J-B Corcuff, J Young and Rapid control of severe 172:4 473–481 Clinical Study others hypercortisolism Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole Jean-Benoıˆt Corcuff*, Jacques Young1,*, Pauline Masquefa-Giraud2, Philippe Chanson1, Eric Baudin3 and Antoine Tabarin2 Department of Nuclear Medicine, Haut Le´ veˆ que Hospital, F-33604 Pessac, France, 1Department of Endocrinology, Correspondence Biceˆ tre Hospital, F-94275 Le Kremlin-Biceˆ tre, France, 2Department of Endocrinology, Haut Le´ veˆ que Hospital, should be addressed CHU Bordeaux, F-33604 Pessac, France and 3Department of Nuclear Medicine and Oncology, Gustave Roussy, to A Tabarin F-94800 Villejuif, France Email *(J-B Corcuff and J Young contributed equally to this work) antoine.tabarin@ chu-bordeaux.fr Abstract Context: Severe Cushing’s syndrome elicited by ectopic ACTH syndrome (EAS) or adrenal carcinoma (ACC) can threaten life in the short term. The effectiveness of oral administration of the inhibitors of steroidogenesis ketoconazole and metyrapone in this situation is poorly described. Objective: To report the short-term effectiveness and tolerability of metyrapone and ketoconazole elicited either by EAS or by ACC in patients exhibiting severe hypercortisolism. Design: Retrospective analysis of data obtained for patients with urinary free cortisol (UFC) level estimated to be fivefold the upper limit of the normal range (ULN). Patients and settings: A total of 14 patients with EAS and eight with ACC treated in two tertiary-care university hospitals. Intervention: Metyrapone and ketoconazole treatment in combination (along with symptomatic treatments for co-morbidities). European Journal of Endocrinology Main outcome: Evolution of clinically relevant endpoints (blood pressure, kalaemia and glycaemia) and biological intensity of hypercortisolism 1 week and 1 month after starting steroidogenesis inhibition. Results: After 1 week of treatment, median UFC fell from 40.0 to 3.2 ULN and from 16.0 to 1.0 ULN in patients with EAS and ACC respectively. Median UFC after 1 month of treatment was 0.5 and 1.0 ULN in patients with EAS and ACC respectively and UFC values were normal in 73 and 86% of patients respectively. Clinical status improved dramatically along with kalaemia, glycaemia and blood pressure, allowing a decrease in the relevant treatments. Side effects were minimal and only two patients (one EAS and one ACC) experienced plasma transaminase elevations necessitating ketoconazole withdrawal. Conclusion: Metyrapone–ketoconazole combination therapy is well tolerated and provides rapid control of endocrine cancer-related life-threatening hypercortisolism. European Journal of Endocrinology (2015) 172, 473–481 Introduction Untreated or inadequately treated Cushing’s syndrome and infections. During severe CS as observed in patients (CS) is a morbid condition leading to numerous compli- with underlying neuroendocrine neoplasms responsible cations. The latter ultimately results in an increased for ectopic adrenocorticotrophin (ACTH) syndrome (EAS) mortality that is mainly due to cardiovascular events and in those with adrenal carcinomas (ACCs) (1), www.eje-online.org Ñ 2015 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0913 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:32:09AM via free access Clinical Study J-B Corcuff, J Young and Rapid control of severe 172:4 474 others hypercortisolism the catabolic and metabolic consequences of CS are The aim of this study was to analyse the short-term exacerbated including severe hypertension, hypokalaemia, clinical and biological effectiveness and tolerability of the major hyperglycaemia and bedridden condition secondary metyrapone and ketoconazole in a significant number of to amyotrophia (2, 3, 4, 5, 6). Severe hypercortisolism also patients with severe hypercortisolism due to EAS or ACC. favours systemic infection, sepsis due to opportunistic pathogens such as Pneumocystis carinii (7) and venous thromboembolism (8). Patients with severe hypercortiso- Patients and methods lism may experience other complications such as acute Patients heart and respiratory failure, peritonitis due to gut perforation, pancreatitis and acute psychosis. In such Data for 22 patients treated in the endocrinology instances, curative surgery of the source of ACTH secretion departments of Biceˆtre and Bordeaux university hospitals or of the ACC may be impossible to perform and cytotoxic (France) were analysed. The data were collected as part of chemotherapy may be associated with an increased risk of routine patient management, and local ethics committee infections and death (9). Essentially, severe hypercortiso- approval was obtained for their analysis. Patients were lism threatens the short-term vital prognosis, pulmonary eligible for the study if they had poor clinical status due embolism and infections being significant causes of death to severe hypercortisolism related to underlying EAS or in patients with EAS (10, 11, 12). Surgical removal of the ACC. Severe hypercortisolism was defined as a mean 24-h neoplasm responsible for CS is not always possible, either urinary free cortisol (UFC) level O5 times the upper limit because ectopic ACTH-secreting tumours may be occult of the normal range (ULN) in at least three samples. at symptom onset or because ectopic ACTH-secreting Fourteen patients (12M/2F; age 53 (24–71) years) had tumours and ACCs are unresectable or metastasised. EAS. The ACTH-secreting tumours were: bronchial (# 1, 2, 6 Bilateral adrenalectomy (BLA) may be an option in patients and 11) or pancreatic (# 5, 7, 10 and 12) or thymic carcinoid with EAS, but pre-operative control of hypercortisolism tumours (# 13), of unknown origin (metastatic neuro- may facilitate surgery and avoid perioperative compli- endocrine carcinoma, # 8), small-cell lung carcinomas cations in patients with poor overall condition (13). (# 3 and 9), medullary thyroid carcinoma (# 14), and one Otherwise, rapid correction of hypercortisolism is occult tumour (# 4). Eight patients had cortisol-secreting recommended before induction of cytotoxic chemother- ACC (2M/6F; age 60 (20–71) years). The ENSAT stages (20) apy in order to minimise the side effects of myelosuppres- were 2 and 4 in three and five patients respectively. sive cytotoxic chemotherapy (14). Thus, rapid control of Complications of hypercortisolism aregiven in Tables 1 European Journal of Endocrinology hypercortisolism is mandatory to ensure short-term survi- and 2. Briefly, 96% of patients were hypertensive, val and enable medical or surgical therapies directed at the 88% had hypokalaemia and 75% developed diabetes. underlying tumour. Yet, very few studies have addressed In addition, half of the patients had at least one other this issue. Glucocorticoid receptor blockade with mife- severe complication due to severe CS (psychiatric dis- pristone has occasionally been reported to be effective (15) orders, opportunistic infections, phlebitis or pulmonary but is difficult to monitor and may worsen pre-existing embolism, fractures, bedsores and bedridden status due to hypertension and hypokalaemia. Inhibition of steroido- sarcopenia). genesis with the anaesthetic drug etomidate has also been reported but its hypnotic properties limit its use (16). Intervention Metyrapone and ketoconazole are fast-acting, orally administered drugs that inhibit distinct enzymes involved All the patients received oral combination therapy with in adrenal steroidogenesis and thereby reduce cortisol metyrapone (Metopirone 250 mg; Novartis) and ketoco- production synergistically (2, 17, 18, 19). There are few nazole (Nizoral 200 mg; Janssen-Cilag, Issy-les-Mouli- published data on the treatment of severe hypercortiso- neaux, France). Metyrapone and ketoconazole were lism with these two drugs, alone or in combination, and introduced either simultaneously or sequentially in the this is especially true for patients with ACC. In addition, time frame of the study. Mitotane (Lysodren 500 mg; the rare published series and case reports often lack HRA-Pharma, Paris, France) was also introduced simul- detailed information about the impact of these drugs on taneously or later in six out of 14 patients with EAS and six the magnitude of the biological response and the impact out of eight patients with ACC. The starting dosages were on hypercortisolism-induced morbidities such as hyper- variable (median: metyrapone 2125 mg/day and ketoco- tension, hypokalaemia and hyperglycaemia (4, 10, 11). nazole 900 mg/day) and were subsequently adjusted www.eje-online.org Downloaded from Bioscientifica.com at 09/30/2021 09:32:09AM via free access Clinical Study J-B Corcuff, J Young and Rapid control of severe 172:4 475 others hypercortisolism Table 1 Clinical and dosage levels of patients with ectopic ACTH syndrome and adrenal carcinomas. Ketoconazole dosage Metyrapone dosage Lysodren dosage BMI Age Low No. Tumour Sex (kg/m2) (years) HT KC DM T0 W1 M1 T0 W1 M1 T0 W1 M1 1 BCa M 25.8 23.9 Yes Yes Yes 1000 1000 1000 1000 1000 2000 0 0 0 2 BCa M 24.3 28.5 No Yes No 1000 1000 1000 1000 1000 1000 0 0 0 3 SCLC M 26.6 57.5 Yes Yes Yes 1200 1200 – 3000 3000 – 3000 3000 – 4 Unk M 28.0 51.7 Yes Yes Yes 1000 1000 1000 3000 3000 3000 3000 3000 3000 5 PCa F 22.7 39.6 Yes Yes Yes 800 800 800 1500 1500 1500 0 0 0 6 BCa M 30.0 35.1 Yes No Yes 800 800 800 500 500 500 0 0 0 7 PCa M 35.3 53.8 Yes Yes Yes 1000 0 0 1500 1500 2250 0 0 4000 8 NET M 60.2 Yes Yes Yes 1000 1200 1200