Perioperative use of a β-blocker and an anti-inflammatory drug in pancreatic cancer
Pancreatic Resection with perioperative Off-label Study of Propranolol and Etodolac – a phase II Randomised trial (PROSPER).
Funding
Why this trial
Pancreatic cancer, is one of the deadliest cancers worldwide, with increasing rates of diagnosis and death. PDAC stands for pancreatic ductal adenocarcinoma, which is the most common type of pancreatic cancer—accounting for over 90% of cases. Even for tumours for which surgery is possible (15-20% of patients)—a major treatment step for some patients—the risk of cancer returning remains very high. Research shows that the body’s reaction to surgery, including stress and inflammation, may actually help the cancer spread. These effects are mainly caused by stress hormones (catecholamines) and inflammatory substances like prostaglandins. Blocking these processes during the period around surgery could help reduce the risk of recurrence.
Why this intervention
Research shows that the time period between diagnosis and surgery represents a window of opportunity for therapy aiming at reducing recurrence. Pancreatic disease recurrence appears to be stimulated by perioperative psychological and surgical stress. Psychological stress is mediated by catecholamines (noradrenalin and adrenalin) and beta-adrenergic signalling, while surgical stress is mediated by prostaglandins synthesised by cyclo-oxygenase 2 (COX2) enzymes, which are typically overexpressed in pancreatic tumour cells.
Many studies indicate that the mechanisms of catecholamines and prostaglandins play an important role in the progression of PDAC, PDAC cell invasion and proliferation, and tumour metastasis. Perioperative co-administration of the beta-blocker propranolol and the COX2-inhibitor etodolac in patients with locally advanced or metastatic pancreatic cancer, showed that overall survival increased with 7 months.
Therefore, the perioperative co-administration of propranolol and etodolac may also contribute to reducing recurrence of newly diagnosed resectable PDAC.
Trial design
This was a phase II, randomised, two-armed, double-blinded, placebo-controlled, single-centre trial of a combination therapy of propranolol and etodolac in 100 patients with operable cancer of the pancreatic head planned for elective pancreatoduodenectomy.
The primary objective was to study the safety, feasibility and generate first efficacy data of perioperative propranolol and etodolac in these patients. Eligible patients were randomised between a daily intake of placebo from 10 days before surgery to 14 days after surgery, or daily intake of 2 doses of 400mg etodolac from 10 days before surgery to 14 days after surgery and 2 doses of 20mg propranolol daily during the 10 days before the surgery, 2 doses of 40mg propranolol on the day of surgery and one week after, and 2 doses of 20mg propranolol the second week after the operation. The total duration of treatment was 25 days and the follow-up was 24 months.
Results
The trial faced challenges with recruitment and had to be closed early after enrolling just 26 of the planned 100 patients, of which only 20 could be analysed. Even so, some analysis was done. This showed that the experimental treatment was safe, with fewer serious adverse events (6 vs. 14) compared to the patients reveiving placebo. Before surgery, both groups took their drugs equally well, while after surgery, adherence to the medication was lower in the patients that received the experimental treatment group.
In terms of cancer outcomes, patients receiving propranolol and etodolac had a median disease-free survival of 16.4 months vs. 11.3 months in the placebo group, meaning that the treatment group had fewer cases of the cancer coming back. In the treatment group, there were fewer cases of recurrence in more distant parts of the body (in 11.1% of treated patients, compared to 54.5% in the placebo group). Although the number of patients in the trial was too small to draw any conclusions, these results suggest the treatment may have potential benefit.
The research on biological changes showed that the treatment helped the immune system to keep functioning after surgery. It reduced the loss of important immune cells and lowered inflammation. Looking at the tissue, there were signs of more immune cells in the tumours from patients in the treatment group, supporting the idea that the therapy may boost the immune cells to fight the cancer.
Conclusion
Although there were no safety concerns, an assessment of the treatment with propranolol and etodolac in the perioperative period surrounding partial pancreatoduodenectomy was not feasible within this trial. Nonetheless, the exploratory results of the trial revealed some interesting findings, which merit further investigation in future projects.
Please find a link to the full publication here.
Partners
Principal Investigators:
- Prof. Dr. Med. Felix J. Hüttner, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Prof. Dr. Med. Markus Diener, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
Sponsor:
- Ruprecht-Karls-University, Heidelberg Medical Faculty, Universitätsklinikum Heidelberg, Heidelberg, Germany
Our role
Why we support this trial
Intervention has little or no commercial value
Expected survival benefit
No major hurdle for clinical implementation
Funding
Questions about participation?
References
Kim-Fuchs, C., et al. (2014). Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain, Behavior, and Immunity, 40, 40-7. doi:10.1016/j.bbi.2014.02.019
Partecke, L.I., et al. (2016). Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade. Pancreatology, 16(3), 423-33. doi:10.1016/j.pan.2016.03.005
Siegel, R.L., et al. (2015). Cancer statistics, 2015. CA Cancer J Clin, 65(1),5-29. doi:10.3322/caac.21254
Valle, J. W., et al. (2014). Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: Ongoing lessons from the ESPAC-3 study. J. Clin. Oncol., 32(6),504-12. doi:10.1200/JCO.2013.50.7657
Hüttner, F. J., et al (2020). Pancreatic resection with perioperative drug repurposing of propranolol and etodolac: trial protocol of the phase-II randomised placebo controlled PROSPER trial. BMJ Journals, 2020 Sep 30;10(9):e040406, doi: 10.1136/bmjopen-2020-040406.
Author: Kristine Beckers (Trial Manager)
Last updated: August 2025