Markov Monte Carlo Simulation Model Research Articles

Germline testing and somatic tumor testing for BRCA1/2 pathogenic variants in ovarian cancer: What is the optimal sequence of testing?

10585 Background: In 2020 ASCO recommended that all women with epithelial ovarian cancer have germline testing (GT) for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing (TT), to determine eligibility for PARP inhibitor (PARPi) therapy (GT-TT strategy). An alternate strategy is to start with tumor testing first, and to conduct germline testing only in those with a PV in the tumor, or a significant family history (TT-GT strategy). The objective was to conduct a cost-effectiveness analysis comparing the 2 testing strategies. Methods: A Markov Monte Carlo simulation model compared the costs (USD) and benefits of the 2 testing strategies. According to local empiric data, a sufficient tissue sample for TT was available in 99% of cases, otherwise the patient would only have GT. Sensitivity of TT was 99% for detecting germline PV. Only those with BRCA1/2 PV were eligible for PARPi. Primary outcomes included the number of women eligible for PARPi, with progression-free years of life (PFLY) gained based on SOLO1 data, and the incremental cost-effectiveness ratio (ICER). Monte Carlo simulation estimated the number of women who would have GT and TT, and the total with germline or somatic BRCA1/2 PV eligible for PARPi. Sensitivity analyses accounted for uncertainty around various parameters. Results: The GT-TT strategy was more effective but more costly than TT-GT in identifying patients eligible for PARPi. Table summarizes the average lifetime costs, benefits, and Monte Carlo simulation estimates for 10,000 women diagnosed with advanced epithelial ovarian cancer annually in the USA. The incremental benefit from the GT-TT strategy would be achieved at substantial cost to the health care system, with an ICER of $119,340 per PFLY gained relative to the TT-GT strategy. The results were highly sensitive to the sensitivity of TT to detect germline PV, and the costs of GT and TT. Assuming that GT was less than 50% of the cost of TT, the sensitivity of TT had to exceed 98% for the TT-GT strategy to be cost-effective. Conclusions: Although the ASCO recommended strategy of BRCA germline testing followed by tumor testing for those without a pathogenic variant may be more effective in identifying ovarian cancer patients for PARP inhibitor therapy, it is more costly. The ASCO strategy is justified if the sensitivity of tumor testing is not sufficiently high. However, assuming high tumor testing performance rates, tumor testing first followed by germline testing if there is a PV in the tumor and/or family history is a cost-effective strategy.[Table: see text]

BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer

BackgroundWomen with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing. MethodsA Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters. ResultsUniversal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy. ConclusionBRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown.

BRCA Mutation Testing for First-Degree Relatives of Women With High-Grade Serous Ovarian Cancer [4OP

INTRODUCTION: Women with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or BRCA2 mutation and are eligible for BRCA testing. Many are untested, therefore their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity or other personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate BRCA mutation testing for these FDR who are otherwise ineligible for testing. METHODS: A Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: 1) no BRCA testing; 2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers (“BRCA testing”); 3) universal RRBSO, without BRCA testing (“RRBSO”). Effectiveness was estimated in quality-adjusted life year (QALY) gains. Sensitivity analyses accounted for uncertainty around various parameters. The time horizon was 50 years. RESULTS: BRCA testing for female FDR of HGSC patients yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an ICER of $7,729 per QALY. BRCA testing was more effective and less costly than RRBSO (19.20 QALYs vs 18.48 QALYs, and $10,108.35 vs $13,959.20, respectively), therefore BRCA testing is the dominant strategy. Results were stable over a wide range of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 84% for RRBSO to be the preferred strategy. CONCLUSION: BRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when their BRCA mutation status is unknown.

Long-Term Consequences of Extended Endocrine Strategies for Premenopausal Breast Cancer [11OP

INTRODUCTION: Breast cancer is the most common cancer among women in America, and gynecologists often encounter these women in their practice. After 5 years of adjuvant tamoxifen, women with ER+ breast cancer benefit from extended endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) is required before starting an AI, but there is concern about the long-term outcomes (osteoporosis, heart disease) and costs of OA. METHODS: A Markov Monte Carlo simulation model estimated the costs and benefits of extended endocrine strategies in a hypothetical cohort of premenopausal women with ER+ cancer: (1) no further treatment; (2) tamoxifen for 5 years; (3) OA followed by AI for 5 years (OA/AI). Effectiveness was measured in years of life expectancy gain. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the American population over a 40-year horizon. RESULTS: Tamoxifen for 5 more years yielded a higher average discounted life expectancy gain than OA/AI (16.57 vs. 16.34 years) at lower average cost ($2,976 vs. $10,150). For 18,000 ER+ premenopausal women diagnosed annually, the simulation estimated 12,526, 11,508, and 10,289 deaths after no further treatment, tamoxifen and OA/AI respectively, but another 2,139 deaths from long-term consequences of OA. According to sensitivity analyses, women had to be over 50.8 years of age before OA/AI became cost-effective. CONCLUSION: As extended endocrine therapy for premenopausal ER+ breast cancer, another 5 years of tamoxifen is more effective and less costly than ovarian ablation followed by 5 years of aromatase inhibitor.

Long-term consequences of ovarian ablation for premenopausal breast cancer.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03years) and less costly ($1566) than GnRHa-AI (17.66years, $93,692) or BSO-AI (17.63years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78years, $25,368) than tamoxifen alone (16.55years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.

Costs and Benefits of Opportunistic Salpingectomy as an Ovarian Cancer Prevention Strategy

Evidence accumulated over the past decade suggests that the majority of ovarian cancers arise in the fallopian tube and not the ovary. This led to the recommendation that opportunistic salpingectomy be offered as an elective concurrent procedure for premenopausal women at average risk of ovarian cancer who undergo either hysterectomy for benign gynecologic conditions or surgical sterilization. It has been estimated that opportunistic salpingectomy could reduce the ovarian cancer risk by 20% to 40% over the next 20 years. There are few hard data, however, on the long-term risks and benefits associated with this procedure. Because a clinical trial is not feasible, a population-based cohort study is essential to establish the long-term risks, benefits, and cost-effectiveness of opportunistic salpingectomy. Such a cohort study would take many years to yield results; more timely data on the likely costs and benefits of this strategy could be obtained from a decision analytic model. The aim of this study was to conduct a cost-effectiveness analysis of opportunistic salpingectomy as an ovarian cancer prevention strategy in the general population. A Markov Monte Carlo simulation model was used to estimate the costs and benefits of opportunistic salpingectomy in a hypothetical cohort of premenopausal Canadian women undergoing hysterectomy for benign gynecologic conditions or surgical sterilization as permanent contraception. Three strategies were compared: hysterectomy alone, hysterectomy with salpingectomy, and hysterectomy with bilateral salpingo-oophorectomy (BSO). The main outcome measure was the incremental cost-effectiveness ratio. Effectiveness was calculated in terms of average years of life expectancy gain. Multiple sensitivity analyses accounted for uncertainty around various parameters, including treatment costs, age at surgery, and estimates of risk reduction attributable to salpingectomy. The number of ovarian cancer cases associated with each strategy was estimated in the simulation model. The model predicted that salpingectomy with hysterectomy would be less costly ($11,044 ± $1.56) and more effective (21.12 ± 0.02 years) than either hysterectomy alone ($11,207 ± $29.81, 21.10 ± 0.03 years) or BSO ($12,627 ± $13.11, 20.94 ± 0.03 years), respectively. The model also predicted that salpingectomy for sterilization would be marginally more costly than tubal ligation ($9720 ± $3.74 vs $9339 ± $26.74) but more effective (22.45 ± 0.02 vs 22.43 ± 0.02 years of life expectancy), with an incremental cost-effectiveness ratio of $27,278 per year of life gained. Results were stable over a wide range of treatment costs and estimates of risk reduction. In the Monte Carlo simulation model, salpingectomy reduced the risk of ovarian cancer by 38.1% (95% confidence interval, 36.5%–41.3%) compared with hysterectomy alone and 29.2% (95% confidence interval, 28.0%–31.4%) compared with tubal ligation. This analytic model shows that opportunistic salpingectomy with hysterectomy for benign conditions has the potential to decrease ovarian cancer risk at acceptable cost and that salpingectomy is a cost-effective alternative to use of tubal ligation for sterilization. These findings suggest that prophylactic salpingectomy should be considered in all women undergoing these procedures.

Intravenous Versus Oral Dexamethasone Premedication in Preventing Paclitaxel Infusion Hypersensitivity Reactions in Gynecological Malignancies

Dexamethasone premedication is required with paclitaxel to prevent infusion-related hypersensitivity reactions (HSRs). Both oral dexamethasone (PO-D; 20 mg 12 and 6 hours before paclitaxel) and intravenous dexamethasone (IV-D; 20 mg 30 minutes before paclitaxel) regimens are used. The optimal premedication regimen and management of patients after HSR are unclear. Data on HSRs in women receiving paclitaxel, 175 mg/m², every 3 weeks at Imperial College Healthcare Trust from May 2011 to February 2012 were obtained from the pharmacy database. During this period, dexamethasone premedication for paclitaxel was administered orally (PO-D; 20 mg 12 and 6 hours before paclitaxel) from May to August 2011, then changed to intravenous dexamethasone (IV-D; 20 mg 30 minutes before paclitaxel) for 3 months, and then reverted to PO-D from November 2011. There were 93 and 55 patients who received PO-D and IV-D before paclitaxel, respectively. Hypersensitivity reaction rates were pooled with those from published studies for analysis. Gynecologic oncology centers in the UK and Canada were surveyed regarding premedication and post-HSR management. A Markov Monte-Carlo simulation model compared costs and benefits of different strategies. Hypersensitivity reaction rates with PO-D and IV-D were 5.4% (5/93) versus 14.5% (8/55) (P = 0.07) in Imperial College Healthcare Trust patients, and 6.8% (20/290) versus 14.1% (30/212) (P = 0.009) on pooled analysis with data from 2 additional studies (502 patients), respectively. However, IV-D is the most common premedication regimen used in the UK and Canada (48.5% and 34.2% of centers). Post-HSR paclitaxel on a desensitization protocol is a cost-effective alternative to discontinuing paclitaxel altogether. Oral dexamethasone seems to be superior to IV-D in preventing HSRs. Post-HSR patients should be considered for desensitization.

Prevalence and Lifetime Risk of Endoscopy-related Complications Among Patients With Inflammatory Bowel Disease

Few studies have analyzed the safety of endoscopy in patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence of procedure-related complications among these patients, compared with the general population, and estimate the lifetime risk of colonoscopy-related complications. We collected data on complications in 685 patients with IBD and 17,000 patients without IBD (controls) using an automated system to track all emergency department visits to the Beth Israel Deaconess Medical Center within 14 days of an endoscopic procedure, from March 1, 2007, to November 30, 2007. We reviewed charts of all IBD patients to determine health care use (telephone calls or visits to a gastroenterologist or primary care physician and visits to other emergency departments or hospitals) after endoscopy. The lifetime risk of procedure-related complications was estimated using a Markov Monte Carlo model. Rates of complications were 1.17% among patients with IBD and 0.96% among controls (P=.55). The chart review showed that 3.8% of the IBD cohort received medical care within 14 days of the endoscopic procedure. Based on a Markov Monte Carlo simulation model, the lifetime risk of complications after a surveillance colonoscopy protocol was 12.7% among patients with IBD and 2.0% in the general population undergoing screening colonoscopy (P<.001). Although the risk of adverse events after each endoscopic procedure was similar for patients with IBD and the general population, IBD patients have an increased lifetime risk of complications after colonoscopies. A higher percentage of patients with IBD also seek medical care after endoscopic procedures than controls.

Prophylactic Salpingectomy and Delayed Oophorectomy as an Alternative for BRCA Mutation Carriers

Prophylactic bilateral salpingo-oophorectomy is advised for women with BRCA mutations, but there are adverse consequences of premature menopause. The majority of BRCA-associated ovarian cancers appear to arise in the fallopian tube; therefore, salpingectomy may be an alternative to bilateral salpingo-oophorectomy. We compared the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers. We developed a Markov Monte Carlo simulation model to compare three strategies for risk reduction in women with BRCA mutations: 1) bilateral salpingo-oophorectomy; 2) bilateral salpingectomy; and 3) bilateral salpingectomy with delayed oophorectomy. Net health benefits were measured in years-of-life expectancy and quality-adjusted life-year expectancy, and the primary outcome was the incremental cost-effectiveness ratio. The model estimated the number of future breast and ovarian cancers and cardiovascular deaths attributed to premature menopause with each strategy. Bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. When quality-of-life measures were included, salpingectomy followed by delayed oophorectomy yielded the highest quality-adjusted life expectancy with incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2, respectively, relative to salpingectomy alone. Bilateral salpingo-oophorectomy yielded the lowest number of future breast and ovarian cancers compared with the other two strategies. Bilateral salpingo-oophorectomy offers the greatest risk reduction for breast and ovarian cancer among BRCA mutation carriers. However, when considering quality-adjusted life expectancy, bilateral salpingectomy with delayed oophorectomy is a cost-effective strategy and may be an acceptable alternative for those unwilling to undergo bilateral salpingo-oophorectomy.

Testing women with endometrial cancer to detect Lynch syndrome.

Women with endometrial cancer as a result of Lynch syndrome may not be identified as such by Amsterdam II criteria. We estimated the costs and benefits of different testing criteria to identify Lynch syndrome in women with endometrial cancer. We developed a Markov Monte Carlo simulation model to compare six criteria for Lynch syndrome testing for women with endometrial cancer: Amsterdam II criteria; age younger than 50 years with at least one first-degree relative having a Lynch-associated cancer at any age (FDR); immunohistochemistry (IHC) triage if age younger than 50 years; IHC triage if age younger than 60 years; IHC triage at any age if 1 FDR; and IHC triage of all endometrial cancers. Net health benefit was life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new colorectal cancers associated with each strategy. IHC triage of women with endometrial cancer having at least 1 FDR yielded a favorable ICER of $9,126 per year of life gained. This strategy would subject fewer cases to IHC but identify more mutation carriers than age thresholds of 50 or 60 years. IHC triage of all endometrial cancers could identify the most mutation carriers and prevent the most colorectal cancers but at considerable cost ($648,494 per year of life gained). IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome.

Preventing Future Cancers by Testing Women With Ovarian Cancer forBRCAMutations

Women with ovarian cancer have a 10% probability of carrying a BRCA mutation. If a mutation is identified, unaffected family members can undergo genetic testing and cancer risk-reducing strategies. We estimated the net health benefits and cost-effectiveness of different criteria for BRCA mutation testing in women with ovarian cancer, and the downstream benefits for their first-degree relatives (FDRs). We developed a Markov Monte Carlo simulation model to compare four criteria for BRCA testing in women with ovarian cancer: no testing (reference); only if personal history of breast cancer, family history of breast/ovarian cancer, or Ashkenazi Jewish ancestry; only if invasive serous cancer; any invasive nonmucinous epithelial cancer. Net health benefit was life expectancy for FDRs and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of future breast and ovarian cancer cases in FDRs. BRCA testing based on personal/family history and ancestry could prevent future cases in FDRs with an ICER of $32,018 per year of life (LY) gained compared with the reference strategy. BRCA testing based on serous or any nonmucinous epithelial ovarian cancer could prevent more cancer cases, but at ICERs of $128,465 and $148,363 per LY gained, respectively. BRCA testing of women with ovarian cancer based on personal/family history of cancer or Ashkenazi Jewish ancestry is a cost-effective strategy to prevent future breast and ovarian cancers among FDRs. More inclusive testing strategies prevent additional cancer cases but at significant cost.

Adapting a Markov Monte Carlo simulation model for forecasting the number of Coronary Artery Revascularisation Procedures in an era of rapidly changing technology and policy

BackgroundTreatments for coronary heart disease (CHD) have evolved rapidly over the last 15 years with considerable change in the number and effectiveness of both medical and surgical treatments. This period has seen the rapid development and uptake of statin drugs and coronary artery revascularization procedures (CARPs) that include Coronary Artery Bypass Graft procedures (CABGs) and Percutaneous Coronary Interventions (PCIs). It is difficult in an era of such rapid change to accurately forecast requirements for treatment services such as CARPs. In a previous paper we have described and outlined the use of a Markov Monte Carlo simulation model for analyzing and predicting the requirements for CARPs for the population of Western Australia (Mannan et al, 2007). In this paper, we expand on the use of this model for forecasting CARPs in Western Australia with a focus on the lack of adequate performance of the (standard) model for forecasting CARPs in a period during the mid 1990s when there were considerable changes to CARP technology and implementation policy and an exploration and demonstration of how the standard model may be adapted to achieve better performance.MethodsSelected key CARP event model probabilities are modified based on information relating to changes in the effectiveness of CARPs from clinical trial evidence and an awareness of trends in policy and practice of CARPs. These modified model probabilities and the ones obtained by standard methods are used as inputs in our Markov simulation model.ResultsThe projected numbers of CARPs in the population of Western Australia over 1995–99 only improve marginally when modifications to model probabilities are made to incorporate an increase in effectiveness of PCI procedures. However, the projected numbers improve substantially when, in addition, further modifications are incorporated that relate to the increased probability of a PCI procedure and the reduced probability of a CABG procedure stemming from changed CARP preference following the introduction of PCI operations involving stents.ConclusionThere is often knowledge and sometimes quantitative evidence of the expected impacts of changes in surgical practice and procedure effectiveness and these may be used to improve forecasts of future requirements for CARPs in a population.

Effectiveness and cost effectiveness of early and late prevention of HIV/AIDS progression with antiretrovirals or antibiotics in Southern African adults

As HIV/AIDS drugs are becoming more widely available in Southern Africa, we compared the effectiveness and cost effectiveness of different treatment options, using a Markov Monte Carlo simulation model based on published estimates of disease progression, treatment effectiveness and health care costs. Cost and outcome values were discounted. Quality of life was considered. Acceptability curves summarized uncertainties. Sensitivity analyses tested assumptions. Results showed that triple antiretroviral therapy (ARV) plus antibiotics would prolong life by 6.7 undiscounted years if provided ‘late’ (CD4 = 200 cells/µl) and by 9.8 years if provided ‘early’ (CD4 = 350 cells/µl). The incremental undiscounted costs per year of life gained, compared to no preventive therapy, were $17 for isoniazid plus cotrimoxazole started late, $244 for both antibiotics started early, $2454 for ARV plus antibiotics started late and $2784 for ARV plus both antibiotics started early. The discounted incremental costs per quality adjusted life year (QALY) gained were, respectively, $29 saving, $254, $4937 and $3057. Late ARV plus both antibiotics was the strategy most likely to be cost effective if society was willing to pay more than $2000 per life year gained. Cost-effectiveness estimates were sensitive to discounting and assumed treatment costs but were less sensitive to assumed treatment effectiveness.