Hindawi Publishing Corporation
`Journal of Oncology
`Volume 2012, Article ID 685213, 9 pages
`doi:10.1155/2012/685213
`
`Review Article
`Management Strategies for Aggressive Cushing’s Syndrome: From
`Macroadenomas to Ectopics
`
`Carlotta Pozza, Chiara Graziadio, Elisa Giannetta, Andrea Lenzi, and Andrea M. Isidori
`
`Pathophysiology Section, Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico,
`155-00161 Rome, Italy
`
`Correspondence should be addressed to Andrea M. Isidori, andrea.isidori@uniroma1.it
`
`Received 27 April 2012; Accepted 13 June 2012
`
`Academic Editor: Marialuisa Appetecchia
`
`Copyright © 2012 Carlotta Pozza et al. This is an open access article distributed under the Creative Commons Attribution License,
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Cushing’s syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence
`excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-
`pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing’s disease, CD) or an ectopic source
`(ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established,
`the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a
`major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists,
`neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy
`for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking
`adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action
`of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine
`agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ “PPAR-γ” ligands) and novel
`chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive
`pituitary or ectopic tumors.
`
`1. Introduction
`
`Cushing’s syndrome (CS) is a rare but severe clinical
`condition caused by cortisol excess of various etiologies. It is
`associated with significant morbidity and mortality and leads
`to metabolic, cardiovascular,
`infectious, psychiatric, and
`gonadal complications (Table 1). This complex endocrine
`disorder is a challenge in terms of efficient treatment. This
`paper will focus on traditional and novel medical therapy
`for hypercortisolism secondary to ACTH-secreting pituitary
`macroadenoma or carcinoma (Cushing’s disease, CD) or to
`ectopic ACTH secretion.
`The natural history of pituitary adenomas varies widely.
`In the majority of cases, ACTH-secreting pituitary adenomas
`are small (<1 cm in diameter) and confined within the sella
`turcica. Pituitary microadenomas have a typically indolent
`growth rate, and clinically significant invasion and malignant
`transformation remain uncommon. However, 4–10% of
`
`patients present with larger tumors (>1 cm in diameter).
`These can cause symptoms due to mass effect before any
`full endocrine manifestations. Moreover, they are more
`refractory to surgical treatment and show a more unfavorable
`prognosis than microadenomas. For their behavior, pre-
`sentation, and outcome, ACTH secreting macroadenomas
`present a distinct profile compared with microadenomas,
`although they probably represent one end of a spectrum
`of tumor autonomy, with specific growth and biochemical
`characteristics [1]. Morbidity and mortality are high with
`aggressive tumor behavior [2]. The 2004 WHO classifi-
`cation of pituitary adenomas now includes an “atypical”
`variant, defined as an MIB-1 proliferative index greater than
`3%, excessive p53 immunoreactivity and increased mitotic
`activity. In the absence of metastases, however, invasive or
`aggressive pituitary tumors are not considered malignant.
`Pituitary carcinomas, defined as primary tumors with intra-
`or extracranial metastases, are rare, encountered in less than
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`Table 1
`
`Clinical features of hypercortisolism
`Weight gain
`Central obesity
`Moon face
`Purple stretch marks
`Plethora
`Easy bruising
`Hirsutism
`Acne
`Severe fatigue and muscle weakness
`High blood pressure
`Depression
`Cognitive impairment
`Diabetes
`Loss of libido
`Menstrual disorders
`Osteoporosis
`Psychosis
`
`1% of all hypophyseal tumors. They generally secrete ACTH
`or Prolactin.
`Ectopic ACTH Secretion (EAS) accounts for 15–20%
`of cases of Cushing’s syndrome and covers a spectrum
`of tumors from undetectable isolated lesions to extensive
`metastatic and aggressive malignancies. EAS is often asso-
`ciated with severe hypercortisolemia causing hypokalemia,
`diabetes, generalized infections, hypertension, and psychotic
`reactions. Isidori et al. [3] proposed a classification based
`on the detection of the source of ectopic secretion. EAS is
`defined as overt when the tumor source is easily detected
`during the initial endocrine and radiological investigations,
`covert in patients presenting with hypercortisolemia where
`the ectopic source is not detected during initial tests but is
`discovered on subsequent evaluation or during prolonged
`followup, and occult when the patient’s clinical features
`suggest CS and all tests indicate an ectopic source, but the
`primary lesion is not identified even after prolonged and
`repeated followup. Occult EAS is one of the most intriguing
`challenges for the clinical endocrinologist, as in some cases
`no tumor is found even after long-term followup or on
`autopsy [3]. The overall prognosis of patients with ectopic
`ACTH secretion is primarily determined by the nature of the
`underlying malignancy and the tumor stage on diagnosis.
`
`2. Management of Cushing’s Syndrome
`
`Management of patients with CS requires a major effort to
`understand the etiology and to control hypercortisolemia
`as soon as the diagnosis is established. The most appro-
`priate management of ACTH-dependent CS derives from a
`multidisciplinary approach that includes endocrinologists,
`neurosurgeons, oncologists, and radiotherapists.
`The definitive treatment of CS consists in surgical
`resection of the tumor secreting ACTH. When the source
`of the excessive secretion is the pituitary gland, the standard
`
`approach is to perform an endoscopic endonasal trans-
`sphenoidal exploration, with excision of the tumor, if found.
`This surgical procedure is demanding and should only be
`performed in centers with extensive experience, to minimize
`operative risks, reduce the possibility of remission, and main-
`tain other pituitary functions. It is successful in about 70%
`of cases (defined by suppressed plasma cortisol levels and
`normal 24 h urinary free cortisol) [4]. Success rates can reach
`90% in selective adenectomy of microadenomas (<10 mm
`in diameter), but decrease to 65% for macroadenomas [5].
`About 20% of tumors recur, and recurrence is more likely
`(and quicker) in larger than in smaller tumors.
`Pituitary irradiation achieves eucortisolism in 50–60%
`of cases, albeit after 3–5 years [4], and patients can
`develop pituitary insufficiency, brain vascular morbidity or
`secondary neoplasms. Stereotactic radiosurgery (RS) proved
`less effective results in macroadenomas, especially if they
`had already infiltrate the cavernous sinus. To obtain optimal
`efficacy, RS should thus be reserved to small well-defined
`lesions. The management of aggressive adenomas invading
`adjacent structures is a real challenge, as they rarely respond
`to any treatment.
`In the presence of ectopic secretion of ACTH, surgical
`resection of the primary tumor is recommended. This
`results in the complete remission, especially in cases of
`benign tumor. Often, however, the tumor may already have
`metastasized, it may not be resectable, or it may not be
`identified despite extensive investigation (occult).
`Bilateral adrenalectomy can be chosen as a final
`approach, reserved for patients who do not respond to
`surgical exploration of the hypophysis or radiation therapy,
`or when the source of ectopic ACTH is not found.
`Adrenalectomy necessarily requires steroid replacement
`therapy for the rest of the patient’s life, as with primary
`adrenocortical insufficiency. There is also a significant risk
`of developing Nelson’s syndrome, which occurs in 5–10% of
`the patients, likely a subset with an aggressive phenotype,
`after adrenalectomy for Cushing’s syndrome [4, 6]. It has
`been demonstrated that patients with invasive corticotrophi-
`nomas have a greater risk of subsequent (and earlier) devel-
`opment of Nelson’s syndrome compared with less aggressive
`forms [7]. Prophylactic, conventional 3-field radiotherapy
`can be used to reduce the incidence of subsequent Nelson’s
`and it should always be considered in the management
`of these patients [8]. When these approaches cannot be
`applied, a treatment is needed that has fewer side effects and
`can quickly reduce symptoms, and severe complications of
`hypercortisolism, aiming for the normalization of ACTH and
`serum cortisol values [9].
`
`3. Medical Treatments
`
`in the treatment of patients with
`The therapeutic goal
`ACTH-dependent Cushing’s syndrome is normalization of
`plasma ACTH and serum cortisol values, tumor shrinkage
`and preservation of anterior pituitary function, in cases
`of pituitary ACTH-secreting tumor. Medical treatment can
`improve the clinical condition of patients with severe
`hypercortisolism pending surgery, during acute diseases
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`(infections, psychosis, etc.), or in patients undergoing radio-
`therapy while awaiting the effects of the radiotherapy itself.
`In addition, patients with ectopic secretion of ACTH may
`be treated while expecting confirmation of the source, in
`the presence of metastatic cancer, or in patients who are not
`candidates for surgery for some reason.
`Current drug-based therapy for CS includes drugs that
`act on the adrenal glands to reduce steroid synthesis, which
`therefore do not treat the underlying cause of the disease, and
`neuromodulators acting at the hypothalamic-pituitary level
`[10]. The existing treatments can be divided according to the
`site of action into adrenal acting drugs and in centrally acting
`drugs (Table 2).
`
`3.1. Adrenal-Acting Drugs. Adrenal function must be care-
`fully monitored, as excessive inhibition of steroidogenesis
`may cause adrenal insufficiency and may require the admin-
`istration of small doses of glucocorticoids.
`
`3.1.1. Ketoconazole. This is the most currently used drug in
`patients with hypercortisolism. It is a synthetic antifungal
`drug that works principally by inhibiting the cytochrome
`P450 system and 17,20-lyase, which are involved in the syn-
`thesis and degradation of steroids. It has also been suggested
`that this drug may directly inhibit the pituitary corticotroph
`function,
`inhibiting ACTH secretion [11–13]. This is a
`fast-acting drug that quickly reduces urinary free cortisol
`(UFC) levels [14]. Its use has been reported as effective in
`50% of patients with ectopic ACTH secretion. The most
`common side effects include gynecomastia, hypogonadism,
`gastrointestinal symptoms and reversible increases in liver
`enzymes. Severe liver toxicity is rare and liver function is
`usually restored after discontinuation. The drug does not
`inhibit the growth of the ACTH-secreting tumor.
`
`3.1.2. Metyrapone and LCI699. Metyrapone predominantly
`inhibits 11β hydroxylase and has been used either as a
`monotherapy, leading to a normalization of cortisol levels
`in 75–80% of patients, or in combination with other
`steroidogenesis inhibitors or with radiation therapy, achiev-
`ing even higher efficacy [15, 16]. It is able to reduce cortisol
`production in patients with ectopic ACTH production and
`Cushing’s disease. Side effects are dose-dependent, with the
`most common being hypertension, edema, increased acne
`and hirsutism in women due to its ability to inhibit the
`synthesis of aldosterone, resulting in an accumulation of
`its precursors with mineralocorticoid and weak androgen
`activity. However, when combined with ketoconazole,
`it
`offers a valuable and safe adjunct to control hypercortisolism.
`Recently, LCI699 [17], a novel orally active drug that inhibits
`at high doses the 11-beta hydroxylase activity (as well as
`aldosterone synthase) is under phase 2 evaluation for the
`management of hypercortisolism (http://clinicaltrial.gov/
`identifier NCT01331239).
`
`3.1.3. Aminoglutethimide. Aminoglutethimide is a potent
`reversible inhibitor of adrenal mineralocorticoid and gluco-
`corticoid synthesis. It blocks cholesterol side-chain cleavage
`to pregnenolone, by inhibiting P450 enzymes. Side effects
`
`are skin rash, headache, a generalized pruritic rash, hypothy-
`roidism, and goiter, and because of its toxicity is reserved for
`adrenal cancer.
`
`3.1.4. Mitotane (o,p’-DDD). It is a DDD (dichlorodiphenyld-
`ichloroethane) isomer and a derivative of DDT. A study of
`177 patients showed a significant increase in the recurrence-
`free interval after radical surgery followed by mitotane
`when compared to surgery alone [18]. Mitotane blocks
`several steroidogenic enzymes,
`thus altering peripheral
`steroid metabolism, directly suppressing the adrenal cortex
`and altering cortisone metabolism. Its adrenolytic function
`appears at high doses (>4 g/day). It is effective in reducing
`UFC levels in 83% of treated patients [19, 20]. A 2006 study
`confirmed that most patients under mitotane treatment in
`a dose ranging from 4 to 6.5 g daily had dramatic increase
`in CBG levels, and serum cortisol levels can be elevated
`even when the circulating free cortisol level is not, thus
`making difficult to control its biochemical effect [21, 22].
`It is commonly used in patients with adrenal carcinoma.
`Its main use is in patients with persistent disease despite
`surgical resection, those who are not candidates for surgery,
`and patients with metastatic disease.
`Serum levels should be monitored to optimize therapy.
`The compound is distributed in the adipose tissue and has a
`long half-life. Gastrointestinal and neurologic symptoms are
`the most common side effects.
`
`3.1.5. Etomidate. Etomidate, an imidazole derivative, is an
`i.v. nonopioid anesthetic used for both induction and
`maintenance of anesthesia. It suppresses corticosteroid syn-
`thesis in the adrenal cortex by reversibly inhibiting 11-β-
`hydroxylase and 17,20 lyase at non-hypnotic doses. It has
`a very rapid onset of action and can be used in acute
`settings in patients with CS [23]. In addition, its intravenous
`administration makes it easily used in patients with no oral
`or enteral access. Studies and case reports support its use
`in patients with Cushing’s syndrome. Chronic therapeutic
`use of ethyl-alcohol-containing Etomidate was effective for
`8 weeks in a patient with ectopic CS and peritonitis [24].
`In a 2001 case report, Etomidate was administered over 5.5
`months, with daily dose modulation on the basis of serum
`cortisol levels. Suppression of steroidogenesis persisted for at
`least 14 days after cessation of the medication [25].
`
`3.1.6. Mifepristone (RU486). Mifepristone is a synthetic ster-
`oid. It is a progesterone receptor antagonist and a powerful
`type-2 glucocorticoid receptor (GR) antagonist. It binds
`to human GR with an affinity three to four times higher
`than that of dexamethasone and about 18 times higher
`than that of cortisol. Its antiglucocorticoid effects are dose
`dependent. Mifepristone affects both the central actions
`of cortisol (negative feedback on CRH/ACTH secretion)
`and its peripheral actions and increases plasma ACTH
`and cortisol levels due to the loss of negative feedback of
`cortisol. This drug, currently used in the interruption of
`early pregnancy, was recently approved in patients with
`hyperglycemia induced by CS who are not candidates for
`surgery or where surgery has failed [26]. Medical literature
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`Table 2: Medical treatments for Cushing’s syndrome (in clinical use or investigational).
`
`Drug
`
`Mechanism of action
`
`Dose (range)
`
`Ketoconazole
`
`Inhibits steroidogenesis via
`inhibition of cytochrome P450
`function
`
`200–1800 mg per os
`(in divided doses,
`b.i.d.-t.i.d.)
`
`Metyrapone
`
`Inhibits 11-β hydroxylase in the
`adrenal gland
`
`Aminoglutethimide
`
`Prevents conversion of
`cholesterol to pregnenolone
`
`Mitotane
`
`Etomidate
`
`Mifepristone
`(RU-486)
`
`Inhibits steroidogenesis via
`inhibition of cytochrome P450;
`adrenolytic (high doses)
`Inhibits 11-β hydroxylase and
`17–20 lyase
`Glucocorticoid, androgen, and
`progesterone receptor
`antagonist
`
`Cabergoline
`
`D2 receptor agonist
`
`Octreotide
`
`Somatostatin receptor agonist
`(isoform 2)
`
`Pasireotide
`(SOM 230)
`
`Somatostatin receptor agonist
`(isoforms 1, 2, 3, 5)
`
`750–6000 mg per os
`(in divided doses,
`t.i.d.-q.i.d.)
`
`250–750 mg per os
`(in divided doses,
`b.i.d.-t.i.d.)
`
`500 mg–12 g per os (daily)
`
`300–1200 mg per os, daily
`dose
`
`1–7 mg per os, weekly
`dose
`200–1000 mcg s.c. t.i.d.,
`or LAR formulation
`10–30 mg i.m. every 4
`weeks
`
`600–900 mcg s.c. b.i.d.,
`LAR formulation under
`investigation
`
`<0.1 mg/kg/hr i.v.
`
`Sedative effects, anesthesia
`
`Side effects
`Reversible liver dysfunction,
`severe liver toxicity, GI
`disorders, skin rash, loss of
`libido, impotence
`
`Safety monitoring
`
`Transaminase,
`testosterone, and SHBG
`in men
`
`Hirsutism, acne, GI disorders,
`dizziness, hypertension, edema,
`hypokalemia
`
`Androgens,
`mineralocorticoid,
`electrolytes
`
`Generalized, self-limiting itchy
`rash, nausea, dizziness, blurred
`vision, cholestasis, bone
`marrow suppression
`Severe nausea, vomiting,
`diarrhea, rash, somnolence,
`ataxia, vertigo, dyslipidemia
`
`Hypoadrenalism, hypokalemia,
`hypertension, irregular menses,
`endometrial hyperplasia
`
`Nausea, vomiting, dizziness,
`valvulopathy
`
`Blood count, thyroid
`hormones, hepatic
`function, abdominal US
`
`Plasma mitotane, blood
`count, electrolytes, liver
`function, cholesterol
`
`Monitoring by
`anesthesiologists
`
`Blood count,
`electrolytes, pelvic US
`
`Echocardiogram
`
`GI disorders, gallstones or
`biliary sludge, hyperglycemia,
`sinus bradycardia
`
`Glycaemia, HbA1c,
`ECG, abdominal US
`
`GI disorders, gallstones or
`biliary sludge, hyperglycemia or
`diabetes mellitus, sinus
`bradycardia
`
`Glycaemia, HbA1c, Q-T
`interval, abdominal US
`
`Toxic effects of vitamin
`A, liver function, blood
`count
`Blood count,
`transaminase, ECG,
`echocardiogram
`
`Retinoic acid
`
`Inhibits POMC transcription
`and cell-cycle progression
`
`No data in vivo in humans
`in Cushing’s syndrome
`
`Anaemia, mucocutaneous and
`ocular symptoms
`
`Rosiglitazone
`
`PPAR-γ agonist
`
`4–16 mg per os, daily
`doses
`
`Weight increase, edema,
`somnolence, hirsutism
`
`Temozolomide
`
`Alkylating agent
`
`Gefitinib
`
`Tyrosine kinase inhibitor
`
`150–200 mg/m2 per os for
`5 days once every 28 days,
`or 75 mg/m2 daily for 21
`days with 7 day break
`
`No data in vivo in humans
`in Cushing’s disease
`
`Bone marrow suppression,
`nausea, vomiting, dizziness
`diarrhea, rash
`
`Blood count, liver and
`renal function,
`electrolytes
`
`Fatigue, nausea, vomiting,
`stomatitis, bone pain, dyspnea,
`interstitial lung disease
`
`Transaminase,
`pulmonary toxicity
`
`Everolimus
`
`mTOR inhibitor
`
`Liver and renal function,
`Bone marrow suppression,
`blood count, glycaemia,
`nausea, angioedema, GI
`HbA1c, lipid profile
`disorders, extremity pain
`b.i.d.: twice daily; t.i.d.: three times daily; q.i.d.: four times daily; i.v.: intravenous; i.m.: intramuscular; s.c.: subcutaneous; POMC: proopiomelanocortin; US:
`ultrasound; HbA1c: glycated hemoglobin; GI: gastrointestinal.
`
`5 mg/day
`
`suggests that mifepristone can improve clinical symptoms
`in 73–80% of patients [27] within one month after starting
`treatment. Castinetti et al. [28] reviewed the data of 37
`treated CS patients (12 with EAS, 5 with Cushing’s disease,
`the others affected by other causes of CS). A third of these
`developed hypokalemia. It was suggested that this resulted
`from cortisol stimulation of the mineralocorticoid receptor,
`
`while GRs were blocked by mifepristone. Spironolactone
`and potassium chloride replacement therapy can readily
`restore hypokalemia and blood pressure. Followup of efficacy
`and the onset of adrenal insufficiency (reported in 16%
`of 37 patients treated with Mifepristone) should only be
`clinical (weight, blood pressure, skin lesions) and biological
`(regular blood potassium sampling). The therapeutic dose
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`adjustments should be based on these parameters. Mifepris-
`tone is often associated with the development of endometrial
`hyperplasia, so regular vaginal ultrasound is recommended
`in long-term treatment.
`
`3.2. Centrally Acting Drugs . In the last years several novel
`therapies have been studied with a view to the potential bio-
`chemical control and inhibition of pituitary tumor growth
`[29].
`
`3.2.1. Dopamine Agonists. Dopamine (DA) is a catechola-
`mine hormone with a wide range of functions. DA receptors
`have been found in a variety of organs (pituitary, adrenals,
`brain, kidney, gastrointestinal tract, cardiovascular system),
`and possibly exert an inhibitory effect when activated. D2-
`receptor agonists inhibit pituitary hormone secretion, par-
`ticularly PRL and proopiomelanocortin-derived hormones,
`and drugs such as cabergoline and bromocriptine effectively
`inhibit PRL secretion in prolactinomas. Studies on corti-
`cotroph adenomas have shown that 80% of these tumors
`express D2 receptors [30, 31]. In recent decades, published
`case reports and case series have demonstrated the effective
`use of DA agonists in persistent or recurrent Cushing’s
`disease.
`The efficacy of bromocriptine in shrinking pituitary
`tumors was first reported in Nelson’s syndrome and in the
`short-term treatment of CD [32–34]. However, the effect was
`not very strong, and response to long-term treatment was
`<30%. Cabergoline has a higher affinity for D2 receptors
`and a longer half-life compared to bromocriptine. In the
`short term [31] UFC levels normalized (40%) or decreased
`(20%) in a total cohort of 20 patients, 10 of whom
`underwent remission during long-term treatment (12–24
`months) [35]. More recently a study demonstrated a 25%
`complete response to cabergoline in 12 patients with a
`followup of 6 months [36, 37] and confirmed that short-term
`treatment of CD with cabergoline improves cortisol secretion
`in half the cohort studied (30 patients), while long-term
`followup (37 months) demonstrated sustained effectiveness
`of cabergoline in 30% of subjects.
`There are a few documented cases of use of DA agonists
`in ectopic ACTH secretion. A study [38] describes 6 cases of
`ectopic tumors, three of which were not cured by surgery.
`UFC was normalized in two of these patients, although one
`exhibited treatment escape. A prospective study [39] evalu-
`ated the efficacy of cabergoline in monotherapy in patients
`with uncured CD, using sleeping midnight serum cortisol
`and the standard Low Dose Dexamethasone Suppression Test
`(LDDST) cut-off value as the response criteria. Cabergoline
`was effective and safe in 28% of 20 treated patients. This
`drug is generally well tolerated by most patients, and none
`of the subjects treated in these clinical trials showed signs
`of secondary heart dysfunction or valvulopathy, except
`a patient with a history of tricuspid regurgitation [40].
`Cabergoline has also been described as having potential
`positive metabolic effects (pressure lowering, improvement
`of glucose tolerance), independently of its cortisol lowering
`effect. These findings renew interest in the potential use of
`dopamine agonists in Cushing’s disease.
`
`3.2.2. PPAR-γ Ligands. Peroxisome proliferative-activated
`receptor-γ (PPAR-γ), a member of the nuclear receptor
`superfamily, functions as a transcription factor mediating
`ligand-dependent transcriptional regulation [41]. PPAR-γ
`is expressed in several organs, and its administration is
`reported to inhibit tumor cell growth in the prostate and
`colon [42, 43]. Heaney et al. [41] documented the abundant
`expression of PPAR-γ in a series of ACTH-secreting tumor
`samples compared with minimal expression in normal
`pituitary tissues, suggesting that thiazolidinediones, that
`activate PPAR-γ receptors, might be effective as a treatment
`for Cushing’s disease. The literature evidence [44, 45]
`does not support this treatment, due to the lack of long-
`term benefit. Despite the finding of an initial reduction of
`ACTH and cortisol levels in a subset of patients with CD,
`clinical symptoms and biochemical parameters subsequently
`relapsed in this group of subjects. The administration of
`thiazolidinediones does not seem to be more effective than
`other currently available neuromodulators [45].
`
`3.2.3. Pasireotide (SOM230). It is a somatostatin receptor
`(SSR) ligand with high binding affinity for multiple receptor
`isoforms (SST1-3 and SST5). SST5 and SST2 are highly
`expressed in ACTH pituitary adenomas, and animal studies
`documented that SSR mediates inhibition of cAMP and
`regulation of ACTH secretion [46]. A phase 2 trial [47]
`suggested that administration of Pasireotide for a 2-week
`period provoked a reduction in UFC in 76% of 29 patients
`affected by newly diagnosed, persistent or recurrent ACTH-
`dependent Cushing’s disease. In a double blind, phase 3 study
`[48], 162 patients were randomly assigned to receive 600 mcg
`or 900 mcg subcutaneously twice daily. At 12 months, 26%
`and 15% of patients receiving, respectively, the higher and
`lower Pasireotide dose showed normalization of UFC levels.
`Serum and salivary cortisol and plasma ACTH decreased,
`and clinical features of hypercortisolism diminished. Side
`effects of this therapy included hyperglycemia (73%) and
`diabetes in 34% of patients, requiring treatment with glucose
`lowering medications in 45%. The other common symptoms
`were gastrointestinal disorders (diarrhea, abdominal pain,
`vomiting).
`The significant results described in this 12-month phase 3
`study support the use of Pasireotide as a targeted therapy for
`ACTH-secreting tumors. It is still not known if this treatment
`could act on pituitary tumor size. Octreotide, which acts
`predominantly on SSTR2 receptors, has not proven effective
`in inhibiting ACTH secretion in patients with Cushing’s
`disease.
`
`3.2.4. Chemotherapy. In most cases, pituitary adenomas are
`benign slow-growing tumors. However, their rate of growth
`can be fast and they can be resistant to standard medical,
`surgical and radiation treatment [49], especially ACTH
`macroadenomas. The Crooke’s cell variant of corticotroph
`adenoma has been described to be more aggressive and
`refractory to therapy, with a predisposition to malignant
`transformation [50–52]. When invasive tumors recur repeat-
`edly despite radical surgery and postoperative radiotherapy,
`with widespread extrasellar extension, proximity to cranial
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`nerves and critical blood vessels [2], combined cytotoxic
`therapy may be useful. It has also been suggested that
`early application of chemotherapy may be useful in patients
`who have already exhausted all surgical and radiotherapy
`options and are at high risk of malignant transformation
`[53, 54]. Kaiser et al. [55] reported a good response to
`cyclophosphamide, doxorubicin and 5-fluorouracil (5FU) in
`a patient with adrenocorticotroph tumor, with regression of
`the metastases. Kaltsas et al. [53] recommended the use of
`CCNU/5FU for relatively indolent tumor in the first instance.
`There have been partial and short-lasting responses to other
`combinations of chemotherapy agents [2], such as paclitaxel
`and etoposide in ectopic Cushing’s syndrome [56]. In animal
`studies, cytotoxic hybrid compounds between the somato-
`statin analog vapreotide (no longer commercially available)
`and doxorubicin increased the effects of doxorubicin without
`increasing its toxicity [57].
`
`3.2.5. Temozolomide. Temozolomide (TMZ) is a second-
`generation alkylating cytostatic agent. Combined with radio-
`therapy, it is known to be effective in some patients with
`glioblastoma multiforme and cerebral metastases of malig-
`nant melanoma. It is administered orally, does not require
`hepatic metabolism for activation, and is able to cross the
`blood-brain barrier. TMZ promotes apoptosis of target cells
`and induces massive cell shrinkage and necrosis, depleting
`the DNA repair enzyme O6-methylguanine-DNA-methyl
`transferase (MGMT) in various cell types. Multiple studies
`suggest that reduced intratumor levels of MGMT predict
`responsiveness to TMZ. TMZ may also inhibit angiogenesis.
`Its use was firstly described in 2006 for the treatment of a
`pituitary carcinoma, and the first corticotroph adenoma was
`treated in 2007 [58]. Since then, more than 30 case reports
`on its use in ACTH-secreting pituitary tumors have been
`published, and on the whole described some type of positive
`response. Recently Raverot et al. [59] described four patients
`with ACTH tumors with 50% positive response after only
`four cycles, in terms of marked shrinkage of the pituitary
`tumor together with a markedly reduced extension of the
`vertebral metastases, and a drop in ACTH levels with clinical
`improvement. Curt `o et al. [60] published a case report of
`a patient with a corticotroph carcinoma in whom a 90%
`reduction in the size of the tumor, and a stabilization of
`the metastases volume was documented after four cycles of
`TMZ. Dillard et al. [61] described a case of an aggressive
`3 cm corticotroph adenoma refractory to multiple surgery
`and radiotherapy which showed a 60% regression in size
`after TMZ administration. TMZ treatment was generally well
`tolerated. It has been reported [59] that the initial response
`does not always correlate with long-term control of the
`disease and that the absence of MGMT expression may be
`associated with a better response. Tumor stabilization or
`reduction of tumor size can improve clinical outcomes, and
`it remains a last-line defense for life-threatening pituitary
`tumors.
`
`of cyclin-dependent kinases (CDKs) and cyclins. There
`is abundant evidence that retinoids, via various signaling
`pathways, inhibit cell-cycle progression in a variety of human
`cancer cells by directly or indirectly modulating cyclins,
`CDKs, and cell-cycle inhibitors.
`Retinoic acid (RA) has been studied in various types of
`tumor. P´aez-Pereda et al. [62] examined its effects on human
`in vitro and mouse in vivo pituitary cells. RA inhibited ACTH
`biosynthesis only in tumorous corticotroph cells, while
`normal cells were unaffected. The authors concluded that RA
`inhibits ACTH synthesis by inhibiting POMC transcription
`through its activity on AP-1 and Nur77/Nurr1 and reduces
`the proliferation and survival of the corticotroph adenoma.
`It is thus of potential therapeutic use in CD [62, 63].
`Castillo et al. [63] published an in vivo animal study in which
`retinoic acid or ketoconazole was administered to 42 dogs
`with Cushing’s canine syndrome. A reduction in ACTH and
`alpha-MSH levels and pituitary adenoma volume was noted
`after 180 days of therapy with retinoic acid or ketoconazole,
`with similar results for both treatments.
`
`3.2.7. mTOR Inhibitors. Mammalian target of rapamycin
`(mTOR) functions as a central element in a signaling
`pathway involved in the control of cell growth and pro-
`liferation. Everolimus is an mTOR inhibitor, and recent
`studies [64] have demonstrated its antineoplastic activity
`in several human cancers, mostly when associated with the
`long-acting repeatable (LAR) formulation of Octreotide in
`neuroendocrine tumors. Jouanneau et al. [65] hypothesized
`its use in pituitary aggressive adenomas and carcinomas.
`The authors described the effects of a combination therapy
`with everolimus (5 mg/day) and octreotide (30 mg/months)
`and studied mTOR expression in 1 pituitary carcinoma
`against 17 ACTH adenomas. Combined therapy did not
`control pituitary tumor growth or ACTH secretion, but the
`authors are waiting for more clinical cases before drawing
`any conclusions on this combined treatment.
`
`3.2.8. Tyrosine Kinase Inhibitors. Epidermal growth factor
`receptor (EGFR) activation, due to either mutation or ligand
`or receptor overexpression, is associated with a variety of
`human cancers. Approximately 60% of pituitary tumors,
`including ACTH-secreting adenomas, express EGFR. In
`pituitary corticotroph tumors expressing EGFR, p27Kip1, a
`cyclin-dependent kinase inhibitor, is down regulated. In a
`recent study [66], the authors hypothesized that the receptor
`could be a novel target for treatment of Cushing’s disease,
`suppressing ACTH in corticotroph adenomas. In human
`ACTH-secreting tumors [67] gefitinib (a tyrosine kinase
`inhibitor targeting EGFR) was found to suppress in vitro
`POMC expression by approximately 95%. This effect was
`confirmed in canine corticotroph adenoma cells. Gefitinib