Antireflux surgery in the prevention of supra-esophageal cancer and mortality

Gastroesophageal reflux disease (GERD), mainly characterized by heartburn or regurgitation, is a common condition in the Western world with an increasing prevalence. GERD is associated with an increased risk of adenocarcinoma of the esophagus, and possibly of supraesophageal cancers of the larynx, pharynx and lung. GERD is typically treated with antireflux medication, mainly proton pump inhibitors, but an alternative is antireflux surgery with fundoplication. The present thesis aimed to assess outcomes of antireflux surgery with regards to supra-esophageal cancer risk and mortality by conducting multinational population-based cohort studies using the Nordic antireflux surgery cohort (NordASCo), which includes all adult individuals with a documented diagnosis of GERD or antireflux surgery procedure in the national patient registries in any of the five Nordic countries from year 1980 to 2014.

Study I and II investigated whether antireflux surgery decreases the risk of laryngeal and pharyngeal squamous cell carcinoma (Study I) and the risk of small cell carcinoma, squamous cell carcinoma and adenocarcinoma of the lung (Study II) in NordASCo. We calculated standardized incidence ratios (SIR) and hazard ratios (HR) with 95% confidence intervals (CI). The overall risk of laryngeal or pharyngeal squamous cell carcinoma were decreased (SIR 0.62 [95% CI 0.44-0.85] and HR 0.55 [95% CI 0.38-0.80]), and the point estimates decreased further >10 years after surgery. The SIRs and HRs of laryngeal squamous cell carcinoma showed a particular decrease >10 years after surgery (SIR 0.28 [95% CI 0.08-0.72] and HR 0.23 [95% CI 0.08-0.69]). Regarding lung cancer, the overall risk was below unity for small cell (SIR 0.57 [95% CI 0.41-0.77] and HR 0.63 [95% CI 0.44- 0.90]) and squamous cell carcinoma (SIR 0.75 [95% CI 0.60-0.92] and HR 0.80 [95% CI 0.62-1.03]), but not for adenocarcinoma (SIR 0.90 [95% CI 0.76-1.06] and HR 1.03 [95% CI 0.84-1.26]).

Study III examined all-cause and disease-specific mortality after antireflux surgery versus antireflux medication in patients with reflux esophagitis or Barrett’s esophagus in NordASCo (except for Norway). Compared to antireflux medication, the HRs of mortality from all causes (HR 0.61, 95% CI 0.58-0.63), cardiovascular disease (HR 0.58, 95% CI 0.55-0.61), respiratory disease (HR 0.62, 95% CI 0.57-0.66), laryngeal or pharyngeal cancer (HR 0.35, 95% CI 0.19-0.65), and lung cancer (HR 0.67, 95% CI 0.58-0.80) were decreased, while mortality from esophageal cancer (HR 1.05, 95% CI 0.87-1.28) was not, after antireflux surgery. Study IV assessed absolute rates and risk factors of poor short-term outcomes following primary laparoscopic and secondary antireflux surgery by using an updated version of NordASCo with the study period 2000-2018. The absolute risk of 90-day mortality and 90- day reoperation was 0.13% and 3.0%, respectively, after primary laparoscopic antireflux surgery, and 0.19% and 6.2%, respectively, after secondary antireflux surgery. Risk estimates of 90-day mortality were increased with higher age and greater comorbidity, and reduced with higher hospital volume, after primary surgery. Risk estimates of 90-day reoperation were increased with greater comorbidity after primary and secondary surgery. Risk estimates of prolonged hospital stay were increased with higher age and comorbidity after both primary and secondary surgery, and were decreased with higher hospital volume after primary surgery.

In conclusion, antireflux surgery seems to decrease the risk of laryngeal and pharyngeal cancer, as well as small cell carcinoma and squamous cell carcinoma of the lung, and may also decrease the risk of all-cause mortality, and has a favorable safety profile, particularly in younger patients without comorbidity who undergo surgery at high-volume hospitals.

List of scientific papers

I. Yanes M, Santoni G, Maret-Ouda J, Ness-Jensen E, Färkkilä M, Lynge E, Pukkala E, Romundstad P, Tryggvadottir L, von Euler-Chelpin M, Lagergren J. Laryngeal and pharyngeal squamous cell carcinoma after antireflux surgery in the five Nordic countries. Annals of Surgery. 2020. [Accepted]
https://doi.org/10.1097/SLA.0000000000004423

II. Yanes M, Santoni G, Maret-Ouda J, Ness-Jensen E, Färkkilä M, Lynge E, Nwaru B, Pukkala E, Romundstad P, Tryggvadottir L, von Euler-Chelpin M, Lagergren J. Antireflux surgery and risk of lung cancer by histological type in a multinational cohort study. European Journal of Cancer. 2020 Oct; 138:80-88.
https://doi.org/10.1016/j.ejca.2020.07.018

III. Yanes M, Santoni G, Maret-Ouda J, Ness-Jensen E, Färkkilä M, Lynge E, Pukkala E, Romundstad P, Tryggvadottir L, von Euler-Chelpin M, Lagergren J. Survival after antireflux surgery versus medication in patients with reflux oesophagitis or Barrett’s oesophagus: a multinational cohort study. British Journal of Surgery. 2021.
https://doi.org/10.1016/j.ejca.2020.07.018

IV. Yanes M, Santoni G, Maret-Ouda J, Markar S, Ness-Jensen E, Kauppila J, Färkkilä M, Lynge E, Pukkala E, Tryggvadottir L, von Euler-Chelpin M, Lagergren J. Mortality, reoperation and hospital stay within 90 days of primary and secondary antireflux surgery in a population-based multinational study. Gastroenterology. 2021. [Accepted]
https://doi.org/10.1053/j.gastro.2021.02.022