Are Patients With Hormonally Functional Phaeochromocytoma and Paraganglioma Initially Receiving a Proper Adrenoceptor Blockade?

A Retrospective Cohort Study

Henrique Vara Luiz; Mary Jane Tanchee; Maria G. Pavlatou; Run Yu; Joan Nambuba; Katherine Wolf; Tamara Prodanov; Robert Wesley; Karen Adams; Tito Fojo; Karel Pacak

Disclosures

Clin Endocrinol. 2016;85(1):62-69. 

In This Article

Abstract and Introduction

Abstract

Objective Pharmacological treatment is mandatory in patients with hormonally functional phaeochromocytoma and paraganglioma (PHAEO/PGL). We evaluated if patients initially diagnosed with hormonally functional PHAEO/PGL by various medical subspecialties received proper adrenoceptor blockade, and analysed factors predicting the prescription of adequate treatment.

Methods In a retrospective cohort study, we reviewed data from patients initially diagnosed with hormonally functional PHAEO/PGL outside the National Institutes of Health and Cedars-Sinai Medical Center, who were referred to these institutions between January 2001 and April 2015. Logistic regression was used to assess factors associated with proper adrenoceptor blockade.

Results A total of 381 patients were included. Adequate pharmacological treatment was prescribed to 69·3%, of which 93·1% received α-adrenoceptor blockers. Regarding patients who were inappropriately treated, 53% did not receive any medication. Independent predictors of the prescription of a proper blockade were the diagnosis by endocrinologists [odds ratio (OR) 4·14; 95% confidence interval (CI), 2·51–6·85; P < 0·001], the presence of high blood pressure (OR 5·94; 95% CI, 3·11–11·33; P < 0·001) and the evidence of metastasis (OR 5·96; 95% CI, 1·93–18·46; P = 0·002).

Conclusions Although most patients received adequate pharmacological treatment, almost one-third were either not treated or received inappropriate medications. The diagnosis by endocrinologists, the presence of high blood pressure and the evidence of metastatic disease were identified as independent predictors of a proper blockade. These results highlight the need to educate physicians about the importance of starting adequate adrenoceptor blockade in all patients with hormonally functional PHAEO/PGL.

Introduction

Phaeochromocytoma and paraganglioma (PHAEO/PGL) are rare neuroendocrine tumours, with an estimated prevalence of 1:6500–1:2500, and an annual incidence of 1·5 to nine cases per million people.[1,2] While PHAEOs are defined as tumours arising from catecholamine-producing chromaffin cells in the adrenal medulla, closely related lesions of extra-adrenal sympathetic and parasympathetic paraganglia are known as PGLs.[3] PHAEOs and sympathetic PGLs almost always secrete catecholamines, whereas parasympathetic PGLs, located mainly in the head and neck, are usually biochemically silent.[1] The main signs and symptoms are related to episodic or permanent catecholamine release and include hypertension, palpitations, headaches, sweating and pallor. Episodic catecholamine secretion is often unpredictable, although it may occur if the tumour is manipulated or stimulated (e.g. during physical examination, anaesthesia, physical or psychological stress, etc.). This may result in severe, often life-threatening, complications such as hypertensive crisis, myocardial infarction, arrhythmia, stroke or organ ischaemia.[1,2,4–6]

It is mandatory to suspect, diagnose and treat PHAEO/PGL. Proper pharmacological treatment, usually referred to as adrenoceptor blockade, is required to control the clinical features and reduce cardiovascular and other organ risks by blocking the effects of released catecholamines. It should be started immediately after the diagnosis of a hormonally functional PHAEO/PGL (defined as catecholamine-producing) and, if surgery is planned, the drugs should be introduced at least 7–14 days before the procedure.[1,4,7,8] Randomized controlled clinical studies comparing the effectiveness of available therapeutic options are missing. However, several authors have reviewed this topic and shared their clinical experience in using different drugs for treatment as well as for preoperative preparation of patients with PHAEO/PGL.[1,4,8–16] Nevertheless, the previous and recent guidelines of the United States (US) Endocrine Society formulated evidence-based recommendations about the perioperative management of patients with catecholamine-producing PHAEO/PGL.[7,17] Thus, α-adrenoceptor blockers are suggested as the first-line drug, including the nonselective α-adrenoceptor blocker phenoxybenzamine and the α1-selective antagonists namely doxazosin, terazosin and prazosin.[18–20] Calcium channel blockers (CCBs) such as amlodipine, nicardipine, nifedipine and verapamil are considered alternative drugs, especially for normotensive or mildly hypertensive patients as well as for those who develop severe adverse effects with α-adrenoceptor blockers.[21–23] If hypertension persists, combined medications can be used. β-Adrenoceptor blockers, either nonselective (e.g. Propranolol; Inderal® Pfizer, Inc., New York, NY, USA) or β1-selective (e.g. Atenolol; Tenormin® AstraZeneca, London, UK and Metoprolol; Lopressor® Novartis Pharmaceuticals Corporation, Basel, Switzerland), are recommended to be added to control tachycardia, but they should never be prescribed before the introduction of an α-adrenoceptor blocker due to the risk of triggering a hypertensive crisis.[24,25] Combined α- and β-adrenoceptor blockers such as labetalol and carvedilol are not indicated as first-line drugs given their more potent β-antagonistic activity.[26,27] α-Methyl-ρ-tyrosine (Metyrosine; Demser® Valeant Pharmaceuticals International, Inc., Laval, Quebec, Canada), a catecholamine synthesis inhibitor, is also recommended as an add-on drug.[28,29] Pharmacological treatment in children is similar to that performed in adults.[30,31] The same recommendations have been in place for many years, particularly during the period of data collection of the present study (last 15 years).

Our long-standing clinical experience at the National Institutes of Health (NIH) and Cedars-Sinai Medical Center suggests that a significant number of patients with PHAEO/PGL do not receive adequate adrenoceptor blockade, although most of these patients present with hormonally functional PHAEO/PGL and have hypertension and/or tachycardia. Therefore, the main aim of the present study was to carefully evaluate if individuals initially diagnosed with hormonally functional PHAEO/PGL were appropriately blocked and to identify factors associated with proper pharmacological treatment or with inadequate prescription.

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