5d

https://wwwhiqaie/sites/default/files/2018-01/HIQA_Economic_Guidelines_2018pdf%5d

https://wwwhiqaie/sites/default/files/2018-01/HIQA_Economic_Guidelines_2018pdf%5d

https://wwwhiqaie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Litpdf%5d

https://wwwhiqaie/sites/default/files/2017-01/Guidelines-Retrieval-and-Interpretation-of-Econ-Litpdf%5d

http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018104527%5d



Page 43 of 56

15. Plaskocinska I, Shipman H, Drummond J, Thompson E, Buchanan V, Newcombe B, et al. New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Journal of Medical Genetics. 2016;53(10):655-61.

16. Slade I, Hanson H, George A, Kohut K, Strydom A, Wordsworth S, et al. A cost analysis of a cancer genetic service model in the UK. Journal of Community Genetics. 2016;7(3):185-94.

17. Kwon J.S., Daniels M.S., Sun C.C., K.H. L. Preventing Future Cancers by Testing Women With Ovarian Cancer for BRCA Mutations. Journal of Oncology. 2010;28(4).

18. Mangili G, Picchio M, Sironi S, Vigano R, Rabaiotti E, Bornaghi D, et al. Integrated PET/CT as a first-line re-staging modality in patients with suspected recurrence of ovarian cancer. Eur J Nucl Med Mol Imaging. 2006;34(5):658-66.

19. Gerke O, Hermansson R, Hess S, Schifter S, Vach W, Høilund-Carlsen PF. Cost-effectiveness of PET and PET/computed tomography: A systematic review. PET Clinics. 2015;10(1):105-24.

20. Hoskins PJ, Gotlieb WH. Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature. CA Cancer Journal for Clinicians. 2017;67(6):493-506.

21. D'Andrea E, Marzuillo C, De Vito C, Di Marco M, Pitini E, Vacchio MR, et al. Which BRCA genetic testing programs are ready for implementation in health care? A systematic review of economic evaluations. Genetics in Medicine. 2016;18(12):1171-80.

22. Snowsill T, Huxley N, Hoyle M, Jones-Hughes T, Coelho H, Cooper C, et al. A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome. Health Technology Assessment. 2014;18(58):i-xxxviii+1-405.

23. Scottish Intercollegiate Guidelines Network. Search filters. [Available from: http://www.sign.ac.uk/search-filters.html]. 2018.

http://www.sign.ac.uk/search-filters.html%5d



Page 44 of 56

Appendix 1: Search terms The search terms for the economic search were modified from the clinical searches

developed by Brendan Leen, Regional Librarian, HSE South. Search terms were developed

for each review question in the clinical search. Accordingly, the economic search was

conducted by combining a generic clinical search to each database and applying the relevant

economic filter.(23) The search terms for the Medline and Embase databases are presented

below.

Medline (via Ebsco Host)

1. (MH "Ovarian Neoplasms+")

2. ( TI ovar* N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

OR ( AB ovar* N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*)

)

3. S1 OR S2

4. (MH "Fallopian Tube Neoplasms")

5. ( TI fallopian N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

OR ( AB fallopian N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR

carcinom*) )

6. ( TI tubal N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) ) OR

( AB tubal N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

7. S4 OR S5 OR S6

8. S3 OR S7

9. S8 AND economic filter

Embase

1. (MH "Ovarian Neoplasms+")

2. ( TI ovar* N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) ) OR

( AB ovar* N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

3. S1 OR S2

4. (MH "Fallopian Tube Neoplasms")

5. ( TI fallopian N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

OR ( AB fallopian N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR

carcinom*) )

6. ( TI tubal N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) ) OR

( AB tubal N5 (cancer* OR neoplasm* OR malignan* OR tumor* OR tumour* OR carcinom*) )

7. S4 OR S5 OR S6

8. S3 OR S7



Page 45 of 56

Economic filters


1. Economics/

2. "costs and cost analysis"/

3. Cost allocation/

4. Cost-benefit analysis/

5. Cost control/

6. Cost savings/

7. Cost of illness/

8. Cost sharing/

9. "deductibles and coinsurance"/

10. Medical savings accounts/

11. Health care costs/

12. Direct service costs/

13. Drug costs/

14. Employer health costs/

15. Hospital costs/

16. Health expenditures/

17. Capital expenditures/

18. Value of life/

19. Exp economics, hospital/

20. Exp economics, medical/

21. Economics, nursing/

22. Economics, pharmaceutical/

23. Exp "fees and charges"/

24. Exp budgets/

25. (low adj cost).mp.

26. (high adj cost).mp.

27. (health?care adj cost$).mp.



Page 46 of 56


28. (fiscal or funding or financial or finance).tw.

29. (cost adj estimate$).mp.

30. (cost adj variable).mp.

31. (unit adj cost$).mp.

32. (economic$ or pharmacoeconomic$ or price$ or pricing).tw.

33. Or/1-32

Embase

1. Health economics/exp

2. Socioeconomics/

3. Cost benefit analysis/

4. Cost effectiveness analysis/

5. Cost minimi?ation analysis/

6. Cost of illness/

7. Cost control/

8. Economic aspect/

9. Financial management/

10. Health care cost/

11. Health care financing/

12. hospital cost/

13. (fiscal or financial or finance or funding)ti,ab.

14. ((cost NEXT/1 variable*) OR (cost NEXT/1 estimate*) OR (unit NEXT/1 cost*)):ab,ti

15. or/1-14



Page 47 of 56

Appendix 2: Grey literature search

The following electronic sources were searched for economic evaluations relevant to the

research questions of this systematic review:

Centre for Health Economics and Policy Analysis (CHEPA) — available from

http://www.chepa.org/

Cost Effectiveness Analysis Registry — available from

http://healtheconomics.tuftsmedicalcenter.org/cear4/SearchingtheCEARegistry/SearchtheC

EARegistry.aspx

HTAi vortal — available from https://www.htai.org/index.php?id=579

Google Scholar and Google — available from https://scholar.google.com/,

https://www.google.ie

Health Service Executive (HSE) — available from https://www.hse.ie/eng/

Health Information and Quality Authority (HIQA) —available from

https://www.hiqa.ie/

Health Research Board (HRB) Ireland — available from http://www.hrb.ie/home/

Institute of Health Economics (Alberta Canada) — available from

https://www.ihe.ca/

Lenus — available from http://www.lenus.ie/hse/

National Centre for Pharmacoeconomics (NCPE) — available from

http://www.ncpe.ie/

National Coordinating Centre for Health Technology Assessment (NCCHTA) —

available from https://www.nihr.ac.uk/funding-and-support/funding-for-research-

studies/funding-programmes/health-technology-assessment/

National Institute for Health and Clinical Excellence (NICE) — available from

https://www.nice.org.uk/

NHS Evidence database (UK) — available from https://www.evidence.nhs.uk/

Open Grey — available from http://www.opengrey.eu/

World Health Organization (WHO) — available from http://www.who.int/en/

http://www.chepa.org/

http://healtheconomics.tuftsmedicalcenter.org/cear4/SearchingtheCEARegistry/SearchtheCEARegistry.aspx

http://healtheconomics.tuftsmedicalcenter.org/cear4/SearchingtheCEARegistry/SearchtheCEARegistry.aspx

https://www.htai.org/index.php?id=579

https://scholar.google.com/

https://www.google.ie/

https://www.hse.ie/eng/

https://www.hiqa.ie/

http://www.hrb.ie/home/

https://www.ihe.ca/

http://www.lenus.ie/hse/

http://www.ncpe.ie/

https://www.nihr.ac.uk/funding-and-support/funding-for-research-studies/funding-programmes/health-technology-assessment/

https://www.nihr.ac.uk/funding-and-support/funding-for-research-studies/funding-programmes/health-technology-assessment/

https://www.nice.org.uk/

https://www.evidence.nhs.uk/

http://www.opengrey.eu/

http://www.who.int/en/



Page 48 of 56

Appendix 3: Excluded studies

List of studies excluded due to full text unavailability (including letters, commentaries, editorials,

abstracts, protocols and conference papers) 1. Clinical Interventional Oncology, CIO 2012. Journal of Vascular and Interventional Radiology.

2011;22(12).

2. Abraham PS, Greene M. The impact of different types of payer on healthcare resource utilization

and costs among cancer patients in India. Value in Health. 2017;20(5):A131.

3. Alvarez-Secord A, Barnett J, Ledermann J, Peterson B, Myers E, Havrilesky L. Cost-effectiveness of

homologous recombination defect testing to target PARP inhibitor use in platinum-sensitive

recurrent ovarian cancer. Gynecologic Oncology. 2012;125:S92-S3.

4. Armstrong A, DeBernardo R, Knight J, Otvos B. Evaluation of the cost of CA-125 measurement,

office visit and CT scan in the diagnosis of recurrent ovarian cancer. Gynecologic Oncology.

2013;130(1):e28-e9.

5. Bang HJ, Littrup PJ, Currier BP, Goodrich DJ, Kassem M. Cryoablation of metastatic ovarian cancer

for local tumor control: Improved survival and estimated cost-effectiveness. Journal of Vascular

and Interventional Radiology. 2011;22(12):1785.e15.

6. Barnett J, Alvarez-Secord A, Cohn D, Leath C, Peterson B, Myers E, et al. Cost-effectiveness of a

predictive biomarker for bevacizumab responsiveness in the primary treatment of ovarian cancer.

Gynecologic Oncology. 2012;125:S66.

7. Biltaji E, Bellows B, Stenehjem D, Brixner D. Validation of a cost-effectiveness model comparing

accuracy of genetic tests for BRCA mutations. Value in Health. 2016;19(3):A79.

8. Brunel-Geuder L, Fasching PA, Bani MR, Löhberg CR, Jud SM, Schrauder MG, et al. Is the care for

women with a hereditary risk for breast and ovarian cancer fundable at all?-Health-economic

analysis of genetic testing intensified early cancer detection and prophylactic surgery from the

perspective of the health care system and the health care provider. Oncology Research and

Treatment. 2014;37:33.

9. Chun K, Brown A, Ng K, Denroche R, McPherson J. Comparison of next generation sequencing with

traditional sequencing and MLPA for BRCA1 and BRCA2 testing. Current Oncology.

2012;19(2):e100.

10. Cicchetti A, Ruggeri M, Di Brino E. Cost-effectiveness of a preventive testing strategy in relatives of

patients with BRCA mutated ovarian cancer versus a no test strategy. Value in Health.

2016;19(7):A696.

11. Danner M, Müller D, Schmutzler R, Rhiem K, Engel C, Stollenwerk B, et al. Economic modeling of

risk-adapted screen-and-treat strategies in women at high-risk for breast or ovarian cancer. Value

in Health. 2016;19(7):A737-A8.

12. Dyer M, Vereecken W, Worrall J, George A, Rahman N. Cost-effectiveness analysis of testing for

BRCA mutations in women diagnosed with ovarian cancer and their female first-degree relatives: A

UK health service perspective. Value in Health. 2014;17(7):A643-A4.

13. Eccleston A, Bentley A, Dyer M, Vereecken W, George A, Rahman N. Cost-effectiveness analysis of

testing for BRCA1 and BRCA2 mutations in women diagnosed with ovarian cancer and their female

first-and second degree relatives using a discrete event simulation: A UK health service

perspective. Value in Health. 2015;18(7):A361.

14. Fust K, Li X, Maschio M, Barron R, Weinstein MC, Parthan A, et al. Cost-effectiveness of prophylaxis

treatment strategies for febrile neutropenia in recurrent ovarian cancer patients. Value in Health.

2013;16(3):A140.

15. Geisler J, Apoian A, Manahan K. Appropriate tumor markers for premenopausal women with an



Page 49 of 56


abstracts, protocols and conference papers) ovarian mass: A cost effectiveness analysis. International Journal of Gynecological Cancer.

2017;27:1502.

16. Grann V, Ashby-Thompson M. Role of genetic testing for screening and prevention for ovarian

cancer. JAMA Internal Medicine. 2013;173(2):103-4.

17. Guzman S, Cervantes A, Rodrigez M, Morales-Vásquez F, Soto H, Marquez M. Comparative

estimation of the out-of-pocket expenses and indirect costs associated ovarian cancer and

parkinson's disease. Value in Health. 2016;19(3):A144.

18. Hensley ML. Big costs for little gain in ovarian cancer. Journal of Clinical Oncology.

2011;29(10):1230-2.

19. Hirst C, Moss S, De Richter P. Profile of BRCA testing in ovarian cancer patients in the United States

and European union. Current Oncology. 2014;21(2):e372.

20. Johnson TV, Master VA. Sensitive biomarkers of cancer recurrence and metastasis: Inexpensive

tools to cut costs and reduce radiation exposure among cancer patients. Molecular Diagnosis and

Therapy. 2012;16(1):13-4.

21. Kaldate R, Huston A, McCoy H, Cardeiro D, Noyes K. Cost effectiveness analysis of genetic testing

for breast and ovarian cancer susceptibility genes: BRCA1 and BRCA2. Breast Journal.

2014;20(3):325-6.

22. Khodorovich OS, Solodkiy VA, Derkach EV. Cost-effectiveness analysis of cancer risk reduction

strategies for BRCA mutation carriers. Value in Health. 2016;19(7):A736.

23. Li Q, Holland M, Huston A, Noyes K. Cost effectiveness analysis of BRCA1/2 genetic testing. Cancer

Research. 2011;71(24).

24. Lopez-Acevedo M, Buchanan AH, Secord AA, Lee PS, Fountain C, Myers ER, et al. Cost comparison

among different genetic testing strategies in women with epithelial ovarian cancer. Gynecologic

Oncology. 2015;137:171.

25. Lu CY. Economic evaluation of whole-genome sequencing in healthy individuals: What can we learn

from CEAs of whole-body CT screening? Genetics in Medicine. 2016;18(1):103-4.

26. Manchanda R. Brca testing in high-risk populations. Clinical Cancer Research. 2015;21(16).

27. Manchanda R, Legood R, Burnell M, McGuire A, Legood R, Loggenberg K, et al. Population based

testing for BRCA mutations is highly cost-effective compared to family history based approach: A

health-economic decision analytical model from the GCaPPS trial. International Journal of

Gynecological Cancer. 2013;23(8):188-9.

28. Manchanda R, Legood R, Burnell M, McGuire A, Loggenberg K, Wardle J, et al. Population-based

testing for BRCA mutations (compared to familyhistory based testing) may be cost saving in

Ashkenazi-Jews: A health-economics decision analytical model. International Journal of


29. Meys EMJ, Rutten IJG, Kruitwagen RFPM, Slangen BF, Bergmans MGM, Mertens HJMM, et al.

Investigating the performance and cost-effectiveness of the simple ultrasound-based rules

compared to the risk of malignancy index in the diagnosis of ovarian cancer (SUBSONiC-study):

Protocol of a prospective multicenter cohort study in the Netherlands. BMC Cancer. 2015.

30. Minocha S. Predictability of RMI and RI for malignancy in ovarian masses-Value in low cost and

secondary care setting. BJOG: An International Journal of Obstetrics and Gynaecology.

2018;125:178.

31. Morscher RJ, Pölsler L, Fiegl H, Wimmer K, Oberaigner W, Müller-Holzner E, et al. Identification of a

highly prevalent BRCA1 stop mutation c.4183C > T in the tyrolean lower inn valley region enables

costeffective testing for inherited breast and ovarian cancer. Medizinische Genetik.



Page 50 of 56


abstracts, protocols and conference papers) 2015;27(1):118.

32. Olson MA, Tutera S, Williams C. Implementation of genetic sequencing in breast and ovarian

cancer patients: A cost analysis. Cancer Research. 2015;75(15).

33. Paez MC, Riggi MC, Gogorza SJ, Petracchi F. Molecular test for BRCA 1 and 2: Hereditary breast and

ovarian cancer syndrome. Analysis of cost effectiveness of its implementation. Cancer Research.

2018;78(4).

34. Pavlik E, Miller RW, Ueland FR, DeSimone CP, Podzielinski I, Elder J, et al. Improved effectiveness in

ovarian cancer screening using serial transvaginal ultrasound-morphology indexing-increased

survival, reduced false positives & cost savings. International Journal of Gynecological Cancer.

2012;22:E105.

35. Pavlik EJ, Van Nagell Jr JR. Early detection of ovarian tumors using ultrasound. Women's Health.

2013;9(1):39-57.

36. Randy Vogenberg F. Economic impact of using tests to guide the treatment of patients with ovarian

cancer. American Health and Drug Benefits. 2017;10(7):359.

37. Reade C, Tsoi B, Tanvejsilp P, Hanson M, Marcotte M, Goeree R. A systematic review of economic

evaluations on the treatment of ovarian cancer: What have we learned in the past 10 years?

Gynecologic Oncology. 2013;130(1):e41.

38. Romagnolo C, Maggino T, Gion M, Berto P. Introduction of novel biomarker testing for ovarian

cancer: Budget impact analysis for an italian regional health care service. Value in Health.

2012;15(7):A348.

39. Romero Prada ME, Roa Cardenas NC, Vasquez Melo EC, Acosta JA. Economic impact analysis of

brca1 and BRCA2 genetic tests in women with advanced stage ovarian cancer in the Colombian

context. Value in Health. 2017;20(5):A240.

40. Scalici J, Straughn J, Estes J, Leath C, Finan M, Rocconi R. Is BRCA mutation screening a cost-

effective strategy to improve targeted therapy in serous epithelial ovarian cancer? Gynecologic

Oncology. 2013;130(1):e106.

41. Sen M, Agrawal P, Vittal PV, Ghosh M, Sheela ML, Vishwanath D, et al. Analytical and technical

validation of a cost-effective diagnostic test for BRCA1, BRCA2 and TP53. Cancer Research.

2015;75(15).

42. Shadbolt CL. Ovarian masses and the role of MRI. Journal of Medical Imaging and Radiation

Oncology. 2014;58:127.

43. Sroczynski G, Gogollari A, Kühne F, Pashayan N, Widschwendter M, Siebert U. A systematic review

on cost-effectiveness of early detection and prevention strategies for ovarian cancer. International

Journal of Gynecological Cancer. 2017;27:542.

44. Stein JC, Pearce K, Samayoa L. Modeling a histology-based referral system to reduce breast and

ovarian cancer in BRCA1/2 carriers. Obstetrics and Gynecology. 2015;125:77S-8S.

45. Straubhar A, Soisson A, Dodson M, Simons E, Kohlmann W, Jarboe E, et al. Cost analysis of

universal screening for lynch syndrome in patients with endometrial cancer. Gynecologic Oncology.

2016;143(1):214.



Page 51 of 56

List of excluded studies due to study design (for example, systematic review or no economic analysis)

1. Bercow AS, Chen L, Chatterjee S, Tergas AI, Hou JY, Burke WM, et al. Cost of care for the initial

management of ovarian cancer. Obstetrics and Gynecology. 2017;130(6):1269-75.

2. D'Andrea E, Marzuillo C, De Vito C, Di Marco M, Pitini E, Vacchio MR, et al. Which BRCA genetic

testing programs are ready for implementation in health care? A systematic review of economic

evaluations. Genetics in Medicine. 2016;18(12):1171-80.

3. D'Andrea E, Marzuillo C, Pelone F, De Vito C, Villari P. Genetic testing and economic evaluations: a

systematic review of the literature. Epidemiologia e prevenzione. 2015;39(4):45-50.

4. Gerke O, Hermansson R, Hess S, Schifter S, Vach W, Høilund-Carlsen PF. Cost-effectiveness of PET

and PET/computed tomography: A systematic review. PET Clinics. 2015;10(1):105-24.

5. Heinz S, De Richter P, Levent A, Moss S, Tyczynski J. Profile of BRCA testing in ovarian cancer

patients in the United States and European Union. Journal of Clinical Oncology. 2015;33(15).

6. Hendricks-Sturrup R. The cost-effectiveness and value of gynecological cancer biomarker screening

in financially vulnerable female populations. Journal of Cancer Policy. 2016;9:14-7.

7. Hermans AJ, Kluivers KB, Siebers AG, Wijnen MHWA, Bulten J, Massuger LFAG, et al. The value of

fine needle aspiration cytology diagnosis in ovarian masses in children and adolescents. Human

Reproduction. 2016;31(6):1236-40.

8. Hoskins PJ, Gotlieb WH. Missed therapeutic and prevention opportunities in women with BRCA-

mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling

and BRCA testing: A review of the literature. CA Cancer Journal for Clinicians. 2017;67(6):493-506.

9. Kumar Dhingra V, Kand P, Basu S. Impact of FDG-PET and -PET/CT imaging in the clinical decision-

making of ovarian carcinoma: An evidence-based approach. Women's Health. 2012;8(2):191-203.

10. Kwon JS. Cost-effectiveness of Ovarian Cancer Prevention Strategies. Clinical Obstetrics and

Gynecology. 2017;60(4):780-8.

11. Liang M, Walsh C, Farias-Eisner R, Cohen J. Genetic counseling and testing in ovarian cancer from

the patient perspective. Gynecologic Oncology. 2016;143(1):220.

12. Liang MI, Wong DH, Walsh CS, Farias-Eisner R, Cohen JG. Cancer Genetic Counseling and Testing:

Perspectives of Epithelial Ovarian Cancer Patients and Gynecologic Oncology Healthcare Providers.

Journal Of Genetic Counseling. 2018;27(1):177-86.

13. Pagano E, Sobrero S, Cavallero C, Zola P, Ciccone G. Economic considerations on the follow-up

practice in gynecologic cancers: Few lights and many shadows from a literature review.

International Journal of Gynecological Cancer. 2015;25(7):1144-50.

14. Pavlik E, Miller R, Ueland F, DeSimone C, Elder J, Hoff J, et al. Achievable balanced costs in ovarian

cancer screening using serial transvaginal ultrasound by preventing progression. Gynecologic

Oncology. 2013;130(1):e93.

15. Prapa M, Solomons J, Tischkowitz M. The use of panel testing in familial breast and ovarian cancer.

Clinical Medicine, Journal of the Royal College of Physicians of London. 2017;17(6):568-72.

16. Schneider JE, Sidhu MK, Doucet C, Kiss N, Ohsfeldt RL, Chalfin D. Economics of cancer biomarkers.

Personalized Medicine. 2012;9(8):829-37.

17. Sfakianos GP, Havrilesky LJ. A review of cost-effectiveness studies in ovarian cancer. Cancer control

: journal of the Moffitt Cancer Center. 2011;18(1):59-64.

18. Sharma V, Sundar SS, Breheny K, Monahan M, Sutton AJ. Methods Used in Economic Evaluations of

Testing and Diagnosis for Ovarian Cancer: A Systematic Review. International journal of

gynecological cancer : official journal of the International Gynecological Cancer Society.

2016;26(5):865-72.

19. Snowsill T, Huxley N, Hoyle M, Jones-Hughes T, Coelho H, Cooper C, et al. A systematic review and

economic evaluation of diagnostic strategies for Lynch syndrome. Health Technology Assessment.



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List of excluded studies due to study design (for example, systematic review or no economic analysis)

2014;18(58):i-xxxviii+1-405.

20. Stuppia L. BRCA1 and BRCA2 molecular testing in women with different risk of hereditary breast

cancer: Cost/effectiveness and psychological implications. Current Women's Health Reviews.

2012;8(1):12-6.

21. Sturgeon CM, Duffy MJ, Walker G. The National Institute for Health and Clinical Excellence (NICE)

guidelines for early detection of ovarian cancer: The pivotal role of the clinical laboratory. Annals of

Clinical Biochemistry. 2011;48(4):295-9.

22. Testa AC, Di Legge A, Virgilio B, Bonatti M, Manfredi R, Mirk P, et al. Which imaging technique

should we use in the follow up of gynaecological cancer? Best Practice and Research: Clinical

Obstetrics and Gynaecology. 2014;28(5):769-91.

23. Winn AN, Ekwueme DU, Guy GP, Neumann PJ. Cost-Utility Analysis of Cancer Prevention,

Treatment, and Control: A Systematic Review. American Journal of Preventive Medicine.

2016;50(2):241-8.

Studies excluded due to ineligible population (for example, analysis of breast cancer patients only)

1. Norum J, Grindedal EM, Heramb C, Karsrud I, Ariansen SL, Undlien DE, et al. BRCA mutation carrier

detection. A model-based cost-effectiveness analysis comparing the traditional family history

approach and the testing of all patients with breast cancer. ESMO Open. 2018;3(3):e000328-e.

2. Pennington M, Gentry-Maharaj A, Karpinskyj C, Miners A, Taylor J, Manchanda R, et al. Long-term

secondary care costs of endometrial cancer: A prospective cohort study nested within the United

Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). PLoS ONE. 2016;11(11).

3. Senter L, O'Connor M, Oriyo F, Sweet K, Toland AE. Linking distant relatives with BRCA gene

mutations: Potential for cost savings. Clinical Genetics. 2014;85(1):54-8.

Studies excluded due to ineligible intervention or comparator

1. Alexander VM, Gordon AN, Howard DH, Khanna N. Outcomes and cost analysis of surveillance

strategies after initial treatment for women with recurrent ovarian cancer. International Journal of


2. Antoñanzas F, Rodríguez-Ibeas R, Hutter MF, Lorente R, Juárez C, Pinillos M. Genetic testing in the

European Union: Does economic evaluation matter? European Journal of Health Economics.

2012;13(5):651-61.

3. Armstrong A, Otvos B, Singh S, Debernardo R. Evaluation of the cost of CA-125 measurement,

physical exam, and imaging in the diagnosis of recurrent ovarian cancer. Gynecologic Oncology.

2013;131(3):503-7.

4. Arvai K, Horváth P, Balla B, Tőkés AM, Tobiás B, Takács I, et al. Rapid and cost effective screening of

breast and ovarian cancer genes using novel sequence capture method in clinical samples. Familial

Cancer. 2014;13(4):583-9.

5. Brodsky BS, Owens GM, Scotti DJ, Needham KA, Cool CL. Economic impact of increased utilization

of multivariate assay testing to guide the treatment of ovarian cancer: Implications for payers.

American Health and Drug Benefits. 2017;10(7):351-8.

6. Chang Y, Near AM, Butler KM, Hoeffken A, Edwards SL, Stroup AM, et al. Economic evaluation

alongside a clinical trial of telephone versus in-person genetic counseling for BRCA1/2 mutations in

geographically underserved areas. Journal of Oncology Practice. 2016;12(1):e1-e13.



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7. Collet G, Parodi N, Cassinari K, Neviere Z, Cohen F, Gasnier C, et al. Cost-effectiveness evaluation of

pre-counseling telephone interviews before face-to-face genetic counseling in cancer genetics.

Familial Cancer. 2017:1-7.

8. Dinh TA, Rosner BI, Atwood JC, Boland CR, Syngal S, Vasen HFA, et al. Health Benefits and Cost-

Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population. Cancer

Prevention Research. 2010.

9. Drescher CW, Hawley S, Thorpe JD, Marticke S, McIntosh M, Gambhir SS, et al. Impact of screening

test performance and cost on mortality reduction and cost-effectiveness of multimodal ovarian

cancer screening. Cancer Prevention Research (Philadelphia, Pa). 2012;5(8):1015-24.

10. Forde GK, Hornberger J, Michalopoulos S, Bristow RE. Cost-effectiveness analysis of a multivariate

index assay compared to modified American College of Obstetricians and Gynecologists criteria

and CA-125 in the triage of women with adnexal masses. Current Medical Research and Opinion.

2016;32(2):321-9.

11. Hampel H, De La Chapelle A. How do we approach the goal of identifying everybody with Lynch

Syndrome? Familial Cancer. 2013;12(2):313-7.

12. Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. Cost-effectiveness of screening for ovarian cancer

amongst postmenopausal women: a model-based economic evaluation. BMC medicine.

2016;14(1):200.

13. Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. Erratum to: Cost-effectiveness of screening for

ovarian cancer amongst postmenopausal women: a model-based economic evaluation. BMC

medicine. 2017;15(1):31-.

14. Koffijberg H, van Zaane B, Moons KG. From accuracy to patient outcome and cost-effectiveness

evaluations of diagnostic tests and biomarkers: an exemplary modelling study. BMC Medical

Research Methodology. 2013;13(1):12.

15. Kulasingam S, Havrilesky L. Health economics of screening for gynaecological cancers. Best Practice

and Research: Clinical Obstetrics and Gynaecology. 2012;26(2):163-73.

16. Lim KK, Yoon SY, Teo SH, Mohd Taib NA, Shabaruddin FH, Dahlui M, et al. Cost effectiveness of

BRCA mutation testing for early-stage breast cancer patients with family history in Malaysia. Value

in Health. 2016;19(7):A889.

17. Lockwood S, Ritzert B. Cost-effectiveness of serum CA125 compared to transvaginal ultrasound as

a screening test for ovarian cancer: A systematic review protocol. JBI Database of Systematic

Reviews and Implementation Reports. 2013;11(10):89-106.

18. Manchanda R, Gordeev V, Antoniou A, Smith S, Lee A, Hopper J, et al. Cost-effectiveness of

systematic population based screening for BRCA1, BRCA2, RAD51C, RAD51D and BRIP1 gene

mutations in unselected general population women. International Journal of Gynecological Cancer.

2016;26:59-60.

19. Manchanda R, Legood R, Burnell M, McGuire A, Legood R, Loggenberg K, et al. Population based

testing for BRCA mutations is highly cost-effective compared to family history based approach: A

health-economic decision analytical model from the GCaPPS trial. International Journal of


20. Manchanda R, Legood R, Burnell M, McGuire A, Raikou M, Loggenberg K, et al. Cost-effectiveness

of population screening for BRCA mutations in Ashkenazi jewish women compared with family

history-based testing. Journal of the National Cancer Institute. 2014;107(1):380-.

21. Manchanda R, Legood R, Burnell M, McGuire A, Raikou M, Loggenberg K, et al. Cost-effectiveness

of population screening for BRCA mutations in Ashkenazi jewish women compared with family

history-based testing. Journal of the National Cancer Institute. 2015;107(1):380.



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22. Manchanda R, Loggenberg K, Gessler S, Sanderson S, Balogun N, Wardle J, et al. Population based

testing for high-penetrance dominant gene mutations: Initial results from the pilot phase of

GCaPPS. International Journal of Gynecological Cancer. 2012;22:S42-S3.

23. Manchanda R, Patel S, Antoniou AC, Levy-Lahad E, Turnbull C, Evans DG, et al. Cost-effectiveness of

population based BRCA testing with varying Ashkenazi Jewish ancestry. American Journal Of

Obstetrics And Gynecology. 2017;217(5):578.e1-.e12.

24. Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, et al. The cost-effectiveness of

screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening

(UKCTOCS). British Journal Of Cancer. 2017;117:619.

25. Moss H, Myers E, Berchuck A, Havrilesky LJ. Cost-effectiveness of ovarian cancer screening: An

analysis of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) from a U.S. health

system perspective. Journal of Clinical Oncology. 2017;35(15_suppl):6608-.

26. Moss HA, Berchuck A, Neely ML, Myers ER, Havrilesky LJ. Estimating Cost-effectiveness of a

Multimodal Ovarian Cancer Screening Program in the United States: Secondary Analysis of the UK

Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). JAMA oncology. 2018;4(2):190-5.

27. Muller D, Danner M, Rhiem K, Stollenwerk B, Engel C, Rasche L, et al. Cost-effectiveness of

different strategies to prevent breast and ovarian cancer in German women with a BRCA 1 or 2

mutation. The European journal of health economics : HEPAC : health economics in prevention and

care. 2018;19(3):341-53.

28. NICE. Tests in secondary care to identify people at high risk of ovarian cancer. 2017.

29. Patel S, Legood R, Evans DG, Turnbull C, Antoniou AC, Menon U, et al. Cost effectiveness of

population based BRCA1 founder mutation testing in Sephardi Jewish women. American Journal of

Obstetrics and Gynecology. 2018;218(4):431.e1-.e12.

30. Piovano E, Cavallero C, Fuso L, Viora E, Ferrero A, Gregori G, et al. Diagnostic accuracy and cost-

effectiveness of different strategies to triage women with adnexal masses: a prospective study.

Ultrasound in obstetrics & gynecology : the official journal of the International Society of

Ultrasound in Obstetrics and Gynecology. 2017;50(3):395-403.

31. Rosenkrantz AB, Xue X, Gyftopoulos S, Kim DC, Nicola GN. Variation in Downstream Relative Costs

Associated With Incidental Ovarian Cysts on Ultrasound. Journal of the American College of

Radiology. 2018.

32. Schwartz MD, Valdimarsdottir HB, Peshkin BN, Mandelblatt J, Nusbaum R, Huang A-T, et al.

Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary

breast and ovarian cancer. Journal Of Clinical Oncology: Official Journal Of The American Society Of

Clinical Oncology. 2014;32(7):618-26.

33. Secord AA, Barnett JC, Ledermann JA, Peterson BL, Myers ER, Havrilesky LJ. Cost-Effectiveness of

brca1 and brca2 mutation testing to target parp inhibitor use in platinum-sensitive recurrent

ovarian cancer. International Journal of Gynecological Cancer. 2013;23(5):846-52.

34. Wiwanitkit V. CA-125 and risk of malignancy index for screening for malignancy in fertile aged

females with ovarian cyst, which is more cost effectiveness? Indian Journal of Medical and

Paediatric Oncology. 2013;34(2):72-3.



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Appendix 4: Quality assessment and transferability of evidence Figure 1: Quality assessment of included studies

Key: RQ — review question



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Figure 2: Transferability of included studies

Key: NA — not applicable; RQ — review question.

Documents

Diagnosis and staging of patients with ovarian cancer