Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

Value of next generation sequencing (NGS) testing in advanced cancer patients.

OBJECTIVE: The availability of targeted therapies for oncology patients is increasing. Available genomic tests to identify treatment-eligible patients include single gene tests and gene panel tests, including the whole-exome, whole-transcriptome OncoExTra test. We assessed the costs and clinical benefits of test choice. METHODS: A Microsoft Excel-based model was developed to evaluate test choice in patients with advanced/metastatic non-small cell lung cancer (NSCLC), breast, prostate, and colorectal cancer. Treatment pathways were based on NCCN guidelines and medical expert opinion. Inputs were derived from published literature. Annual economic results and lifetime clinical results with OncoExTra testing were projected per-tested-patient and compared with single gene testing and no testing. Separately, results were estimated for a US health plan without the OncoExTra test and with its use in 5% of patients. RESULTS: Compared with no genomic testing, OncoExTra test use increased costs by $4,915 per patient; however, 82%-92% of individuals across tumour types were identified as eligible for targeted therapy or a clinical trial. Compared with single gene testing, OncoExTra test use decreased costs by $9,966 per-patient-tested while increasing use of approved or investigational targeted therapies by 20%. When considering a hypothetical health plan with 1 million members, 858 patients were eligible for genomic testing. Using the OncoExTra test in 5% of those eligible, per-member per-month costs decreased by $0.003, ranging from cost-savings of $0.026 in NSCLC patients to a $0.009 increase in prostate cancer patients. Cost-savings were driven by reduced treatment costs with increased clinical trial enrolment and reduced direct and indirect medical costs associated with targeted treatments. LIMITATIONS: Limitations include the required simplifications in modelling complex conditions that may not fully reflect evolving real-world testing and treatment patterns. CONCLUSIONS: Compared to single-gene testing, results indicate that using next generation sequencing test such as OncoExTra identified more actionable alterations, leading to improved outcomes and reduced costs.

Real-world impact of disease on functioning and activity: what is missed when using general instruments to estimate quality-adjusted life years.

OBJECTIVE: Economic evaluations conducted to inform healthcare resource allocation often rely on quality-adjusted life years (QALYs) to measure therapeutic benefit. However, QALYs, with underlying health utilities estimated using the EQ-5D or SF-36, may fail to capture the impact of disease for all patients. How well-being and heath utility differ across several common conditions was explored. METHODS: This study examined eight diseases: arthritis, asthma, cancer, depression, diabetes, heart disease, lung disease and stroke. Health utilities for each disease were obtained from published literature. Other measures of disease burden, including physical functioning, cognitive functioning and physical activity, were estimated from the National Health and Nutrition Examination Survey (NHANES). Group rankings by these measures were compared to rankings by health utility. RESULTS: Health utilities were lowest for patients with depression (0.44), and highest for those with cancer (0.81). Physical functioning was most limited (higher score) among those with stroke (28.2) and had the least impact for cancer (24.4). Physical activity was most impacted by heart disease (27.3) and least impacted by depression (40.7). Cognitive functioning was lowest in stroke (41.6) and highest in asthma (52.0). CONCLUSION: Differences in rankings of disease severity by metric indicate that the results of cost-utility analyses might be biased against treatments for certain diseases. As patient preferences for clinical outcomes vary, the full burden of disease should be considered in evaluations. Restricting access to treatments based on an incomplete estimate of burden could lead to misallocation of resources and a withholding of therapies that patients find valuable.

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States.

PURPOSE: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. CONCLUSIONS: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

Budget impact of somatostatin analogs as treatment for metastatic gastroenteropancreatic neuroendocrine tumors in US hospitals.

OBJECTIVE: With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs). PATIENTS AND METHODS: A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. RESULTS: In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity analyses, the results were most sensitive to changes in dosing assumptions. CONCLUSION: Results suggest that factors beyond drug acquisition cost can influence the budget impact to a hospital. When considering preparation and administration time, and real-world dosing, use of lanreotide has the potential to reduce health care expenditures associated with metastatic gastroenteropancreatic neuroendocrine tumor treatments.

Cost-effectiveness of treatments for high-risk myelodysplastic syndromes after failure of first-line hypomethylating agent therapy.

PURPOSE: To evaluate optimal salvage therapy in high-risk myelodysplastic syndromes patients who have failed a first-line hypomethylating agent (HMA) therapy, given that treatment choice is challenging. METHODS: Using published literature and expert opinion, we developed a Markov model to evaluate the cost-effectiveness of current treatments for patients who failed first-line HMA therapy. The model predicted costs, life years, quality-adjusted life years and incremental cost-effectiveness ratios. Sensitivity analyses were conducted to assess the impact of uncertainty in model inputs. RESULTS: Supportive care was the least expensive option ($65,704/patient) with the shortest survival (0.48 years). Low- and high-intensity chemotherapies and hematopoietic cell transplantation increased survival and costs with incremental cost-effectiveness ratios of $108,808, 306,103 and 318,163/life year, respectively. Switching HMA was more costly and less efficacious than another treatment option, namely low-intensity chemotherapy. CONCLUSIONS: Subsequent treatments in myelodysplastic syndrome patients who failed first-line HMA significantly increase costs, while only providing marginal clinical benefit and substantially increasing treatment-related morbidities. Additional treatment options would benefit resource allocation, clinical decision-making and patient outcomes.

Cost-effectiveness of bronchial thermoplasty in commercially-insured patients with poorly controlled, severe, persistent asthma.

OBJECTIVES: We examined the cost-effectiveness of treating poorly controlled, severe, persistent asthma patients with bronchial thermoplasty (BT), a novel technology that uses thermal energy to reduce airway smooth muscle mass, with 5-year outcome data demonstrating a durable reduction in asthma exacerbations. STUDY DESIGN: We conducted a model-based cost-effectiveness analysis assessing 5-year healthcare utilization, patient quality of life and adverse events. METHODS: We utilized Markov modeling to estimate the costs and quality-of-life impact of BT compared with high-dose combination therapy among poorly controlled, severe, persistent asthma patients: those requiring high-dose combination therapy and having experienced an asthma exacerbation-related ER visit in the past year. RESULTS: The cost-effectiveness of BT was US$5495 per quality-adjusted life year; and approximately 22% of sensitivity analysis iterations estimated BT to reduce costs and increase quality of life. CONCLUSIONS: BT is a cost-effective treatment option for patients with poorly controlled, severe, persistent asthma.

Cost effectiveness of a 92-gene assay for the diagnosis of metastatic cancer.

OBJECTIVES: To estimate the clinical and economic trade-offs involved in using a molecular assay (92-gene assay, CancerTYPE ID) to aid in identifying the primary site of difficult-to-diagnose metastatic cancers and to explore whether the 92-gene assay can be used to standardize the diagnostic process and costs for clinicians, patients, and payers. METHODS: Four decision-analytic models were developed to project the lifetime clinical and economic impact of incorporating the 92-gene assay compared with standard care alone. For each model, total and incremental costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and the proportion of patients treated correctly versus incorrectly were projected from the payer perspective. Model inputs were based on published literature, analyses of SEER (Surveillance Epidemiology and End RESULTS) data, publicly available data, and interviews with clinical experts. RESULTS: In all four models, the 92-gene assay increased the proportion of patients treated correctly, decreased the proportion of patients treated with empiric therapy, and increased quality-adjusted survival. In the primary model, the ICER was $50,273/QALY; thus, the 92-gene assay is therefore cost effective when considering a societal willingness-to-pay threshold of $100,000/QALY. These findings were robust across sensitivity analyses. CONCLUSIONS: Use of the 92-gene assay for diagnosing metastatic tumors of uncertain origin is associated with reduced misdiagnoses, increased survival, and improved quality of life. Incorporating the assay into current practice is a cost-effective approach to standardizing diagnostic methods while improving patient care. Limitations of this analysis are the lack of data availability and resulting modeling simplifications, although sensitivity analyses showed these to not be key drivers of results.

Health and economic impact of HPV 16/18 vaccination and cervical cancer screening in Eastern Africa.

Eastern Africa has the world's highest cervical cancer incidence and mortality rates. We used epidemiologic data from Kenya, Mozambique, Tanzania, Uganda, and Zimbabwe to develop models of HPV-related infection and disease. For each country, we assessed HPV vaccination of girls before age 12 followed by screening with HPV DNA testing once, twice, or three times per lifetime (at ages 35, 40, 45). For women over age 30, we assessed only screening (with HPV DNA testing up to three times per lifetime or VIA at age 35). Assuming no waning immunity, mean reduction in lifetime cancer risk associated with vaccination ranged from 36 to 45%, and vaccination followed by screening once per lifetime at age 35 with HPV DNA testing ranged from 43 to 51%. For both younger and older women, the most effective screening strategy was HPV DNA testing three times per lifetime. Provided the cost per vaccinated girl was less than I$10 (I$2 per dose), vaccination had an incremental cost-effectiveness ratio [I$ (international dollars)/year of life saved (YLS)] less than the country-specific per capita GDP, a commonly cited heuristic for "very cost-effective" interventions. If the cost per vaccinated girl was between I$10 (I$2 per dose) and I$25 (I$5 per dose), vaccination followed by HPV DNA testing would save the most lives and would be considered good value for public health dollars. These results should be used to catalyze design and evaluation of HPV vaccine delivery and screening programs, and contribute to a dialogue on financing HPV vaccination in poor countries.

Trade-offs in cervical cancer prevention: balancing benefits and risks.

BACKGROUND: New screening and vaccination technologies will provide women with more options for cervical cancer prevention. Because the risk of cervical cancer diminishes with effective routine screening, women may wish to consider additional attributes, such as the likelihood of false-positive results and diagnostic procedures for mild abnormalities likely to resolve without intervention in their screening choices. METHODS: We used an empirically calibrated simulation model of cervical cancer in the United States to assess the benefits and potential risks associated with prevention strategies differing by primary screening test, triage test for abnormal results (cytologic testing, human papillomavirus [HPV] DNA test), and screening frequency. Outcomes included colposcopy referrals, cervical intraepithelial neoplasia (CIN) types 1 and 2 or 3, lifetime cancer risk, and quality-adjusted life expectancy. RESULTS: Across strategies, colposcopy referrals and diagnostic workups varied 3-fold, although diagnostic rates of CIN 2 or 3 were similar and 95% of positive screening test results were for mild abnormalities likely to resolve on their own. For a representative group of a thousand 20-year-old women undergoing triennial screening for 10 years, we expect 1038 colposcopy referrals (7 CIN 2 or 3 diagnoses) from combined cytologic and HPV DNA testing and fewer than 200 referrals (6-7 CIN 2 or 3 diagnoses) for strategies that use triage testing. Similarly, for a thousand 40-year-old women, combined cytologic and HPV DNA testing led to 489 referrals (9 CIN 2 or 3), whereas alternative strategies resulted in fewer than 150 referrals (7-8 CIN 2 or 3). Using cytologic testing followed by triage testing in younger women minimizes both diagnostic workups and positive HPV test results, whereas in older women diagnostic workups are minimized with HPV DNA testing followed by cytologic triage testing. CONCLUSIONS: Clinically relevant information highlighting trade-offs among cervical cancer prevention strategies allows for inclusion of personal preferences into women's decision making about screening and provides additional dimensions to the construction of clinical guidelines.