Successful Lifetime/Long-Term Medical Treatment of Acid Hypersecretion in Zollinger-Ellison Syndrome (ZES): Myth or Fact? Insights from an Analysis of Results of NIH Long-Term Prospective Studies of ZES

SIMPLE SUMMARY: Zollinger-Ellison syndrome (ZES) has, since its original description, been characterized by extreme acid hypersecretion due to a neuroendocrine tumor ectopically secreting gastrin, resulting in severe, recalcitrant peptic ulcer disease/gastroesophageal reflux disease (GERD) that is refractory to standard anti-acid treatments. From the very beginning of its description in 1955, it has been well recognized that control of the acid hypersecretion, both acutely and long-term, is essential to all aspects of management of these patients. Originally, no medical treatment was effective at controlling the acid hypersecretion long-term, resulting in total gastrectomy being the initial treatment of choice. However, starting in the late 1970s with the discovery of histamine H(2)-receptor antagonists (H(2)Rs) and then in the 1980s with the widespread use of gastric H+K+ ATPase inhibitors (also called proton pump inhibitors [PPIs]), medical control of gastric acid hypersecretion became possible in almost all patients. Even though acute acid control studies, as well as short-term maintenance studies (<5 years), suggest that long-term/lifelong acid antisecretory control may be possible, this approach has been called into question recently in both case reports and small series and is becoming increasingly controversial, with the result that the best long-term strategy for treating these patients is becoming unclear. This is occurring because the long-term cure rate, even with increasingly sensitive tumor localization techniques, is <20%; thus, the majority of patients require lifelong treatment. Unfortunately, in contrast to short-term studies, there are no long-term/lifetime treatment studies of acid antisecretory control in ZES patients to address this issue. Whereas studies of long-term/lifetime treatment of patients with GERD are providing insights into the increasing number of questions about the possible long-term side effects of lifelong PPI treatment, which has applicability to ZES patients, no studies are dealing with the larger question about the continued efficacy of medical acid treatment in these patients, as well as the ability to individually manage acid secretion in all patients, which requires a different treatment approach from GERD and thus cannot be addressed by lifelong studies on GERD. The current study attempts to address these issues by analyzing the pharmacology and long-term/lifelong efficacy of medical acid antisecretory agents in ZES patients in a large, long-term NIH prospective study on ZES. ABSTRACT: Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H(2)Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H(2)Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.