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Pheochromocytoma is a rare, catecholamine (ex. adrenaline) secreting tumor that requires preoperative alpha blockade to minimize intraoperative hemodynamic instability, thereby reducing intra- and postoperative morbidity and mortality. Phenoxybenzamine is a non-selective alpha blocker that is significantly more expensive and is associated with increased adverse effects in comparison with selective alpha blockers such as doxazosin. Retrospective studies show minimal differences in hemodynamic instability and no differences in postoperative morbidity and mortality between selective vs. non-selective alpha blockers. This study is a randomized controlled trial that will compare hemodynamic instability, morbidity, mortality, cost, and quality of life between patients blocked with phenoxybenzamine vs. doxazosin.
Pheochromocytoma is a catecholamine (ex. adrenaline) secreting tumor for which the primary treatment is surgical resection. Due to the hormones secreted by the tumor, alpha receptors on peripheral blood vessels are activated, causing constriction of these blood vessels and dangerously high blood pressure. During resection of the tumor, the source of excess hormone secretion is abruptly removed, which can lead to life-threatening blood pressure fluctuations during surgery.
Alpha blockers are a class of medication that blocks the alpha receptor on blood vessels. Given preoperatively over a few weeks, these medications negate the effects of the excess hormones secreted by the pheochromocytoma, reducing the frequency and severity of dangerous blood pressure fluctuations intraoperatively and postoperatively. Preoperative alpha blockade is therefore critical to safely perform surgery to resect pheochromocytoma.
Phenoxybenzamine, a non-selective alpha blocker, is the most common medication used to alpha block patients prior to pheochromocytoma resection. However, due to increasing drug costs and increased side effects in comparison with selective alpha blockers, there is a renewed interest in studying alternatives to phenoxybenzamine.
Selective alpha blockers such as doxazosin are also commonly used to alpha block patients prior to pheochromocytoma resection. Selective alpha blockers are significantly less expensive and are associated with fewer side effects than phenoxybenzamine. Most retrospective studies comparing phenoxybenzamine with selective alpha blockers show no difference in intraoperative blood pressure fluctuations, morbidity, or mortality in pheochromocytoma resection. However, no prospective, randomized controlled trials comparing phenoxybenzamine to selective alpha blockers have been performed.
The purpose of our study is to analyze preoperative, intraoperative, and postoperative outcomes in patients randomized to receive phenoxybenzamine (non-selective) or doxazosin (selective) for alpha blockade prior to pheochromocytoma resection. Outcomes will include postoperative morbidity and mortality, intraoperative hemodynamic instability, quality of life, and cost.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phenoxybenzamine | Active Comparator | 3-4 weeks prior to date of surgery, patient will start phenoxybenzamine 10mg PO twice daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). |
|
| Doxazosin | Experimental | 3-4 weeks prior to date of surgery, patient will start doxazosin 1 mg PO daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phenoxybenzamine | Drug | Non-selective alpha blocker |
|
| Measure | Description | Time Frame |
|---|---|---|
| Hemodynamic Instability | Proportion of operative time outside target thresholds: SBP >180 or <80; DBP > 90; MAP>150 or <50; HR>90. Arterial line blood pressure measurements were extracted from the electronic medical record every 60 seconds. | Intraoperative, approximately 90 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| Mortality | Death within 30 days of surgery | 30 days postoperatively |
| Daily Cost of Drug | Preoperative (2-3 weeks prior to surgery) | |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Yeh, MD | University of California, Los Angeles | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Los angeles | Los Angeles | California | 90025 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25822781 | Background | Livingstone M, Duttchen K, Thompson J, Sunderani Z, Hawboldt G, Sarah Rose M, Pasieka J. Hemodynamic Stability During Pheochromocytoma Resection: Lessons Learned Over the Last Two Decades. Ann Surg Oncol. 2015 Dec;22(13):4175-80. doi: 10.1245/s10434-015-4519-y. Epub 2015 Mar 31. | |
| 27552619 | Background | Kesselheim AS, Avorn J, Sarpatwari A. The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform. JAMA. 2016 Aug 23-30;316(8):858-71. doi: 10.1001/jama.2016.11237. |
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19 patients pretreated with phenoxybenzamine included for analysis: 15 historical patients who were pre-treated with phenoxybenzamine by their provider, 4 prospective randomized patients.
20 patients pretreated with doxazosin included for analysis: 8 prospective randomized patients, 6 crossover patients (initially assigned phenoxybenzamine but elected to receive only doxazosin due to treatment cost), 6 prospective non-randomized patients
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| ID | Title | Description |
|---|---|---|
| FG000 | Phenoxybenzamine | 3-4 weeks prior to date of surgery, patient will start phenoxybenzamine 10mg PO twice daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Phenoxybenzamine: Non-selective alpha blocker |
| FG001 | Doxazosin | 3-4 weeks prior to date of surgery, patient will start doxazosin 1 mg PO daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Doxazosin: Selective alpha blocker |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Phenoxybenzamine | 3-4 weeks prior to date of surgery, patient will start phenoxybenzamine 10mg PO twice daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Phenoxybenzamine: Non-selective alpha blocker |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Hemodynamic Instability | Proportion of operative time outside target thresholds: SBP >180 or <80; DBP > 90; MAP>150 or <50; HR>90. Arterial line blood pressure measurements were extracted from the electronic medical record every 60 seconds. | Posted | Median | Inter-Quartile Range | percentage of total operative time | Intraoperative, approximately 90 minutes |
|
30 days post-surgery
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phenoxybenzamine | 3-4 weeks prior to date of surgery, patient will start phenoxybenzamine 10mg PO twice daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Phenoxybenzamine: Non-selective alpha blocker |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Masha Livhits, MD | University of California Los Angeles | 310-206-0585 | mlivhits@mednet.ucla.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 15, 2021 | Jan 6, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010673 | Pheochromocytoma |
| D010235 | Paraganglioma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D010643 | Phenoxybenzamine |
| D017292 | Doxazosin |
| ID | Term |
|---|---|
| D005021 | Ethylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011224 | Prazosin |
| D011799 |
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| Doxazosin | Drug | Selective alpha blocker |
|
|
| Quality of Life- Physical Functioning, Role Limitations Due to Physical Problems, Bodily Pain, General Health Perceptions, Vitality, Social Functioning, Role-limitations Due to Emotional Problems, and Mental Health |
Patients will take the SF-36 as well as a symptom survey describing the frequency and impact on their quality of life at several time points including prior to starting alpha blockade, immediately prior to surgery after being sufficiently blocked, and postoperatively at 30 days, 3 months, 6 months, and 1 year |
| From date of surgery (-2 to 3 weeks, -1 day, 30 days, 3 months, 6 months, 1 year) |
| Morbidity as Assessed by Occurrence of Adverse Events | Morbidity will be graded by Clavien Classification of adverse events | Postoperatively during inpatient stay and during readmissions up to 30 days postoperatively |
| Participants Admitted to Post-operative Intensive Care Unit (ICU) | up to 30 days post-surgery |
| 27561909 | Result | Randle RW, Balentine CJ, Pitt SC, Schneider DF, Sippel RS. Selective Versus Non-selective alpha-Blockade Prior to Laparoscopic Adrenalectomy for Pheochromocytoma. Ann Surg Oncol. 2017 Jan;24(1):244-250. doi: 10.1245/s10434-016-5514-7. Epub 2016 Aug 25. |
| 24939623 | Result | Kiernan CM, Du L, Chen X, Broome JT, Shi C, Peters MF, Solorzano CC. Predictors of hemodynamic instability during surgery for pheochromocytoma. Ann Surg Oncol. 2014 Nov;21(12):3865-71. doi: 10.1245/s10434-014-3847-7. Epub 2014 Jun 18. |
| 25456922 | Result | Brunaud L, Boutami M, Nguyen-Thi PL, Finnerty B, Germain A, Weryha G, Fahey TJ 3rd, Mirallie E, Bresler L, Zarnegar R. Both preoperative alpha and calcium channel blockade impact intraoperative hemodynamic stability similarly in the management of pheochromocytoma. Surgery. 2014 Dec;156(6):1410-7; discussion1417-8. doi: 10.1016/j.surg.2014.08.022. Epub 2014 Nov 11. |
| 20546874 | Result | Weingarten TN, Cata JP, O'Hara JF, Prybilla DJ, Pike TL, Thompson GB, Grant CS, Warner DO, Bravo E, Sprung J. Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma. Urology. 2010 Aug;76(2):508.e6-11. doi: 10.1016/j.urology.2010.03.032. Epub 2010 May 23. |
| 12192533 | Result | Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg. 2002 Aug;26(8):1037-42. doi: 10.1007/s00268-002-6667-z. Epub 2002 Jun 19. |
| BG001 | Doxazosin | 3-4 weeks prior to date of surgery, patient will start doxazosin 1 mg PO daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Doxazosin: Selective alpha blocker |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Doxazosin |
3-4 weeks prior to date of surgery, patient will start doxazosin 1 mg PO daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Doxazosin: Selective alpha blocker |
|
|
|
| Secondary | Mortality | Death within 30 days of surgery | Posted | Count of Participants | Participants | 30 days postoperatively |
|
|
|
| Secondary | Daily Cost of Drug | Posted | Median | Inter-Quartile Range | Dollars | Preoperative (2-3 weeks prior to surgery) |
|
|
|
| Secondary | Quality of Life- Physical Functioning, Role Limitations Due to Physical Problems, Bodily Pain, General Health Perceptions, Vitality, Social Functioning, Role-limitations Due to Emotional Problems, and Mental Health | Patients will take the SF-36 as well as a symptom survey describing the frequency and impact on their quality of life at several time points including prior to starting alpha blockade, immediately prior to surgery after being sufficiently blocked, and postoperatively at 30 days, 3 months, 6 months, and 1 year | Due to staff turnover and COVID-19 restrictions, data was not collected or analyzed. | Posted | From date of surgery (-2 to 3 weeks, -1 day, 30 days, 3 months, 6 months, 1 year) |
|
|
| Secondary | Morbidity as Assessed by Occurrence of Adverse Events | Morbidity will be graded by Clavien Classification of adverse events | Posted | Number | events | Postoperatively during inpatient stay and during readmissions up to 30 days postoperatively |
|
|
|
| Secondary | Participants Admitted to Post-operative Intensive Care Unit (ICU) | Posted | Count of Participants | Participants | up to 30 days post-surgery |
|
|
|
| 0 |
| 19 |
| 0 |
| 19 |
| 0 |
| 19 |
| EG001 | Doxazosin | 3-4 weeks prior to date of surgery, patient will start doxazosin 1 mg PO daily. Phenoxybenzamine will then be titrated to a blood pressure <120/80 (sitting) with mild orthostatic hypotension (drop in systolic blood pressure by 20 points or diastolic blood pressure by 10 points from sitting to standing position); systolic blood pressure not less than 90 (standing). Doxazosin: Selective alpha blocker | 0 | 20 | 0 | 20 | 0 | 20 |
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| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| Quinazolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |