Cost and Clinical Effectiveness of High-Intensity Focused Ultrasound versus Open Radical Prostatectomy, Robot-Assisted Radical Prostatectomy, or External Beam Radiation Therapy in Men with Localized Low and Intermediate Risk Prostate Cancer: A Cost-Utility Analysis

Prostate cancer (PCa) is the fifth leading cause of cancer death among Canadian men. Open radical prostatectomy (ORP), robot-assisted radical prostatectomy (RARP), and external beam radiation therapy (RT) are main lines of primary treatment for localized low and intermediate risk PCa. ORP is a major surgery in which a single large incision is made to access the pelvis and to completely remove the prostate, while RARP is a minimally invasive surgery in which several small incisions are made to access the abdomen and completely remove the prostate using a robotic device. In RT, a machine delivers focused beams of radiation from outside the body on the prostate gland to treat PCa. Focal therapies like high intensity focused ultrasound (HIFU) are emerging, less invasive treatment strategies with potential advantages as organ preservation, short recovery time, and few adverse events. There is limited published literature comparing HIFU with the standard of care (ORP, RARP, and RT) for primary treatment of localized low and intermediate-risk PCa and none of the previously published studies assessed the cost-effectiveness of primary HIFU from the Canadian healthcare payer’s perspective or provided insight into clinical subgroups of patients. We conducted an economic evaluation (cost-utility analysis) to compare the cost-utility of HIFU vs the standard of care as primary treatment for localized low and intermediate risk PCa in Ontario. To conduct the cost-utility analysis, we estimated the parameters of a Markov cohort state-transition model. To run the model, we collected the transition probabilities, the direct costs, and the utility values for HIFU and the standard of care, and calculated the number of life years gained, the quality adjusted life years (QALYs) gained, the cost per QALY gained for HIFU and the standard of care, and the incremental cost-utility ratio (ICUR) for HIFU vs the standard of care. In addition, we conducted a one-way deterministic analysis that evaluated the sensitivity of the model results to variations of the parameters, a probabilistic sensitivity analysis which assessed the probability of cost-effectiveness for HIFU vs the standard of care at the willingness to pay (WTP) threshold, and a value of Information (VOI) analysis to calculate the expected value of perfect information (EVPI) and the expected value of partial perfect Information (EVPPI). Initially, we conducted a systematic review of all relevant published case-control, cohort, and randomised controlled studies that evaluated cancer related and functional outcomes of HIFU and the standard of care from inception through August 31, 2021 to collect the transition probabilities. The cancer related and functional outcomes were stratified into subgroups according to patient’s anthropometric, socio-demographic, and medical characteristics. Meta-analysis was performed with Microsoft Excel® Data Analysis Toolpak version 16.77 using maximum likelihood estimation and reported as a point estimate (ˆp) and Cochrane Tools using a random effects model with Mantel Haenszel (M-H) estimator for Tau2 statistic and reported as odds ratio (OR). Fourteen studies were included in the review for a total number of 34,927 participants. Among the 8 studies of HIFU as the primary treatment of localized low and intermediate risk PCa, 4 studies reported 5-year failure free survival (FFS) rates ranging from 67.8% to 97.8%, 3 studies reported 5-year biochemical disease-free survival ranging from 58% to 85.4%, 5 studies reported 1-year urinary incontinence (UI) rates ranging from 0% to 6%, and 4 studies reported 1-year erectile dysfunction (ED) rates ranging from 11.4% to 38.7%. Furthermore, our search revealed 5-year FFS benefit favoring ORP compared to RT (OR = 3.56, 95% CI = 2.50 - 5.08), 1 year UI rate favoring ORP compared to RARP (OR = 0.54, 95% CI = 0.10 - 2.89), and 1-year ED rate favoring ORP compared to RARP (OR = 0.46, 95% CI = 0.12 - 1.73). The direct costs of 20 patients with localized low or intermediate risk PCa who received whole-gland HIFU at a privately-owned clinic in Ontario were collected and compared with the direct costs of the standard of care in primary treatment of localized low and intermediate risk PCa. Our one-way deterministic analysis revealed that the main parameters that influenced the ICUR for HIFU vs RARP included the stable disease health state utilities for both groups, the clinic and amortization costs of HIFU, and the hospital, consumables, amortization, and maintenance costs of RARP, respectively. When we varied the annual transition probability of stable disease health state progressing towards metastasis after delivering HIFU from 0.01 to 0.05, the total QALYs generated with HIFU were 14.85 QALYs, and after a lifetime horizon, the ICUR of HIFU compared to RARP increased to $28,740.09 per QALY gained, which was still accepted as cost-effective when compared to RARP at a WTP threshold of $50,000/QALY. The probabilistic sensitivity analysis showed that, for HIFU vs RARP, a total of 9,444 ICURs out of the 10,000 ICURs resulting from the Monte Carlo simulations are situated below the WTP threshold, which means that the cost-effectiveness probability of HIFU compared to RARP is 94.44% when we trade-off between the lower cost of RARP and the higher effectiveness of HIFU and confirms our base case analysis result that showed HIFU to be highly cost-effective when compared to RARP. Our VOI analysis showed an EVPI over all simulations of 0.04 net benefit (NB) when all parameters were varied, a population EVPI for low and intermediate risk PCa in Ontario of 3,120.48 and 7,253.54 NB which is equivalent to $156,024,000 and $362,677,000 when assuming a WTP threshold of $50,000/QALY, respectively, an EVPPI over all simulations of 0.02 NB when the utilities subset of parameters was varied, an EVPPI over all simulations of 0.00 NB when the cost subset of parameters was varied, and concluded a very high value associated with further research on the cost-utility of HIFU vs RARP with special emphasis on the utility parameters. We concluded that the data collected in our mixed quantitative and qualitative research study can be utilized by patients in Ontario to engage in the shared decision-making process and mapped by policy makers to the current treatment landscape of localized low and intermediate risk PCa to identify policy gaps, evaluate HIFU’s eligibility for public funding and reimbursement, and leverage a data-driven policy that considers the allocation of HIFU within the existing treatment algorithm.

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