Phenoxybenzamine Versus Doxazosin in PCC Patients
Information source: University Medical Center Groningen
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Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pheochromocytoma
Intervention: Phenoxybenzamine (Drug); Doxazosin (Drug)
Phase: Phase 4
Sponsored by: University Medical Center Groningen
Official(s) and/or principal investigator(s):
Michiel N. Kerstens, MD PhD, Study Director, Affiliation: University Medical Center Groningen
Thera P. Links, MD PhD, Principal Investigator, Affiliation: University Medical Center Groningen
Gütz J. Wietasch, MD PhD, Principal Investigator, Affiliation: University Medical Center Groningen
Jaques W. Lenders, MD PhD, Principal Investigator, Affiliation: UMC St Radboud Nijmegen
G D. Valk, MD PhD, Principal Investigator, Affiliation: UMC Utrecht
E M. Eekhoff, MD PhD, Principal Investigator, Affiliation: Free University UMC Amsterdam
P H. Bisschop, MD PhD, Principal Investigator, Affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
R A Feelders, MD PhD, Principal Investigator, Affiliation: Erasmus Medical Center Rotterdam
Bas Havekes, MD PhD, Principal Investigator, Affiliation: Maastricht University Medical Center
Peter Oomen, MD PhD, Principal Investigator, Affiliation: Medical Center Leeuwarden
I Eland, MD PhD, Principal Investigator, Affiliation: St. Antonius Ziekenhuis Nieuwegein
P H. Geelhoed- Duijvestijn, MD PhD, Principal Investigator, Affiliation: Medical Center Haaglanden
P Groote Veldman, MD PhD, Principal Investigator, Affiliation: Medisch Spectrum Twente
H R Haak, MD PhD, Principal Investigator, Affiliation: Máxima Medisch Centrum
J R. Meinardi, MD PhD, Principal Investigator, Affiliation: Canisius-Wilhelmina Hospital
C B. Brouwer, MD PhD, Principal Investigator, Affiliation: Canisius-Wilhelmina Hospital
P L. van Battum, MD, Principal Investigator, Affiliation: Atrium Medical Center
A A. Franken, MD PhD, Principal Investigator, Affiliation: Isala Klinieken Zwolle
Michiel N Kerstens, MD PhD, Phone: 0031- 50-3613962, Email: email@example.com
- 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
- 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 frequency
of intraoperative blood pressure episodes 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
Official title: Pheochromocytoma Randomised Study Comparing Adrenoreceptor Inhibiting Agents for Preoperative Treatment
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: The number of patients demonstrating more than three intraoperative episodes of 5 minutes with blood pressure outside the predefined target range after pretreatment with either phenoxybenzamine or doxazosin.
To attain preoperative blood pressure target values without co-medication
Resolution of (paroxysmal) symptoms and signs of pheochromocytoma.
Need for additional antihypertensive agents
Adverse effects of study medication
Length of preoperative treatment in either outpatient or inpatient clinic.
Control of blood pressure and heart rate.
Length of hospital stay.
Composite semi-quantitative score of intra- and postoperative hemodynamic control.
Perioperative cardiovascular morbidity.
Composite endpoint of perioperative mortality and perioperative cardiovascular morbidity.
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.
- 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.
Minimum age: 18 Years.
Maximum age: N/A.
- age > 18 years
- diagnosis of benign Pheochromocytoma (adrenal or extra-adrenal, sporadic or
- elevated plasma and/or urinary (nor)metanephrines. From each patient, a blood
sample is collected for measurement of plasma (nor)metanephrines with the
reference laboratory assay (i. e. XLC-MS/MS) at the Department of Laboratory
Medicine of the UMCG.
- localisation of PCC by anatomical (MRI/CT) and functional imaging (I123-MIBG
scintigraphy or 18F-DOPA PET)
- planned for surgical removal of the PCC
- age < 18 years
- malignant PCC, i. e. presence of lesions on imaging studies suggestive of distant
- severe hemodynamic instability before surgery necessitating admission to intensive
- incapability to adhere to the study protocol
Locations and Contacts
Michiel N Kerstens, MD PhD, Phone: 0031- 50-3613962, Email: firstname.lastname@example.org
Department of Endocrinology, University Medical Center Groningen, Groningen 9700 RB, Netherlands; Recruiting
Michiel N. Kerstens, MD PhD, Phone: 0031-50-3613962, Email: email@example.com
Thera P. Links, MD PhD, Principal Investigator
Gütz J. Wietasch, MD PhD, Principal Investigator
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Starting date: December 2011
Last updated: February 3, 2015