Neoplasms

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Rare Diseases

Pheochromocytoma

Paraganglioma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Antihypertensive Agents

All Drugs and Chemicals

Vasodilator Agents

Doxazosin

Phenoxybenzamine

Adrenergic Agents

Adrenergic alpha-1 Receptor Antagonists

Adrenergic alpha-Antagonists

Adrenergic Antagonists

Neurotransmitter Agents

Phenoxybenzamine (capsules 10 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC.

Phenoxybenzamine (slow release tablets 4 or 8 mg, once to twice daily) is administered orally, starting 2-3 weeks before planned resection of PCC.

Starting dosage of phenoxybenzamine in hypertensive subjects:20 mg q.d. (=10 mg b.i.d.) and in normotensive subjects 10 mg q.d. (in the evening). Dose escalation until blood pressure targets are reached, with a maximum dose of 140 mg q.d. (=70 mg b.i.d.)

Starting dosage of doxazosine in hypertensive subjects:8 mg q.d. (=4 mg b.i.d.)and in normotensive subjects starting dose 4 mg q.d. (in the evening). Dose escalation until blood pressure targets are reached, with a maximum dose of 48 mg q.d. .(=24 mg b.i.d.)

Michiel N. Kerstens, MD PhD

Thera P. Links, MD PhD

Gütz J. Wietasch, MD PhD

Jaques W. Lenders, MD PhD

G D. Valk, MD PhD

E M. Eekhoff, MD PhD

P H. Bisschop, MD PhD

R A Feelders, MD PhD

Bas Havekes, MD PhD

Peter Oomen, MD PhD

I Eland, MD PhD

P H. Geelhoed- Duijvestijn, MD PhD

P Groote Veldman, MD PhD

H R Haak, MD PhD

J R. Meinardi, MD PhD

C B. Brouwer, MD PhD

P L. van Battum, MD

A A. Franken, MD PhD

* Rationale: The optimal preoperative medical management for patients with a pheochromocytoma is currently unknown. In particular, there is no agreement with respect to whether phenoxybenzamine or doxazosin is the optimal alfa-adrenoreceptor antagonist to be administered before surgical resection of a pheochromocytoma. We hypothesized that the competitive alfa1-antagonist doxazosin is superior to the non-competitive alfa1- and alfa2-antagonist phenoxybenzamine.
* Objective: comparing effects of preoperative treatment with either phenoxybenzamine or doxazosin on intraoperative hemodynamic control in patients undergoing surgical resection of a pheochromocytoma.
* Study design: Randomised controlled open-label trial.
* Study population: 18 - 55 yr old. Adult patients with a recently diagnosed benign pheochromocytoma.
* Intervention: Patients are randomised to receive oral treatment with either phenoxybenzamine or doxazosin preoperatively.
* Main study parameters/endpoints: The main study parameter is defined as the percentage of intraoperative time that blood pressure is outside the predefined target range after pretreatment with either phenoxybenzamine or doxazosin.

In this multicenter trial, we compare the effects of two commonly used drugs in patients being medically prepared for resection of a benign pheochromocytoma. Participants are not subjected to an experimental treatment of any kind, as we merely aim to describe in detail the perioperative course in general and, in particular, the intraoperative hemodynamic control in patients treated preoperatively with either phenoxybenzamine or doxazosin. A routine diagnostic work-up for pheochromocytoma will be performed in all participants. One extra blood sample (volume: 48,5 mL) is drawn before start of the study medication, and participants need to record their symptoms in a diary. In addition, patients who are pretreated in the outpatient clinic monitor their blood pressure and pulse rate at home with an automated device. Treatment with an alfa-adrenoreceptor antagonist is initiated at least 2 - 3 weeks prior to surgery. Patients who are admitted to the hospital for pretreatment with an alfa-adrenoreceptor antagonist have their blood pressure and pulse rate measured by the nursing staff. The final site visit is planned at 30 days after surgery, in line with current practice.

1. INTRODUCTION AND RATIONALE Pheochromocytoma (PCC) is a rare but clinically important catecholamine secreting neuro-endocrine tumour that typically arises from the adrenal gland. In addition, this neuro-endocrine tumour can also originate from chromaffin cells in sympathetic ganglia(1)(2). In this protocol, PCC refers to both adrenal and extra-adrenal chromaffin tumours with hypersecretion of catecholamines (i.e. norepinephrine and/or epinephrine). The annual incidence rate in the US population has been estimated to be 1-2 cases per 100,000 adult individuals (3). Data on the incidence and prevalence of PCC in the Netherlands have not been published. Based on the Dutch registry of pathology diagnoses (PALGA), we found an incidence of 117 cases of PCC in the year 2007 (unpublished observation).

   PCCs may occur as part of an autosomal dominant inherited tumor syndrome, caused by germline mutations in the RET proto-oncogene (Multiple Endocrine Neoplasia type 2 syndrome), VHL gene (von Hippel-Lindau disease), NF1 gene (Neurofibromatosis type 1), or in one of the genes encoding the subunits of mitochondrial complex II, also called succinate dehydrogenase (SDHB, SDHC, SDHD)(4). PCCs are termed 'sporadic' when the family history for PCC is negative. Overall, about 25% of all PCC patients harbour a germline mutation. Notably, germline mutations in one of the PCC susceptibility genes may also be present in a significant number of patients with a sporadic PCC, with mutation rates varying between 7.5 - 14.6% in the populations studied(5-7). Therefore, genetic testing is recommended in all patients with PCC(7). Very recently, a new PCC susceptibility gene has been described, and it seems likely that future research will result in the discovery of other genetic mutations associated with PCC(8).

   PCC constitutes a surgically curable cause of hypertension. Hypertension in patients with PCC can be either persistent or paroxysmal, but is absent in a minority of patients. It is a potentially life-threatening disease with a high risk for cardiovascular complications such as myocardial infarction, arrhythmias, cardiomyopathy, stroke and pulmonary edema(1). The clinical picture results from release of catecholamines by the tumour. This release can be evoked by stimuli that would normally not pose a hazard, such as surgery or general anaesthesia. Thus, preoperative treatment with alpha-adrenoceptor antagonists is usually recommended for prevention of these serious and potentially fatal complications(9). In one of the largest surgical series reported so far, perioperative mortality and morbidity were 2.4% and 23.6%, respectively(10).

   According to the literature, about 10% of the patients with PCC are normotensive(1). A normal blood pressure at diagnosis is relatively frequent among carriers of one the aforementioned germline mutations, as these individuals are subjected to periodic biochemical screening for the presence of PCC. It has been demonstrated that intraoperative hemodynamic instability during adrenalectomy for PCC occurred to the same extent in MEN2a patients (most of whom were normotensive) as in patients without MEN2a (most of whom were hypertensive)(11). Thus, preoperative treatment with alpha -adrenoceptor antagonists is also recommended for normotensive patients with PCC (9,11), Historically, the noncompetitive and nonselective alpha -adrenoceptor antagonist phenoxybenzamine has been the drug of choice(12). Alternatively, doxazosin - a competitive and selective alpha 1-adrenoceptor antagonist - might be at least as effective asphenoxybenzamine with fewer side effects. Notably, it has been suggested that doxazosin results in a significant and clinically relevant reduction of postoperative hypotension(13). Severe postoperative hypotension necessitates admission to the intensive care unit (ICU), where volume resuscitation and norepinephrine are administered under strict monitoring of hemodynamics. Data on the optimal preoperative pharmacological management of patients with PCC are conflicting. For example, a recent study reported comparable effects of phenoxybenzamine and doxazosin on intraoperative hemodynamic control(14).This study, however, was retrospective in design and therefore affected by several confounding factors such as lack of randomisation, non-standardised intraoperative care, and use of historical controls. Until now, prospective randomised controlled trials comparing phenoxybenzamine and doxazosin have not been conducted. Thus, the preoperative drug therapy of choice remains an unresolved issue, and at a recent international PCC symposium it was concluded that no specific recommendations can be made on this subject(9). We performed a survey among all university medical centers in the Netherlands, showing that almost half of the centers prescribed phenoxybenzamine, whereas the other centers used doxazosine as the preoperative drug of choice for patients with PCC(15). Usually, these drugs are administered during 2-3 weeks before surgery. This preoperative medical preparation takes place either in the outpatient or inpatient clinic, depending on patient-related factors (e.g. disease severity, geographical considerations) and local experience.

   Preoperative volume expansion is recommended in all patients with PCC(9). The rationale behind this recommendation is based on the notion that PCC is associated with a decreased intravascular volume, which is restored under influence of treatment with alpha -adrenoceptor antagonists. Without administration of volume expansion severe hypotension might ensue. Therefore, it is common practice to advise a liberal salt intake during alpha -adrenoceptor antagonist therapy and to administer a saline infusion (e.g. 2L NaCL 0.9% in 24 hours) shortly before surgery(9,15).

   Several drugs, including certain anaesthetics, may evoke an uncontrolled catecholamine release with resulting severe hemodynamic instability(16). Patients are advised to carry a document enlisting all medications which are contra-indicated in case of a PCC. There is no consensus on the optimal anaesthetic management during resection of a PCC, as randomised controlled trials on this subject are not available(16,17). In a survey on the anaesthetic management of PCC in the Netherlands, we found as many different protocols as the number of hospitals (=10) which had responded (including all university medical centers; unpublished observation).

   PRESCRIPT represents the first randomised controlled trial comparing the effects of pretreatment with either phenoxybenzamine or doxazosin on the intraoperative hemodynamic control in patients with PCC. The relevance of conducting a trial as described in this study protocol was recently expressed again by experts in the field of PCC research(18). In addition, PRESCRIPT provides a unique opportunity to prospectively collect data containing detailed information on items such as presenting symptoms and signs, perioperative outcome and results of biochemical, imaging and genetic studies in patients with PCC. Of interest, results of this study are expected to have a direct impact on national and international guidelines regarding the perioperative care of patients with PCC.
2. OBJECTIVES Primary Objective: The primary objective is to determine which of two commonly used drugs for preoperative management provides the best intraoperative hemodynamic control in patients undergoing resection of a PCC.

   Secondary Objective(s):
   * to identify other determinants of intraoperative hemodynamic control. Potential determinants are: gender or age of the patient, clinical setting for preoperative management (i.e. outpatient or inpatient clinic), preoperative levels, of catecholamines or N-terminal pro-brain-type natriuretic peptide (NT-proBNP) PCC size, sporadic or hereditary PCC,
   * to describe prospectively symptoms and signs of PCC in a large cohort of patients. Note: until now, data on symptoms and signs have been described retrospectively
   * to describe prospectively the results of several diagnostic techniques
   * to assess prospectively the distribution of sporadic and hereditary PCC in a large cohort of Dutch patients
   * to build a biobank with blood and tissue samples for future studies on PCC
3. STUDY DESIGN Randomised open-label controlled trial.

Phenoxybenzamine Versus Doxazosin in PCC Patients

Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment

Blood pressure and heart rate will be monitored continuesly during surgery.

success rate of doxazosin and phenoxybenzamine to attain preoperative blood pressure target values without co-medication

Resulution of headache, palpitations, sweeting, paleness, nausea, flushes, fatigue and anxiety.

Assessment of the number of patients who need additional antihypertensive drugs on top of the study drugs

Adverse effects of doxazosin or phenoxybenzamine

Comparing duration of preoperative treatment in either outpatient or inpatient clinic

* number of episodes with systolic blood pressure (SBP) \> 160 mmHg
* number of episodes with mean arterial blood pressure (MAP) \< 60 mmHg
* duration (in minutes) of SBP \> 160 mmHg
* duration (in minutes) of MAP \< 60 mmHg
* number of episodes with heart rate \> 100/min
* duration (in minutes) of heart rate \> 100/min
* amount and type of vasoactive agents needed during surgery for adequate blood pressure control.
* cumulative amount and type of intravenous fluids administered

Number of days the patient is staying in the hospital before and after surgery

Composite semi-quantitative score of intra- and postoperative hemodynamic control based on the following parameters:

* blood pressure and heart rate outside target range
* need for administration of vasoactive agents
* need for administration of intravenous fluids

Frequency and severity (in mmol/L)of hypoglycaemia during first 24 hours after surgery.

Death from any cause occurring during period from first administration of study medication until 30 days after surgery.

Cardiovascular events occurring during period from first administration of study medication until 30 days after surgery. Cardiovascular events are: myocardial infarction, cardiac arrhythmia requiring medical intervention, heart failure, cerebrovascular ischemia, cerebrovascular haemorrhage.

Death from any cause occurring or cardiovascular events occurring during period from first administration of study medication until 30 days after surgery.

Radboud University Medical Center

UMC Utrecht

VU University of Amsterdam

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Leiden University Medical Center

Erasmus Medical Center

Maastricht University Medical Center

St. Antonius Hospital

Medisch Spectrum Twente

Maxima Medical Center

Canisius-Wilhelmina Hospital

Onze Lieve Vrouwe Gasthuis

Atrium Medical Center

Isala

University Medical Center Groningen

MD, PhD

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).

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).

Michael Yeh, MD

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.

Preoperative Alpha Blockade for Pheochromocytoma

Randomized Controlled Trial of Preoperative Alpha Blockade for Pheochromocytoma

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.

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 will be graded by Clavien Classification of adverse events

University of California, Los Angeles

Co-Principal Investigator

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

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

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black

Asian

Other/unknown

Race/Ethnicity, Customized

United States

Region of Enrollment

Masha Livhits, MD

Null hypothesis: hemodynamic instability time will not differ between arms

Hemodynamic Instability

Mortality

Daily Cost of Drug

Due to staff turnover and COVID-19 restrictions, data was not collected or analyzed.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phenoxybenzamine Versus Doxazosin in PCC Patients	NCT01379898	Pheochromocytom...	Phenoxybenzamin... Doxazosin	18 Years -	University Medical Center Groningen
Phenoxybenzamine Versus Doxazosin in PCC Patients	NCT01379898	Pheochromocytom...	Phenoxybenzamin... Doxazosin	18 Years -	University Medical Center Groningen
Preoperative Alpha Blockade for Pheochromocytoma	NCT03176693	Pheochromocytom... Paraganglioma	Phenoxybenzamin... Doxazosin	18 Years -	University of California, Los Angeles

Spots Global Cancer Trial Database for doxazosin

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Spots Global Cancer Trial Database for doxazosin

Every month we try and update this database with for doxazosin cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for doxazosin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.