Original Article
Alimentary Tract
Optimal Timing of Total Gastrectomy to Prevent Diffuse Gastric Cancer in Individuals With Pathogenic Variants in CDH1

https://doi.org/10.1016/j.cgh.2019.06.009Get rights and content

Background & Aims

Carriers of pathogenic variants in CDH1 have a high risk of hereditary diffuse gastric cancer (HDGC). Guidelines recommend prophylactic total gastrectomy (PTG) at age 20–30 years, although there is controversy over the optimal age. We developed a simulation model to analyze the effects of PTG at different ages on quality-adjusted life-years (QALYs), cancer mortality, and life expectancy.

Methods

We used a Markov model of HDGC progression associated with pathogenic variants in CDH1 to simulate outcomes of hypothetical cohorts with different ages at time of PTG (ages 20–79 years). Model inputs including health state transition probabilities, mortality and complication rates, quality of life utility values, and endoscopic surveillance sensitivity were derived from publications. The primary outcome, used to determine the optimal strategy, was age at which PTG yielded the highest QALYs. Secondary outcomes were cancer mortality and unadjusted life-years.

Results

Our model found that for men, the optimal age for PTG is 39 years, resulting in 32.01 incremental QALYs, 58.81 life-years (biologic age, 72.81 years), and lifetime cancer mortality of 8.5%. Incorporating endoscopic surveillance prior to PTG decreased cancer mortality to 6.7%, but had lower QALYs (31.59). PTG at age 30 reduced cancer mortality to 3.2%, with 31.45 incremental QALYs. For women, the optimal age for PTG was calculated to be 30 years, with 33.09 incremental QALYs, 66.17 life-years (biologic age, 80.17 years), and lifetime cancer mortality of 1.6%. Addition of endoscopic surveillance did not decrease the risk of HDGC mortality in women.

Conclusions

Using a Markov model of HDGC progression associated with pathogenic variants in CDH1 to simulate outcomes, we found the optimal ages for PTG to be 39 years for men and 30 years for women, when QALYs are the primary endpoint. These ages for PTG are older than those of current recommendations.

Section snippets

Target Population and Study Perspective

The target population for this analysis was patients with pathogenic CDH1 mutations. The goal of this study was to use modeling to help patients and providers compare available HDGC management strategies.

Model Overview

We developed a state-transition (Markov) cohort-level model of the natural history of CDH1 mutation carrier progression to HDGC using Python 3.7 (Figure 1). The model was used to simulate hypothetical clinical trials of a cohort undergoing PTG at varying ages (20–79) to determine the impact

Natural History Model

Lifetime HDGC mortality for men and women in the base case with no intervention was 61.62% and 54.10%, respectively (Supplementary Figures 1 and 2). These rates are similar to published cumulative risk estimates for men and women (70% and 56%, respectively) after accounting for all-cause mortality, providing assurance that our model outputs are clinically plausible.4 QALYs associated with base case risk were 30.89 for men and 32.63 for women. Life-years with no intervention were 47.17 for men

Discussion

Our modeling analysis finds that the “optimal” age for CDH1 carriers to undergo PTG is age 39 for men and age 30 for women when QALYs are the primary outcome. This is considerably later than current guideline recommendations of age 20–30, highlighting important considerations in the decision-making process for individual patients.11

Implicit in current guidelines is the assumption that mitigating underlying cancer risk is the primary factor driving the decision process. Our modeling analysis

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    Conflicts of interest The authors disclose no conflicts.

    a

    These authors contributed equally.

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