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Abstract

Background

Recent advances of precision medicine (PM) in cancer care offer promising potential to improve health outcomes and reduce costs and healthcare resource utilisation, by tailoring treatment to individual patients based on their genomic information. One of the most exciting prospects in PM is circulating-tumour DNA (ctDNA) testing, or what is generically known as ‘liquid biopsy’. Clinical research over the past decade has generated promising evidence to support its clinical utility in the management of patients with stage II and III colorectal cancer (CRC) following curative surgery. Yet, the health economic evidence on its cost-effectiveness is rather limited.

Aims and Objectives

To explore the cost-effectiveness and economic value of implementing ctDNA testing in the management of patients with high-risk stage II and stage III CRC following curative surgery.

Methods

I conducted a systematic literature review for full economic evaluations of PM in cancer care to investigate the economic evidence on the cost-effectiveness of PM in cancer, the various methods employed in the analysis and the factors that influenced the cost-effectiveness results.

Next, I performed a cost-utility analysis of using ctDNA testing to guide adjuvant chemotherapy decisions in patients with resected high-risk stage II and stage III CRC in the UK. A decision-tree model was employed to estimate the short-term cost-effectiveness of ctDNA testing over a 5-year time-horizon. Series of one-way deterministic sensitivity analyses, in addition to probabilistic sensitivity analysis via Monte Carlo simulation of 5,000 iterations were performed to investigate the impact of structural and parameter uncertainty on the cost-effectiveness results.

Finally, I performed a cost-utility analysis of using ctDNA testing to predict cancer recurrence and guide adjuvant chemotherapy decisions in patients with resected high-risk stage II and stage III CRC. A decision tree, combined with a Markov cohort simulation model was employed to estimate the long-term cost-effectiveness of ctDNA testing over a lifetime horizon. One-way deterministic sensitivity analyses, probabilistic sensitivity analysis via Monte Carlo simulation of 5,000 iterations and scenario analyses were performed to investigate the impact of structural and parameter uncertainty on the cost-effectiveness results.

Findings

The systematic review indicated that PM contributed to better health outcomes but at an additional cost and is projected to be cost-effective in cancer care. The existing evidence on the cost effectiveness of ctDNA testing in cancer care is significantly scarce given the accelerating research activity and promising evidence generated.

Cost-effectiveness results varied among the four types of PM tests that were identified. Results were more favourable for studies on germline testing for cancer risk and prognostic genomic testing to guide treatment decisions, than companion diagnostics with targeted therapies and pharmacogenomic tests to guide existing treatment. The main determinants of cost-effectiveness results included prevalence of disease and/or actionable mutations, costs of testing, costs of standard and targeted chemotherapy, uncertainty in effectiveness and efficacy of treatments, and uncertainty in test performance. Contextual factors which influenced cost-effectiveness results were the source of funding, compliance and adherence to treatment decisions. The effect these determinants and contextual factors had on the results varied across different types of tests identified.

The results of the cost-utility analysis of the short-term consequences of using ctDNA testing indicated that ctDNA testing was dominant to no testing. The average incremental QALYs per patient were 0.03 QALYs (0.065 for high-risk stage II vs. 0.023 for stage III patients), and the average cost savings per patient were £-£1,678.35 (£2,050 for high-risk stage II vs. £1,607.57 for stage III). The INMB at £20,000/QALY and £30,000/QALY cost-effectiveness thresholds were £2,275.69 and £2,574.35, respectively. The ICER was calculated to be - £56,194.97 per QALY. Testing was associated with a 20.67% reduction in chemotherapy utilisation and annual cost savings of £54,782,809 and £11,894,809 from treating chemotherapy-associated adverse events. The results were moderately sensitive to costs of ctDNA testing and cost of CAPOX, and slightly sensitive to rates of chemotherapy-
associated adverse events. Probabilistic sensitivity analysis showed the probability of ctDNA being cost-effective was 100% at the £20,000/QALY and £30,000/QALY cost-effectiveness thresholds.

Cost-utility analysis of the long-term consequences of using ctDNA testing demonstrated that testing was the dominant strategy compared with standard of care. The mean incremental QALYs and costs per patient were 0.007 QALYs (0.048 for high-risk stage II vs - 0.000175 for stage III patients) and - £1,784.62103 ( - £2,096.92 for high-risk stage II vs - £1,725.14 for stage III), respectively. The INMB at £20,000/QALY and £30,000/QALY cost-effectiveness thresholds were £1,934.23 and £2,009.03, respectively. The ICER was calculated to be - £238,574.92 / QALY. The cost-effectiveness results were moderately sensitive to costs of ctDNA testing, decreasing specificity of ctDNA testing and ten-year recurrence probabilities for stage III CRC patients. Nevertheless, results remained robust and the INMB remained cost-effective. The results of Monte Carlo simulation revealed that the likelihood of ctDNA testing being cost-effective at the £20,000/QALY and £30,000/QALY thresholds was 99.86% and 99.7%, respectively. The probability of ctDNA testing being associated with inferior outcomes to standard of care was 19.5%.

Conclusions

The current economic evidence on the cost-effectiveness of ctDNA in cancer care is significantly scarce. Despite the early nature of the evidence on the clinical utility of ctDNA in detecting recurrence following surgery in CRC, and the high uncertainty surrounding long-term benefits, this early economic evaluation has found that ctDNA testing would likely be cost-effective and highly cost-saving. The cost-effectiveness of ctDNA testing was contingent on the stage of CRC, as testing was found to be more effective and cost-effective in high-risk stage II patients than in stage III. The long-term analysis showed that testing for stage III CRC patients produced similar health outcomes, but was associated with significant cost savings.

Sensitivity analyses supported the robustness of the results. Key determinants of the cost-effectiveness results included the cost of ctDNA testing, sensitivity and specificity of ctDNA, cost of CAPOX and recurrence probabilities for the stage III CRC cohort. In the light of uncertainty surrounding the evidence on the long-term utility of ctDNA testing, it is essential to optimise decision-making and escalation/de-escalation of treatment protocols following testing, for that is where the real value of ctDNA testing lies. Despite the uncertainty surrounding long-term benefits of early detection of MRD, the short-term benefits combined with the continuous improvements in ctDNA testing performance would be sufficient for ctDNA testing to be cost-effective.

Publication Type:	Thesis (Doctoral)
Subjects:	H Social Sciences > HB Economic Theory R Medicine > RC Internal medicine
Departments:	School of Health & Psychological Sciences > Healthcare Services Research & Management School of Health & Psychological Sciences > School of Health & Psychological Sciences Doctoral Theses Doctoral Theses

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