Perioperative Propranolol During Prostatectomy to Decrease Cancer Recurrence
- Registration Number
- NCT05679193
- Lead Sponsor
- Oslo University Hospital
- Brief Summary
The purpose of this study is to assess the feasibility of conducting a larger randomized controlled trial to assess the efficacy of perioperative propranolol capsules compared with placebo capsules in decreasing recurrence of prostate cancer (PCa) after robotic assisted laparoscopic prostatectomy (RALP) in participants with intermediate to high-risk for prostate cancer recurrence.
- Detailed Description
PCa is the most commonly diagnosed cancer in Norway (2020) and RALP is the most frequent curative treatment offered to men with non-metastatic PCa. Biochemical recurrence (BCR) is estimated to occur to 40% of patients with EAU IR and HR PCa. Attempts to combat the high recurrence rates after RALP with neoadjuvant treatment, aiming to reduce the local tumor burden and treat possible micrometastasis, has of yet not proven beneficial.
The prostate is highly innervated and recent evidence has shown the importance of nerves in the development and progression of PCa. The action of particularly adrenergic nerves, in sum lead to a pro-cancerous and metastatic state by influencing key hallmarks of cancer like apoptosis resistance, angiogenesis, immune suppression, invasiveness and metastasis.
Perioperative stress caused by the cancer surgery, in this case RALP, has been found to promote cancer progression and recurrence both by enhancing growth of preexisting residual tumor/micrometastasis and facilitating formation of new metastasis. The surgical stress response cause a catecholamine-induced cancer progression where β2-adrenergic receptor (ADRB2) have a key role.
Our newly published pharma co-epidemiologic study indicate perioperative stress can be targeted by a non-selective ß-blocker (nsBB) like propranolol \[1\]. RCTs have found perioperative administration of propranolol alone, or in conjunction with COX-2 inhibition, to be safe and to reduce biomarkers associated with poor prognosis compared with the control group receiving placebo medication in patients undergoing radical surgery for breast-, ovarian- and colorectal cancer \[2-7}.
The result of our register study, together with existing evidence of an effect of propranolol/nsBBs, provides foundation for PeP-RALP, a pilot study to establish the recruitment- and infrastructure feasibility of a double-blinded, placebo controlled RCT. The results of this pilot study will be used to investigate the feasibility of a formal larger RCT aiming to assess efficacy of perioperative propranolol to reduce PCa recurrence and progression after RALP.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 40
- European Association of Urology Intermediate- and High Risk for Biochemical recurrence and planned for curative RALP
- ECOG Performance Status 0-1
Medical Conditions
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Sick sinus syndrome
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Atrioventricular (AV) block grade 2 and 3
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Recent (3 months) myocardial infarction
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Known unstable- or vasospastic- angina
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Heart failure (New York Heart Association [NYHA] > 2)
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Symptomatic peripheral vascular disease (e.g. intermittent claudication)
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Known pulmonary hypertension
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Known carotid artery stenosis or recent (3 months) stroke
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Bronchial asthma or other chronic obstructive pulmonary disease (COPD)
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Kidney failure (estimated Glomerular filtration rate [eGFR]<50)
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Liver failure (cirrhosis, jaundice, signs of hepatic decompression)
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Unregulated diabetes mellitus
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Untreated thyroid disorder
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Depressive episode within last 6 months (within last 12 months if major depressive episode)
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Known drug allergy against propranolol or excipients
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Any medical conditions considered to prohibit Propranolol use as judged by the treating physician (including frailty).
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Participants with known substance- or alcohol-abuse
Prior/Concomitant Therapy
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Recent (<3 month) use of systemic beta-blockers prior to screening.
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Patients receiving non-dihydropyridine calcium channel blocking agents (eg diltiazem, verapamil)
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Patients receiving anti-arrhythmic agents (e.g. amiodarone, sotalol, digoxin, verapamil, flecainide)
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Patients receiving digoxin, rizatriptan, hydralazine, fluvoksamin, or fluoksetin
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Patients using daily anxiolytics (e.g. benzodiazepines), alpha-receptor adrenergic agonists (e.g. clonidine)
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Recommendations in the Summary of Product Characteristics for propranolol regarding concomitant use of other medications will be adhered to.
Diagnostic assessments
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Sinus bradycardia (<60 beats/minute)
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Resting blood pressure <110/60mmHg OR hypertension BP >160/100
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AV-block 2 or 3 on ECG
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Propranolol Participants will receive Propranolol capsule for a period of 22-28 days, low dose (1 capsule twice daily) treatment the first- and last- three days of the treatment period. Higher dose (2 capsules twice daily) for the rest of the treatment period. Propranolol Propranolol Participants will receive Propranolol capsule for a period of 22-28 days, low dose (1 capsule/20mg propranolol twice daily) treatment the first- and last- three days of the treatment period. Higher dose (2 capsules/40mg propranolol twice daily) for the rest of the treatment period.
- Primary Outcome Measures
Name Time Method The feasibility of conducting a formal larger RCT to compare the efficacy of propranolol vs placebo to decrease PCa recurrence following RALP. The total duration of study participation from screening to end of follow-up is 50-102 days per participant. The primary outcome will be assessed when inclusion is completed, or if inclusion is not completed within 12 months. Numbers of eligible participants needed to screen to include 40 patients in the study, reported as % of eligible participants that subsequently were included in the study.
Compliance of study intervention (defined as \>80% of doses taken). Reported as % of participants compliant to the study intervention before RALP and % of participants compliant to the study intervention after RALP.
- Secondary Outcome Measures
Name Time Method Determine the effect of preoperative propranolol treatment on the serum level of PSA 7-14 days Changes in PSA levels after 7-14 days of PeP-RALP medication.
To determine the effect of propranolol on post-operative biochemical failure Up to 9 weeks Proportion of patients with serum PSA levels above 0.1 ng/ml at 6 weeks post-RALP.
Surgical complications Up to 9 weeks Frequence (n=) and severity of surgical complications as classified by the Clavian-Dindo classification.
Intraoperative anesthesiological and surgical challenges Surgical complications in PeP RALP patients 1 day Anesthesiological challenges are assed by:
Proportion of patients (%) in each intervention group requiring vasopressors to maintain an acceptable mean arterial pressure (MAP \>60mmhg). Amount of vasopressor needed.
Surgical challenges are assed by:
The surgical procedure time (minutes) and estimated intraoperative blood loss (milliliters).Safety and tolerability of PeP-RALP intervention 9 weeks Safety:
Proportion (%) of patients experiencing treatment related clinical significant hypotension and/or bradycardia.
Adverse events of PeP-RALP medication as assessed by CTCAE v5.0.
Tolerability:
Proportion (%) of patients tolerating daily dose of 80mg propranolol.Determine the effect of RALP on catecholamine levels Up to 5 weeks Changes in catecholamine levels in the perioperative period.
Determine the bioavailability of propranolol Up to 5 weeks Serum levels of propranolol pre-operatively and at end of PeP-RALP medication.
Trial Locations
- Locations (1)
Oslo University Hospital The Norwegian Radium Hospital
🇳🇴Oslo, Norway