Preventive medicines
Evidence review M
NICE Guideline, No. 241
Preventive medicines
Review question
How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
Introduction
Women with a familial ovarian cancer risk are motivated to take steps to reduce their risk of developing ovarian cancer. These women are offered surgery to remove their tubes and ovaries to mitigate this risk; however, surgery comes with its own inherent risk which may be unacceptable to some. Other women with familial ovarian cancer do not wish to have surgery due to its impact on fertility. Finally, others are not well enough to have the risk reducing surgery. In addition, surgery cannot reduce the risk of developing ovarian cancer completely. Therefore, other ways to reduce an individual’s risk of familial ovarian cancer are a priority to those with an inherited risk and their clinicians. It is known that certain medications can reduce the risk of ovarian cancer in all or specific inherited ovarian cancer syndromes. The evidence review will consider those medications, the evidence that supports them, their side effects and the effective doses needed to reduce ovarian cancer in those with a familial ovarian cancer risk.
Summary of the protocol
See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
For further details see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
Effectiveness evidence
Included studies
Eight studies were included for this review, 1 systematic review of case-control and cohort studies (van Bommel 2023), 3 individual patient data meta-analyses (Hurwitz 2021, Hurwitz 2022, Hurwitz 2023), 1 cohort study (Michels 2018) and 3 case-control studies (Gross 1992, McLaughlin 2007, Vicus 2009).
Three individual patient data meta-analyses (Hurwitz 2021, Hurwitz 2022, Hurwitz 2023) compared frequent/daily aspirin use to infrequent/no aspirin use. Although there was some overlap in the study participants included in these studies, the studies focused on, and analysed different populations, namely women with a history of ovarian cancer only (Hurwitz 2021), women with a history of both ovarian cancer or breast cancer (Hurwitz 2022) and women with genetic data available (Hurwitz 2023). One systematic review compared oral contraceptive use to no oral contraceptive use among BRCA1/2 carriers (van Bommel 2023). One cohort study (Michels 2018) compared oral contraceptive use to no oral contraceptive use. Three case-controls studies compared oral contraceptive use to no oral contraceptive use (Gross 1992, McLaughlin 2007, Vicus 2009).
The included studies are summarised in Table 2.
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
The landmark CAPP2 trial (Burn 2020) comparing aspirin to placebo for cancer prevention in people with Lynch syndrome could not be included as results were not reported separately for women.
Studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.
Summary of included studies
Summaries of the studies that were included in this review are presented in Table 2.
Table 2
Summary of included studies.
See the full evidence tables in appendix D and the forest plots in appendix E.
Summary of the evidence
Frequent aspirin use versus infrequent or no aspirin use
The evidence showed no important differences from frequent aspirin use in terms of ovarian cancer incidence relative to no or non-frequent use in women at all levels of risk, and the evidence also showed no evidence of an important difference in women with a family history of ovarian or breast cancer or in women with a family history of ovarian cancer only. This was also the case for different histological types of ovarian cancer in women with a family history of ovarian or breast cancer. This evidence was of low to moderate quality. Very low quality evidence showed no important difference in non-mucinous epithelial ovarian cancer incidence between frequent and infrequent/no aspirin use in women at all levels of risk.
The evidence also showed no evidence of important differences from frequent aspirin use on ovarian cancer risk relative to no or non-frequent use in women with a polygenic risk score for ovarian cancer at or above the median value, below the median value, or in any of the quintiles of polygenic risk score, with the exception of women with a polygenic risk score in the 60 – 80 percentile where an important benefit of frequent aspirin use was observed. However, this is likely to be a spurious finding since the interaction between polygenic score quintile and frequency of aspirin use was not statistically significant. There was also no evidence of important differences for the different histological types of ovarian cancer in women with a polygenic risk score for ovarian cancer at or above the median value. This evidence was of very low to low quality.
Oral contraceptive use versus no oral contraceptive use
When comparing oral contraceptive with no oral contraceptive use in women with BRCA1 or BRCA2 mutations there was an important benefit of oral contraceptive use in terms of reduced ovarian cancer incidence. This evidence was rated as moderate to high quality. However, there was some very low quality evidence that showed no evidence of important difference between oral contraceptive use and no use in terms of ovarian cancer incidence in women with BRCA1 mutation only. However, in this study the population was mixed, that is women with ovarian cancer and a history of breast cancer.
Different duration of oral contraceptive use versus no oral contraceptive use
When comparing different durations (0 to 1 year, 1.1 to 3 years, 3.1 to 5 years and more than 5 years) of oral contraceptive with no oral contraceptive use in women with BRCA1 or BRCA2 mutations there was an important benefit of oral contraceptive use in terms of reduced ovarian cancer incidence. This evidence was rated as moderate to high quality. However, other very low to low quality evidence showed no evidence of important differences between short-term (3 to 11 months) or longer term (1 to 4 years, 5 to 9 years, more than 10 years) use and no oral contraceptive use in terms of ovarian cancer incidence in women with a family history of ovarian cancer.
No evidence was identified for health related quality of life, treatment related adverse effects or overall survival.
See appendix F for full GRADE tables.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.
A single economic search was undertaken for all topics included in the scope of this guideline. See supplementary material 2 for details.
Excluded studies
Economic studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.
Summary of included economic evidence
No economic studies were identified which were applicable to this review question.
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.
The committee’s discussion and interpretation of the evidence
The outcomes that matter most
Ovarian cancer incidence was prioritised as a critical outcome by the committee. This is because the aim of the question was to determine whether medicines could prevent ovarian cancer in women at increased risk. Additionally, health related quality of life was also chosen as a critical outcome to capture the impact of medicines on the day-to-day lives of these women, including psychological and emotional factors.
Treatment related adverse effects was selected as an important outcome because any benefits in terms of incidence of ovarian cancer must be balanced against side effects caused by the medicines themselves. Finally overall survival was an important outcome because both prevention of ovarian cancer and serious adverse effects of treatment could impact overall survival and the balance of these is an important consideration when making treatment decisions.
The quality of the evidence
The quality of the evidence was assessed using GRADE and ranged from very low to high quality. Evidence was downgraded mainly due to imprecision in the effect estimates, as well as risk of bias: in some studies aspirin use was determined retrospectively by asking women to recall their usage. The evidence was also downgraded for indirectness in some cases due to the inclusion of women at all risk levels or for unexplained heterogeneity or because of the indirect study population (women with ovarian and breast cancer). Moreover, in 1 case-control study cases and controls were not matched.
No evidence was identified for health-related quality of life, treatment related adverse effects or overall survival. Due to the lack of evidence on some outcomes the committee also relied on their experience when making recommendations.
Benefits and harms
Aspirin
The committee noted that there was some overlap in the study participants included in the studies comprising this evidence but also that the studies focused on and analysed different populations. They discussed the evidence that showed no important difference in terms of ovarian cancer incidence when comparing frequent aspirin use to no or non-frequent use in women at all levels of risk and the evidence that showed no evidence of an important difference either in women with a family history of ovarian or breast cancer, in women with a family history of ovarian cancer only and in women with all levels of polygenic risk score values. They noted that this was also the case for different histological types of ovarian cancer. They therefore concluded that aspirin did not show a protective effect in terms of ovarian cancer and agreed that there was insufficient evidence to recommend the general use of aspirin for women with high risk of familial ovarian cancer. So, the committee did not recommend it for the sole purpose of reducing ovarian cancer risk. They discussed the quality of the evidence and noted that it was very low to moderate, despite the evidence not being of the highest quality rating it was consistent with their experience in expertise and so they did not recommend it for general protective use for ovarian cancer. The committee noted that there was existing NICE guidance on the use of aspirin to reduce the risk of colorectal cancer in people with Lynch syndrome. As people with Lynch syndrome were included in the scope of this guideline, the committee felt it was important to make cross reference to the NICE colorectal cancer guideline to ensure they were aware of this recommendation.
Combined oral contraceptives
The committee discussed the evidence for both comparisons (oral contraceptive use versus no use and different durations of use versus no use) that showed that there was an important benefit in reducing the risk of ovarian cancer associated with oral contraceptive. Whilst this was moderate to high quality evidence the committee drew on their knowledge that long-term use of oral contraceptives increased risk of breast cancer. They noted that this rather than the evidence quality was the important factor in clinical decision making and the strength of the recommendation that can be made because it is the balance between the protective benefit in relation to ovarian cancer and the risk of breast cancer that needs to be weight up. Although breast cancer was not an outcome in this evidence review, the committee agreed that this increased risk of breast cancer needs to be taken into account when thinking about oral contraceptives to prevent ovarian cancer. They agreed that the balance of risks and benefits will depend on the individual (for example how strong the family history is, which pathogenic variant the person may have and other potential risk factors). They therefore decided to only recommend oral contraceptives as a preventive medicine in particular circumstances: when the reduction in ovarian cancer risk (based on for example age, family history) may outweigh an increased breast cancer risk, and after taking into account whether the timing of risk-reducing surgery is appropriate or not (for example, it may not be appropriate because of age and planned pregnancy).
In the committee’s experience people are not always fully informed about the potential risks (increased risk of developing breast cancer) and benefits (reduced risk of developing ovarian cancer) of combined oral contraceptives which is necessary for informed decision making.
Research recommendation
The committee noted a lack of relevant evidence on preventive medicines and its inconsistency in women at increased risk of ovarian cancer to support decision making. They thought that some women may not want to undergo risk-reducing surgery and preventative medicine would then be a good option. Therefore they agreed to make a research recommendation on the effectiveness on preventive medicines.
Cost effectiveness and resource use
No existing economic evidence was identified for this review. The recommendations in this area reinforce current practice and implementing them will not require additional resources. Furthermore, the recommendations regarding oral contraceptives to prevent ovarian cancer will only apply to a small number of people since risk-reducing surgery is the preferred first-line treatment option for the majority of people.
Recommendations supported by this evidence review
This evidence review supports one cross reference and recommendations 1.7.1 to 1.7.43 and research recommendation 6 (on primary preventive medicines) in the NICE guideline.
References – included studies
Gross 1992
Gross, T P, Schlesselman, J J, Stadel, B V et al. The risk of epithelial ovarian cancer in short-term users of oral contraceptives. American journal of epidemiology 136(1): 46–53, 1992 [PubMed: 1415131]Hurwitz 2021
Hurwitz, Lauren M; Michels, Kara A; Cook, Michael B et al. Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two large U.S. cohorts. Cancer causes & control: CCC; vol. 32 (no. 1); 57–65, 2021 [PMC free article: PMC7855934] [PubMed: 33104910]Hurwitz 2022
Hurwitz, Lauren M, Townsend, Mary K, Jordan, Susan J et al. Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 40(36): 4207–4217, 2022 [PMC free article: PMC9916035] [PubMed: 35867953]Hurwitz 2023
Hurwitz, Lauren M, Webb, Penelope M, Jordan, Susan J et al. Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility. JAMA network open 6(2): e230666, 2023 [PMC free article: PMC9958519] [PubMed: 36826816]McLaughlin 2007
McLaughlin John R, Risch, Harwey A, Lubinski, Jan et al. Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. The Lancet. Oncology; 2007; vol. 8 (no. 1); 26–34, 2007 [PubMed: 17196508]Michels 2018
Michels, Kara A, Pfeiffer, Ruth M, Brinton, Louise A et al. Modification of the Associations Between Duration of Oral Contraceptive Use and Ovarian, Endometrial, Breast, and Colorectal Cancers. JAMA oncology 4(4): 516–521, 2018 [PMC free article: PMC5885214] [PubMed: 29346467]Van Bommel 2023
van Bommel, Majke H D, IntHout, Joanna, Veldmate, Guus et al. Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis. Human reproduction update 29(2): 197–217, 2023 [PMC free article: PMC9976973] [PubMed: 36383189]Vicus 2009
Vicus D, Rosen B, Lubinski J, et al. Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers. Gynecol Oncol.115(1):135–137, 2009 [PMC free article: PMC3756313] [PubMed: 19577280]Burn 2020
Burn J, Sheth H, Elliott F et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet (London, England) 395(10240): 1855–1863, 2020 [PMC free article: PMC7294238] [PubMed: 32534647]
Effectiveness
Economic
No economic studies were identified which were applicable to this review question.
Other
Appendices
Appendix A. Review protocols
Appendix B. Literature search strategies
Appendix C. Effectiveness evidence study selection
Appendix D. Evidence tables
Appendix E. Forest plots
Forest plots for review question: How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
No meta-analysis was conducted for this review question and so there are no forest plots.
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Study selection for: How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
No economic evidence was identified which was applicable to this review question.
Appendix H. Economic evidence tables
Economic evidence tables for review question: How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
No economic evidence was identified which was applicable to this review question.
Appendix I. Economic model
Economic model for review question: How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
No economic analysis was conducted for this review question.
Appendix J. Excluded studies
Excluded studies for review question: How effective are preventive medicines for reducing the incidence of ovarian cancer for women at increased risk of familial ovarian cancer?
Excluded effectiveness studies
Table 9
Excluded studies and reasons for their exclusion.
Excluded economic studies
No economic evidence was identified for this review. See supplementary material 2 for further information.
Appendix K. Research recommendations – full details
Final
Evidence review underpinning recommendations 1.7.1 to 1.7.4 and research recommendation 6 in the NICE guideline
These evidence reviews were developed by NICE
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
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