gms | German Medical Science

Background: Basic research has suggested that sustained adrenergic activation can promote pancreatic cancer growth. In preclinical animal studies it has been shown that psychological stress stimulates tumor growth and increases adrenaline, noradrenaline, VEGF and NGF levels. Furthermore, patients with pancreatic cancer demonstrate higher elevated levels of psychological distress than other cancer patients. The aim of the current studies was to investigate the impact of beta-blockers in surgical resected pancreatic cancer patients.

Materials and methods: Patients from two European pancreatic centers who had undergone curative-intent resection of pancreatic ductular adenocarcinoma between 2002 and 2012 (n=631) were studied. Unvariate and multivariate analyses were performed in three groups (no beta-blocker, beta1-selective agents and non-selective agents). Furthermore, primary microtumors from human pancreatic cancer specimen were generated and treated with beta1-selective blockers (atenolol), beta2-selective blockers (ICI118, 551) and a non-selective agents (propranolol) in addition to Gemcitabine.

Results: The median age of patients in the current study was 68 years (range, 22-88 years). The sample included 176 patients who received beta-blockers. Of those, 158 (90%) were receiving beta-1–adrenergic receptor selective agents, and the remaining patients were receiving nonselective beta antagonists (n=18; 10%). The primary indication for beta-blocker use was hypertension but also included arrhythmia and postmyocardial infarction management. For patients receiving any beta-blocker, the median overall survival (OS) was 24 months versus 23 months for nonusers. The median OS of patients receiving non-selective beta-blocker was 40 months versus 23 months for for nonusers (p=0.033). Hypertension was associated with decreased OS compared with no hypertension across all groups. However, even among patients with hypertension, a longer median OS was observed among users of a nonselective beta-blockers compared with nonusers (40 months vs 19 months; p=0.041). Additionally, microtumors when treated in vitro using non-selective or beta2-selective antagonists in addition to Gemcitabine showed a significantly lower residual metabolic activity in comparison to Gemcitabine alone (p=0.032). In contrast administration of beta1-seelctive drugs did not reveal any difference.

Conclusion: Die Verabreichung von nicht-selektiven Betablockern war fast mit einer Verdopplung des Gesamtüberlebens in Patienten assoziiert, die unter kurativer Intention an einem Pankreaskarzinom operiert wurden. Eine Therapie mit selektiven beta1-Rezeptoren hatte keinen Einfluss auf das Überleben. Da sowohl durch die Verabreichung von nicht-selektiven Betablockern, als auch durch selektive beta2-Blocker, aber nicht durch selektive beta1-Blocker, die metabolische Restaktivität von Mikrotumoren gesenkt werden konnte, implizieren diese Daten, dass die zielgerichtete Therapie des beta2-adrenergen Signalwegs einen vielversprechenden Therapieansatz im Pankreaskarzinom darstellt.