Prostate Cancer
Conditions
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.
Interventions
DRUGPropranolol
Propranolol capsules 20mg taken orally. Day: 1-3: 20mg twice daily Day: 4-19 (25 , In cases of delayed RALP an extension of up to 6 days is allowed.in cases of delayed surgery). 2x 20mg twice daily Day 20-22 20mg twice daily
Sponsors
Ivar, Ragna og Morten Holes legat til fremme av kreftforskningen i Norge
Fondsstiftelsen ved Oslo Universitetssykehus
Oslo University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
parallel-group, phase 2, double-blind, 2-arm study
Eligibility
Sex/Gender
MALE
Age
40 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* European Association of Urology Intermediate- and High Risk for Biochemical recurrence and planned for curative RALP * ECOG Performance Status 0-1
Exclusion criteria
Medical Conditions 1. Sick sinus syndrome 2. Atrioventricular (AV) block grade 2 and 3 3. Recent (3 months) myocardial infarction 4. Known unstable- or vasospastic- angina 5. Heart failure (New York Heart Association \[NYHA\] \> 2) 6. Symptomatic peripheral vascular disease (e.g. intermittent claudication) 7. Known pulmonary hypertension 8. Known carotid artery stenosis or recent (3 months) stroke 9. Bronchial asthma or other chronic obstructive pulmonary disease (COPD) 10. Kidney failure (estimated Glomerular filtration rate \[eGFR\]\<50) 11. Liver failure (cirrhosis, jaundice, signs of hepatic decompression) 12. Unregulated diabetes mellitus 13. Untreated thyroid disorder 14. Depressive episode within last 6 months (within last 12 months if major depressive episode) 15. Known drug allergy against propranolol or excipients 16. Any medical conditions considered to prohibit Propranolol use as judged by the treating physician (including frailty). 17. Participants with known substance- or alcohol-abuse Prior/Concomitant Therapy 18. Recent (\<3 month) use of systemic beta-blockers prior to screening. 19. Patients receiving non-dihydropyridine calcium channel blocking agents (eg diltiazem, verapamil) 20. Patients receiving anti-arrhythmic agents (e.g. amiodarone, sotalol, digoxin, verapamil, flecainide) 21. Patients receiving digoxin, rizatriptan, hydralazine, fluvoksamin, or fluoksetin 22. Patients using daily anxiolytics (e.g. benzodiazepines), alpha-receptor adrenergic agonists (e.g. clonidine) 23. Recommendations in the Summary of Product Characteristics for propranolol regarding concomitant use of other medications will be adhered to. Diagnostic assessments 24. Sinus bradycardia (\<60 beats/minute) 25. Resting blood pressure \<110/60mmHg OR hypertension BP \>160/100 26. AV-block 2 or 3 on ECG
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Determine the bioavailability of propranolol | Up to 5 weeks | Serum levels of propranolol pre-operatively and at end of PeP-RALP medication. |
| 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. |
| 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). |
| Surgical complications | Up to 9 weeks | Frequence (n=) and severity of surgical complications as classified by the Clavian-Dindo classification. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Difference in prognostic markers (e.g. Decipher GRID transcriptome analysis) between treatment arms. Identify predictive biomarkers for propranolol responsiveness (e.g. Decipher GRID transcriptome analysis) | up to 1 year | Determine the effect of pre-operative propranolol treatment on prognostic markers and assess for predictive biomarkers. Identify predictive biomarkers for propranolol responsiveness. |
| Differences between intervention arms with regard to intraoperative alterations in cerebral autoregulation and intracranial pressure, measured by transcranial doppler (TCD) floe velocity. | up to 1 year | Intraoperative alterations in cerebral autoregulation and intracranial pressure by Transcranial Doppler flow velocity measurement of the middle cerebral artery. |
| Immunohistochemistry and Image mass cytometry of tumor to assess for differences between treatment arms. Flow cytometry to assess of periferal blood to assess for differences between treatment arms. | Up to 9 weeks | Immunohistochemistry and image mass cytometry to assess for differences between treatment arms in intra-tumor immune cell infiltration. Flow cytometry to assess differences between treament arms in systemic immune cell acitivity. |
| Change in perceived distress during the study. | Up to 9 weeks | Investigate alterations in perioperative perceived distress, assessed by Hospital Anxiety and Depression Scale (HADS) |
Countries
Norway
Outcome results
None listed