Abstract
Introduction
Based on translational and epidemiological evidence, perioperative inhibition of beta-adrenergic
and COX2 signaling can reduce the risk for post-surgical metastatic disease. Here
we aimed to assess in a pilot study the impact of a perioperative combined COX-2 and
beta-adrenergic blockade on long-term cancer outcomes in colorectal cancer patients
undergoing curative surgery.
Materials and methods
Thirty-four newly diagnosed colorectal cancer patients without evidence of metastases
enrolled in this double-blinded placebo-controlled randomized clinical trial (treatment,
n = 16; placebo, n = 18). A 20-day oral treatment of propranolol and etodolac regimen
was initiated 5 days before surgery. Beneficial effects on short-term molecular biomarkers
of cancer progression were reported earlier. Here we present outcomes of five postoperative
years of disease-free-survival and overall survival.
Results
Adverse event rates were equivalent between the two groups. Intent-to-treat analyses
of 5-year follow-up showed that 2/16 (12.5%) vs 9/18 (50%) patients exhibited recurrence
in treatment vs placebo groups, respectively (p = 0.033), and 2/16 (12.5%) vs 4/18
(22%) died (p = 0.467). In protocol compliant patients 0/11 (0%) vs. 8/17 (47%) exhibited
recurrence in treatment vs. placebo groups, respectively (p = 0.007), and 0/11 (0%)
and 3/17 (17.6%) died (p = 0.151).
Conclusions
In this pilot clinical trial, a combined perioperative treatment with propranolol
and etodolac significantly improved 5-year disease-free-survival. The small sample
size and a single center study design merits caution in interpreting these results,
specifically in estimating the effect-size. Larger studies in colorectal cancer are
warranted and needed.
Keywords
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References
- Pattern, stage, and time of recurrent colorectal cancer after curative surgery.Clin Colorectal Cancer. 2019; 18: e223-e228https://doi.org/10.1016/j.clcc.2019.01.003
- Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials.J Clin Oncol. 2005; 23: 8664-8670https://doi.org/10.1200/JCO.2005.01.6071
- Exploiting the critical perioperative period to improve long-term cancer outcomes.Nat Publ Gr. 2015;12(April; : 213-226https://doi.org/10.1038/nrclinonc.2014.224
- Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling.Cancer. 2019; 125: 45-56https://doi.org/10.1002/cncr.31594
- Molecular pathways: beta-adrenergic signaling in cancer.Clin Cancer Res. 2012; 18: 1201-1206https://doi.org/10.1158/1078-0432.CCR-11-0641
- Stress and cancer. Part I: mechanisms mediating the effect of stressors on cancer.J Neuroimmunol. 2020; 346577311https://doi.org/10.1016/j.jneuroim.2020.577311
- Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674https://doi.org/10.1016/j.cell.2011.02.013
- The impact of postoperative inflammation on recurrence in patients with colorectal cancer.Int J Clin Oncol. 2020; 25: 602-613https://doi.org/10.1007/s10147-019-01580-1
- Reducing the risk of post-surgical cancer recurrence: a perioperative anti-inflammatory anti-stress approach.Future Oncol. 2018; 14: 1017-1021https://doi.org/10.2217/fon-2017-0635
- Tumor excision as a metastatic Russian roulette: perioperative interventions to improve long-term survival of cancer patients.Trends in Cancer. 2020; 6: 951-959https://doi.org/10.1016/J.TRECAN.2020.06.004
- Perioperative events influence cancer recurrence risk after surgery.Nat Rev Clin Oncol 2017 154. 2017; 15: 205-218https://doi.org/10.1038/nrclinonc.2017.194
- Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: a randomized controlled trial.Cancer. 2020; 126: 3991-4001https://doi.org/10.1002/cncr.32950
- Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial.Clin Cancer Res. 2017; 23: 4651-4661https://doi.org/10.1158/1078-0432.CCR-17-0152
- Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome.Brain Behav Immun. 2018; 73: 294-309https://doi.org/10.1016/j.bbi.2018.05.014
- Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: a randomized controlled trial.Cancer. 2020; 126: 3991-4001https://doi.org/10.1002/cncr.32950
- Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.JNCI J Natl Cancer Inst. 2007; 99: 998-1003https://doi.org/10.1093/JNCI/DJM024
- Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481https://doi.org/10.1080/01621459.1958.10501452
- Preoperative β-blockade with propranolol reduces biomarkers of metastasis in breast cancer: a phase II randomized trial.Clin Cancer Res. 2020; 26 (doi:10.1158/1078-0432.CCR-19-2641/75779/AM/PRE-OPERATIVE-BLOCKADE-WITH-PROPRANOLOL-REDUCES): 1803-1811
- Propranolol inhibits molecular risk markers in HCT recipients: a phase 2 randomized controlled biomarker trial.Blood Adv. 2020; 4: 467-476https://doi.org/10.1182/BLOODADVANCES.2019000765
- Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial.Clin Cancer Res. 2017; 23: 4651-4661https://doi.org/10.1158/1078-0432.CCR-17-0152
- Stress and cancer: mechanisms, significance and future directions.Nat Rev Cancer 2021 2112. 2021; 21: 767-785https://doi.org/10.1038/s41568-021-00395-5
- Sex differences in colorectal cancer survival: population-based analysis of 164,996 colorectal cancer patients in Germany.PLoS One. 2013; 8e68077https://doi.org/10.1371/journal.pone.0068077
- Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?.J Clin Oncol. 2004; 22: 1797-1806https://doi.org/10.1200/JCO.2004.09.059
- Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor.J Immunol. 2010; 184: 2449-2457https://doi.org/10.4049/JIMMUNOL.0903301
- Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2 inhibition.Brain Behav Immun. 2016; 58: 91-98https://doi.org/10.1016/J.BBI.2016.05.017
- Improved disease-free survival after prehabilitation for colorectal cancer surgery.Ann Surg. 2019; 270: 493-501https://doi.org/10.1097/SLA.0000000000003465
- Impact of the preoperative controlling nutritional status (CONUT) score on the survival after curative surgery for colorectal cancer.PLoS One. 2015; 10e0132488https://doi.org/10.1371/journal.pone.0132488
- Follow-up after curative resection of colorectal cancer: a meta-analysis.Dis Colon Rectum. 2007; 50: 1783-1799https://doi.org/10.1007/s10350-007-9030-5
- Five-year follow-up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer.Br J Surg. 2010; 97: 1638-1645https://doi.org/10.1002/bjs.7160
- Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery.N Engl J Med. 1994; 331: 502-507https://doi.org/10.1056/NEJM199408253310803
- Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial.Lancet. 2008; 371: 1839-1847https://doi.org/10.1016/S0140-6736(08)60601-7
- Selective β1-antagonism with bisoprolol is associated with fewer postoperative strokes than atenolol or MetoprololA single-center cohort study of 44,092.Anesthesiology. 2013; 119: 777-787
- ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American college of cardiology/American heart association task force on practice guidelines.J Am Coll Cardiol. 2014. 2014; 64: e77-e137https://doi.org/10.1016/j.jacc.2014.07.944
- New ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management.Eur Heart J. 2014; 35: 2344-2345https://doi.org/10.1093/eurheartj/ehu285
- Enhanced Recovery after Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice.Acta Anaesthesiol Scand. 2016; 60: 289-334https://doi.org/10.1111/aas.12651
- Clinical trial: the impact of cyclooxygenase inhibitors on gastrointestinal recovery after major surgery - a randomized double blind controlled trial of celecoxib or diclofenac vs. placebo.Aliment Pharmacol Ther. 2009; 30: 987-998https://doi.org/10.1111/j.1365-2036.2009.04126.x
- Analgesic efficacy of celecoxib in postoperative oral surgery active- and placebo-controlled study.Clin Therapeut. 2007; 29: 2498-2510
- Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation.Pain. 2007; 129: 279-286https://doi.org/10.1016/j.pain.2006.10.020
- Risk of anastomotic leakage with nonsteroidal anti-inflammatory drugs within an enhanced recovery program.J Gastrointest Surg. 2016; 20: 776-782https://doi.org/10.1007/S11605-015-3010-1/TABLES/5
- Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer.Colorectal Dis. 2022; 24: 933-942https://doi.org/10.1111/CODI.16074
- Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling.Cancer. 2019; 125: 45-56https://doi.org/10.1002/CNCR.31594
Article info
Publication history
Published online: October 20, 2022
Accepted:
October 17,
2022
Received in revised form:
September 30,
2022
Received:
July 19,
2022
Identification
Copyright
© 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
