Endoscopic ablation is a cost-effective cancer preventative therapy in patients with Barrett's esophagus who have elevated genomic instability

Abstract

Background: The surveillance of patients with nondysplastic Barrett's esophagus (NDBE) has a high cost and is of limited effectiveness in preventing esophageal adenocarcinoma (EAC). Ablation for NDBE remains expensive and controversial. Biomarkers of genomic instability have shown promise in identifying patients with NDBE at high risk for progression to EAC. Here, we evaluate the cost-effectiveness of using such biomarkers to stratify patients with NDBE by risk for EAC and, subsequently, the cost-effectiveness of ablative therapy.

Methods: A Markov decision tree was used to evaluate four strategies in a hypothetical cohort of 50-year old patients with NDBE over their lifetime: strategy I, natural history without surveillance; strategy II, surveillance per current guidelines; strategy III, ablation for all patients; strategy IV, risk stratification with use of a biomarker panel to assess genomic instability (i. e., mutational load [ML]). Patients with no ML underwent minimal surveillance, patients with low ML underwent standard surveillance, and patients with high ML underwent ablation. The incremental cost-effectiveness ratio (ICER) and incremental net health benefit (INHB) were assessed.

Results: Strategy IV provided the best values for quality-adjusted life years (QALYs), ICER, and INHB in comparison with strategies II and III. RESULTS were robust in sensitivity analysis. In a Monte Carlo analysis, the relative risk for the development of cancer in the patients managed with strategy IV was decreased. Critical determinants of strategy IV cost-effectiveness were the complete response rate, cost of ablation, and surveillance interval in patients with no ML.

Conclusion: The use of ML to stratify patients with NDBE by risk was the most cost-effective strategy for preventive EAC treatment. Targeting ablation toward patients with high ML presents an opportunity for a paradigm shift in the management of NDBE.

Supplementary Fig. 1

The hybrid model of the linear decision tree terminating in Markov models. In the decision tree, a square node represents the decision node at entry, the filled circles are chance nodes, and the circles with the letter M represent Markov nodes. In strategy I, after the diagnosis of nondysplastic Barrett’s esophagus (NDBE) was established, the natural history of this condition was modeled without any specific intervention. In strategy II, all patients with NDBE underwent periodic endoscopic surveillance according to the current guidelines of the American College of Gastroenterology. In strategy III, all patients with NDBE underwent endoscopic ablation. In strategy IV, all patients with NDBE underwent risk stratification for esophageal adenocarcinoma, and subsequently ablation, based on mutational load (ML); Patients with no ML underwent minimal surveillance, patients with low ML underwent standard surveillance or ablative therapy (another decision point), and patients with high ML were treated selectively with endoscopic ablation.

Supplementary Fig. 2

Health and disease state transitions in the Markov model. The natural history of patients with nondysplastic Barrett’s esophagus (NDBE) was modeled for various health and disease states, each associated with a different set of costs and utilities. A single arrowhead indicates transition from one state to another in the direction of the arrowhead; double arrowheads indicate that transitions in both directions are allowed in the model. Half-circle arrowheads represent states in which a patient can remain indefinitely. The light blue area represents stages associated with endoscopic ablative therapy (EAT), if allowed in the model. Normal, no Barrett’s esophagus; LGD, low grade dysplasia; HGD, high grade dysplasia; EAC, esophageal adenocarcinoma; AEAC, advanced esophageal adenocarcinoma; S/P Surgery, status post surgery.

Fig. 1

Tornado diagram for a series of one-way sensitivity analyses showing the impact of various clinical and cost variables on the net health benefit of the two most competitive strategies: a strategy based on standard surveillance (strategy II) and a strategy based on risk stratification with mutational load (strategy IV). These particular variables were examined because they were supported by the most limited available data. Although the incremental cost-effectiveness ratio changed significantly as the variables changed, the overall conclusion of the model that strategy IV yields the highest NHB at a willingness to pay of $ 50,000 was unchanged. The relative impact on the NHB is signified by the width of the horizontal bars. ML, mutational load; EGD, esophagogastroduodenoscopy.

Supplementary Fig. 3

The proportions of iterations in the Monte Carlo analysis (y-axis) that are acceptable as cost-effective for each strategy against increasing willingness to pay (x-axis). A strategy of risk stratification based on mutational load (strategy IV, blue) was the most cost-effective strategy in terms of incremental net health benefit, particularly when compared with the currently practiced strategy of endoscopic surveillance (strategy II, green).