Paraganglioma, Pheochromocytoma
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGPhenoxybenzamine
Non-selective alpha blocker
DRUGDoxazosin
Selective alpha blocker
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults with pheochromocytoma / paraganglioma undergoing surgical resection
Exclusion criteria
* Children \< 18 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemodynamic Instability | Intraoperative, approximately 90 minutes | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 30 days postoperatively | Death within 30 days of surgery |
| Daily Cost of Drug | Preoperative (2-3 weeks prior to surgery) | — |
| 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 | From date of surgery (-2 to 3 weeks, -1 day, 30 days, 3 months, 6 months, 1 year) | 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 |
| Morbidity as Assessed by Occurrence of Adverse Events | Postoperatively during inpatient stay and during readmissions up to 30 days postoperatively | Morbidity will be graded by Clavien Classification of adverse events |
| Participants Admitted to Post-operative Intensive Care Unit (ICU) | up to 30 days post-surgery | — |
Countries
United States
Participant flow
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| 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 | 19 |
| 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 | 20 |
| Total | 39 |
Baseline characteristics
| Characteristic | Phenoxybenzamine | Doxazosin | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 56 years | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 15 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other/unknown | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 16 Participants | 26 Participants |
| Region of Enrollment United States | 19 participants | 20 participants | 39 participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 0 / 19 | 0 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 |
Outcome results
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.
Time frame: Intraoperative, approximately 90 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phenoxybenzamine | Hemodynamic Instability | 14 percentage of total operative time |
| Doxazosin | Hemodynamic Instability | 13 percentage of total operative time |
Comparison: Null hypothesis: hemodynamic instability time will not differ between armsp-value: 0.56Wilcoxon (Mann-Whitney)
Secondary
Daily Cost of Drug
Time frame: Preoperative (2-3 weeks prior to surgery)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phenoxybenzamine | Daily Cost of Drug | 442.20 Dollars |
| Doxazosin | Daily Cost of Drug | 5.06 Dollars |
Secondary
Morbidity as Assessed by Occurrence of Adverse Events
Morbidity will be graded by Clavien Classification of adverse events
Time frame: Postoperatively during inpatient stay and during readmissions up to 30 days postoperatively
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenoxybenzamine | Morbidity as Assessed by Occurrence of Adverse Events | 0 events |
| Doxazosin | Morbidity as Assessed by Occurrence of Adverse Events | 0 events |
Secondary
Mortality
Death within 30 days of surgery
Time frame: 30 days postoperatively
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenoxybenzamine | Mortality | 0 Participants |
| Doxazosin | Mortality | 0 Participants |
Secondary
Participants Admitted to Post-operative Intensive Care Unit (ICU)
Time frame: up to 30 days post-surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenoxybenzamine | Participants Admitted to Post-operative Intensive Care Unit (ICU) | 2 Participants |
| Doxazosin | Participants Admitted to Post-operative Intensive Care Unit (ICU) | 1 Participants |
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
Time frame: From date of surgery (-2 to 3 weeks, -1 day, 30 days, 3 months, 6 months, 1 year)
Population: Due to staff turnover and COVID-19 restrictions, data was not collected or analyzed.