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DOI 10.1007/s12020-017-1428-9


Adding metyrapone to chemotherapy plus mitotane for Cushings

syndrome due to advanced adrenocortical carcinoma
Mlanie Claps1 Sara Cerri1 Salvatore Grisanti1 Barbara Lazzari1

Vittorio Ferrari1 Elisa Roca1 Paola Perotti2 Massimo Terzolo2 Sandra Sigala3

Alfredo Berruti1

Received: 19 June 2017 / Accepted: 16 September 2017

Springer Science+Business Media, LLC 2017

Introduction which needs to be treated promptly not only to ensure a

rapid correction of the metabolic complications that may be
Adrenocortical carcinoma (ACC) is a rare and aggressive life-threatening when cortisol excess is severe, but also to
endocrine tumor that is actively secreting in approximately improve patient well being aiming to make feasible anti-
50% of adult patients. Cushings syndrome is the most neoplastic therapies. Thus, there is a need to associate drugs
commonly associated endocrine disorder [1] that negatively able to reduce serum cortisol levels in an effective and fast
inuences the outcome of ACC patients, due to cortisol- way.
related comorbidities [2] and the immunosuppressive Metyrapone (Cormeto, HRA Paris) is an adrenolytic
effects of cortisol excess that may promote tumor progres- molecule targeting the 11-beta-hydroxylase that is currently
sion [3]. The management of ACC patients is challenging used to treat Cushings syndrome of different etiologies [8].
and demanding because physicians have to deal with either The drug inhibits the conversion of 11-deoxycortisol into
oncological or endocrinological issues [4]. cortisol obtaining the reduction of cortisol synthesis within
Currently, the standard systemic treatment for advanced 2 h after the rst drug administration [9].
ACC patients not amenable to surgery with radical intent is Metyrapone metabolism and elimination are not altered
mitotane, administered either alone or in combination with by concomitant mitotane, which is known to be a strong
etoposide, doxorubicin and cisplatin (EDP-M scheme) [1]. hepatic enzyme inducer [10]. Indeed, metyrapone is mainly
Mitotane exerts both adrenolytic and cytotoxic activities [5] metabolized by hepatic reduction; metyrapone and reduced
and has a narrow therapeutic index dened by circulating metyrapone are then conjugated to the corresponding glu-
levels of the drug between 14 and 20 mg/L [6]. These curonides and nearly 40% of the administered dose is
concentrations have been associated with drug activity and excreted in the urine within 2 days [11]. There is limited
are usually obtained after several weeks to months of evidence from isolated case reports or small case series that
treatment [7]. A slow onset of mitotane activity is a main metyrapone is effective in the management of hypercorti-
limitation also for the management of Cushings syndrome, solism induced by ACC, but the drug administered alone did
not show to have an effective antineoplastic action [8, 12].
We reported herein the feasibility and activity of the
* Alfredo Berruti
combination of metyrapone with EDP-M in three con- secutive advanced ACC patients with Cushings syndrome.
Oncology Unit, Department of Medical and Surgical Specialties,
Radiological Sciences, and Public Health, ASST Spedali Civili di
Brescia, University of Brescia, Brescia, Italy Patients and methods
Internal Medicine 1, Department of Clinical and Biological
Sciences, S. Luigi Hospital, University of Turin, Torino, Italy From January to June 2016, three consecutive male patients
Section of Pharmacology, Department of Molecular and with newly diagnosed ACC and full-blown Cushings syn-
Translational Medicine, University of Brescia, Brescia, Italy drome were referred to the Medical Oncology Unit of ASST
Table 1 Clinical features, laboratoy assays, and hormonal evaluations of three patients with severe Cushings Syndrome induced by advanced ACC at baseline and after 4, 8, and 12 weeks of
treatment with metyrapone, EDP, and mitotane
Patient 1 Patient 2 Patient 3
Reference range Baseline Week 4 Week 8 Week 12 Baseline Week 4 Week 8 Week 12 Baseline Week 4 Week 8 Week 12

Age (years) 66 53 40
Disease stage IV IV III
PS ECOG 1 1 2 2 3 3 2 2 2 1 1 1
Secretory status Cortisol Cortisol Cortisol
Mitotane daily 3000 Discontinued 3000 3000 3000 3000 3000 3000 3000 3000 3000 3000
dose (mg)
Metyrapone daily 750 Discontinued 500 250 750 500 250 250 750 750 Discontinued Discontinued
dose (mg)
Mitotane serum 1420 6 13 1
level (g/dL)
Serum cortisol 520 (morning values) 36 24 21 17 29 19 8 6 32 11 15 14
UFC (g/24 h) 10116 334 114 n.a. 87 136 13 13 n.a. >600 26 n.a. 61
ACTH (pg/mL) < 46 <5 12 9 <5 <5 <5 <5 <5 <5 21 55 94
DHEAS (ng/mL) 0.805.6 13 12 4 n.a. 0 0 <0.15 <0.15 7 1 0 0
Weight Kg (BMI) 70 (26.53) 57 (21.45) 60 (22.58) 57.5 (21.64) 116 (39.21) 105 (35.49) 105 (35.49) 107 (36.17) 78.5 (25.63) 78.5 (25.63) 78 (25.47) 74.5 (24.33)
Central obesity Yes No No No Yes Yes Yes Yes Yes Yes No No
Glucose (mg/dL) 70100 77 72 75 110 124 89 79 90 148 87 91 92
K+(mEq/L) 3.34.7 3 5 4 4 3 4 4 4 3 4 4 4
EDP major toxicities
Nausea/Vomiting G3 G3 G2 G0 G0 G0 G2 G1 G1
Asthenia G3 G3 G3 G2 G2 G1 G2 G1 G1
Neutropenia Primary Primary Primary
prophylaxis prophylaxis prophylaxis
Anemia G3 G1 G1 G3 G1 G1 G2 G1 G1
Thrombocytopenia G2 G1 G1 G0 G0 G0 G0 G0 G0
Disease response PD MR PR

Disease stage according to ENSAT (European Network for the Study of Adrenal Tumors), PS ECOG Eastern Cooperative Oncology Group Performance Status, UFC urinary free cortisol, ACTH
adrenocorticotropic hormone, DHEAS dehydroepiandrosterone, BMI Body Mass Index, K+ serum potassium levels, yes precence of the charateristic, no absence of the charateristic, EDP
etoposide, doxorubicin and cisplatin (chemotherapy scheme), n.a. not available, Toxicities according to CTCAE, Common Toxicity Criteria for Adverse Event ver. 4.03 (2010), G1 mild, G2
moderate, G3 severe, G4 life-threatening, G5 death, Disease response according to RECIST (Response Evaluation Criteria in Solid Tumors) ver. 1.1: CR complete response, disappearance of all
target lesions, PR partial response, at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, MR/SD minimal response/stable disease, neither
sufcient shrinkage to qualify for PR nor sufcient increase to qualify for PD, PD progressive disease, at least 20% increase in the sum of diameters of target lesione, taking as reference the
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least
5 mm. (Note: the appearance of one or more new lesions is also considered progression)


Spedali Civili of Brescia, Italy. Two patients had metastatic in the management Cushings syndrome associated with ACC
disease (lung and supra-clavicular lymphnode involvement, either administered alone or in association with other inhibi-
respectively), one had inoperable locally advanced disease. tors of steroidogenesis [8], or chemotherapy [13, 14]. At the
All patients presented with poor general conditions, ele- best of our knowledge, there are no published data on feasi-
vated levels of serum and urinary cortisol and severe bility and activity of this drug in association with the current
hypokalemia (Table 1). A complete hormonal evaluation standard therapy for advanced ACC, EDP plus mitotane.
was performed at baseline and immediately after the Due to its pharmacokinetic characteristics, metyrapone
patients received EDP-M (etoposide 100 mg/m2 iv. on days displays a good safety prole with minor drug-to-drug
2, 3 and 4, doxorubicin 40 mg/m2 iv. on day 1, cisplatin interactions [15]. No interactions have been reported with
40 mg/m2 iv. on days 3 and 4, plus mitotane at an initial mitotane and/or EDP [11].
dose of 1 g daily, with progressive increase up to 6 g daily, In the present case series, the addition of metyrapone to
or the maximum tolerated dose). The chemotherapy regi- EDP-M led to a rapid resolution of symptoms and signs of
men was given in association with metyrapone at the initial Cushings syndrome and a signicant improvement of the
daily dose of 250 mg/tid per os [8, 9] and, at each cycle, patient general conditions. The control of cortisol hyperse-
patients received pegylated granulocyte colony stimulating cretion was obtained in few days in patient 2; the rapid
factor (G-CSF) for chemotherapy-induced neutropenia pri- increase of mitotane serum levels in this patient may have
mary prophylaxis. likely contributed to the effect. We would like to underline
this nding, because EDP-M requires several weeks to
attain a control of hypercortisolism. Metyrapone was well
Results tolerated and did not increase the toxicity of the EDP-M
regimen, since we did not observe unexpected toxicities
During the rst 4 weeks of treatment, the patients conditions [16, 17]. The three patients included in this report com-
markedly improved and urinary free cortisol (UFC) dropped pleted the chemotherapy plan and adding metyrapone to the
signicantly, while the reduction of serum cortisol was less EDP-M regimen did not alter EDP-M efcacy in terms of
evident (Table 1). The metyrapone dose was gradually tumor control, since two patients obtained a disease
tapered over time according to clinical improvement of the response and underwent radical surgery.
Cushings syndrome. The drug was then discontinued after In conclusion, this case series shows that the combina-
16 weeks in patient 1, 12 weeks in patient 2, and 8 weeks in tion of EDP-M with metyrapone is effective and leads to a
patient 3. None of the patients received steroid replacement rapid control of Cushings syndrome induced by cortisol-
over the 12 weeks of therapy considered in this case series. secreting ACC. This combination may represent a rapid,
Disease restaging performed at week 12 showed a partial effective and well-tolerated treatment of excess hormone
response and a minor response (<30% reduction not quali- secretion in advanced ACC. Our results, although interest-
fying for a partial response according to the RECIST cri- ing, need validation in a prospective study.
teria) in patient 3 and 2, respectively (Table 1). Both patients
underwent surgery and are currently disease free at 9 and Acknowledgements Grant IG 2015-17678 from Associazione Itali-
ana per la Ricerca sul Cancro (AIRC) to MT. Private grant from the
7 months of follow-up (patient 3 and 2, respectively). The amateur dramatics group Attori non per caso, parish church of Collio
patient 1 developed disease progression after three months Valtrompia (Brescia) to BL.
and was subsequently referred to a palliative-care program,
due to the deterioration of his general conditions. Funding This study was funded by Associazione Italiana per la
Ricerca sul Cancro (AIRC), grant n. IG 2015-17678 to MT and by a
During the EDP-M-metyrapone combination regimen, the private grant from the amateur dramatics group Attori non per caso,
major toxicities observed were asthenia and nausea. Two parish church of Collio Valtrompia (Brescia) to BL.
patients (patient 1 and 2) received red blood cell transfusion
for severe grade anemia. None of the patients developed
neutropenia, due to the adoption of primary prophylaxis. Compliance with ethical standards
Patient 1 transiently interrupted both metyrapone and mito- Conict of interest The authors declare that they have no competing
tane for 6 days, due to the persistence of severe nausea and interests.
asthenia after chemotherapy administration.

1. M. Terzolo, F. Daffara, A. Ardito, B. Zaggia, V. Basule, L. Fer-
rari, A. Berruti, Management of adrenal cancer: a 2013 update. J.
Metyrapone is an effective drug to manage Cushings syn- Endocrinol. Invest. 37, 207217 (2014).
drome of either origin [8]. The drug has been also employed s40618-013-0049-2

2. A. Berruti, M. Fassnacht, H. Haak et al. Prognostic role of overt 10. M. Kroiss, M. Quinkler, W.K. Lutz, B. Allolio, M. Fassnacht,
hypercortisolism in completely operated patients with adrenocor- Drug interactions with mitotane by induction of CYP3A4 meta-
tical cancer. Eur. Urol. 65, 832838 (2014). bolism in the clinical management of adrenocortical carcinoma.
1016/j.eururo.2013.11.006 Clin. Endocrinol. 75, 585591 (2011).
3. P. Malandrino, A. Al Ghuzlan, M. Castaing, J. Young, B. Caillou, 13652265.2011.04214.x
J.P. Travagli, D. Elias, T. de Baere, C. Dromain, A. Paci, P. 11. Metyrapone. In: DRUGDEX System [Internet database].
Chanson, M. Schlumberger, S. Leboulleux, E. Baudin, Prognostic (Thomson Micromedex, Greenwood Village, Colo). Updated
markers of survival after combined mitotane- and platinum-based periodically, Accessed 18
chemotherapy in metastatic adrenocortical carcinoma. Endocr. Jan 2016
Relat. Cancer. 17, 797807 (2010). 12. I. Veytsman, L. Nieman, T. Fojo, Management of endocrine
09-0341 manifestations and the use of mitotane as chemotherapeutic agent
4. A. Berruti, E. Baudin, H. Gelderblom, H.R. Haak, F. Porpiglia, M. for adrenocortical carcinoma. J. Clin. Oncol. 27, 46194629
Fassnacht, G. Pentheroudakis; ESMO Guidelines Working (2009).
Group., Adrenal cancer: ESMO clinical practice guidelines for 13. S.P. Rajeev, S. McDougall, M. Terlizzo, D. Palmer, C. Daousi, D.
diagnosis, treatment and follow-up. Ann. Oncol. 23, J. Cuthbertson, Evolution in functionality of a metastatic pan-
vii131vii138 (2012). creatic neuroendocrine tumor (pNET) causing Cushings syn-
5. S. Hahner, M. Fassnacht, Mitotane for adrenocortical carcinoma drome: treatment response with chemotherapy. BMC Endocr.
treatment. Curr. Opin. Investig. Drugs. 6(4), 386394 (2005) Disord. 14, 70 (2014).
6. I.G. Hermsen, M. Fassnacht, M. Terzolo et al. Plasma con- 14. M. Wojcik, A. Kalicka-Kasperczyk, T. Luszawska-Kutrzeba, W.
centrations of o,pDDD, o,pDDA, and o,pDDE as predictors of Balwierz, J.B. Starzyk, The rst description of metyrapone use in
tumor response to mitotane in adrenocortical carcinoma: results of severe Cushing Syndrome due to ectopic ACTH secretion in an
a retrospective ENS@T multicenter study. J Clin 96, 18441851 infant with immature sacrococcygeal teratoma. Case Report.
(2011). Neuro Endocrinol. Lett. 36(7), 653655 (2015)
7. M. Terzolo, A. Pia, A. Berruti, A. Osella Gm Al, V. Carbone, E. 15. R.E. Galinsky, E.B. Nelson, D.E. Rollins, Pharmacokinetic con-
Testa, L. Dogliotti, A. Angeli, Lowe-dose monitored mitotane sequences and toxicologic implications of metyrapone-induced
treatment achieve the therapeutic range with manageable side alterations of acetaminophen elimination in man. Eur. J. Clin.
effects in patients with adrenocortical cancer. J. Clin. Endocrinol. Pharmacol. 33(4), 391396 (1987)
Metab. (2000). 16. A. Berruti, M. Terzolo, P. Sperone et al. Etoposide, doxorubicin
8. E. Daniel, S. Aylwin, O. Mustafa et al. Effectiveness of metyr- and cisplatin plus mitotane in the treatment of advanced adreno-
apone in treating cushings syndrome: a retrospective multicenter cortical carcinoma: a large prospective phase II trial. Endocr.
study in 195 patients. J. Clin. Endocrinol. Metab. 100, 41464154 Relat. Cancer 12(3), 657666 (2005).
(2015). 01025
9. J.A. Verhelst, P.J. Trainer, T.A. Howlett, L. Perry, L.H. Rees, A. 17. M. Fasssancht, M. Terzolo, B. Allolio et al. Combination che-
B. Grossman, J.A. Wass, G.M. Besser, Short and long-term motherapy in advanced adrenocortical carcinoma. N. Engl. J.
responses to metyrapone in the medical management of 91 Med. 366, 21892197 (2012).
patients with Cushings syndrome. Clin. Endocrinol. 35(2), l1200966
169178 (1991)