The options of treatment for patients who do not achieve remission after TSS are: second pituitary surgery, pituitary radiotherapy, long-term medical therapy to control hypercortisolemia and bilateral adrenalectomy (BA) detailed below. In subjects with uncured/recurrent CD, treatment options must be individualized.
Pituitary radiotherapy
Pituitary radiotherapy is a good first-line treatment when the surgery cannot be performed or a second-line approach in the case of persistent disease/recurrence after surgery, especially when the tumor is invasive [
2,
19,
21]. Conventional fractionated external beam radiotherapy delivers dosage of 4500–5000 cGy total, and is usually given in 180–200 rad fractions over a period of 6 weeks [
20]. Intensity-modulated radiotherapy (IMRT) enables dose adjustment for tumor contours and spares nearby crucial structures. There are newer forms of RT available now: stereotactic RT, photon knife (computer-assisted linear accelerator) and the gamma knife (cobalt–60).
From available literature (Table
2), mean time to cure in adults is 1.5–5 years [
71,
72] and the cure rates of conventional fractionated RT are 56–83% [
71,
72]. Despite the published data of the results in children are limited, available date provide that the mean time to cure in children is shorter: 0.75–2.86 years and that the cure rates are higher in comparison to adults—50–100% [
5,
10,
73‐
75]. According to studies in adults (by Schteingart) and children (by Jennings), there are some promising results of a combined pituitary RT and mitotane, which improves the success rate of either modality given alone curing ~66% patients [
74,
76].
Table 2
Outcome of pituitary radiotherapy in children
| 45 Gy, in 25 fractions | 7 | 7/7 (100%) | 0,94 yrs (0,25-2,86) | 6.9 yrs | GHD in 33% (6/18) patients (follow-up 0.6–2.5 yrs) At 2 yrs post RT, puberty occurred early in one male patient (age, 9.8 yrs); normal in the others. Serum T4, TSH, and PRL levels within the normal reference ranges throughout follow-up |
| 45 Gy in 25 fractions | 8 | 4/8 (50%) | 9-18 mos. | 2 yrs | 5 patients were hypogonadal; 1 patient was hypothyroid. All patients were below their target height at the time of last follow up. None of the patients had posterior pituitary dysfunction |
| 45 Gy in 25 fractions | 15 | 12/15 (80%) | 1-18 mos. | 1–18.25 yrs | Growth resumed in 12; Sexual development proceeded normally in all 15 |
| stereotactic external RT using 60 Co gamma radiation (dose 50-70 Gy) | 8 | 7/8 (87,5%) | | 2.6–6.75 yrs | GHD in all 2/8 p were given thyroxine substitution in 3/8 secondary hypogonadism |
| 45 Gy in 25 fractions | 12* (*long term data in 6/12 patients) | 11/12 (92%) | 0.13–2.86 yrs | 6.6–16.5 yrs; mean 10.5 yrs | At a mean of 1.0 year (0.11–2.54) following RT, GHD in 5/6 patients. On retesting at a mean of 9.3 years (7.6–11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2–50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up |
The outcome of pituitary irradiation in CD has been reported in a number of small studies that focus mainly on adult population. Hypopituitarism is the most common adverse effect of RT, more frequent if TSS is performed before RT [
24]. The other adverse effects of RT (visual impairment, radiation oncogenesis) are very rare [
77,
78]. Estrada et al. in his analysis of 30 adult patients with persistent or recurrent CD have shown that 57% of patients (17/30) had GHD after RT (GHD was diagnosed if plasma growth values were <15 mIU/L after the inducement of hypoglycemia), 33% (10/30) had gonadotropin deficiency, 13% (4/30) had a deficiency of thyrotropin, and 3% (1/30) had a deficiency of corticotropin [
77]. 83% had remissions during a median follow-up of 42 months (range: 18–114). The remissions began 6–60 months after RT, but in most cases (73%) remission occurred during the first 2 years. None of the patients had a relapse of CD after remission was achieved [
79].
Results from studies performed on pediatric population present that in children after RT pituitary deficiencies do not occur so often. Storr et al. described the efficacy of RT in 7 children treated by pituitary RT post-TSS [
10]. GH secretion was assessed at 0.6–2.5 yrs post RT in all patients: 33% (6/18) of patients had GHD (GHD was defined as peak GH <20 mIU/L). At 2 yrs post RT, puberty occurred early in one male patient (age 9.8 yrs) but was normal in the others [
10]. Serum T4, TSH, and PRL levels remained within the normal reference ranges throughout mean 6.9 yrs follow-up. Similarly, Chan et al. reported in their retrospective analysis the results of anterior pituitary function in 6 patients treated with pituitary RT after >6 yrs follow-up [
73]. Despite the fact that at a mean of 1.0 year (0.11–2.54) following RT, GHD was present in 83% patients (GHD in childhood was defined as peak GH on provocation testing <20 mIU/L; severe GHD in pediatric and adult patients was defined as peak GH level <9 mIU/l), on retesting at a mean of 9.3 yrs (7.6–11.3) after RT 75% patients were GH sufficient. Other anterior pituitary functions including serum PRL in 5/6 patients were normal on follow-up [
73].
Pharmacotherapy
Definitive treatment such as TSS (and RT in the case off TSS failure), rather than pharmacotherapy, is currently recommended for the management of pediatric CD. Drug therapies for children with CD are limited and not well studied. They can be applied to urgently lower cortisol level in patients with severe hypercortisolemia in preparation for surgery or whilst awaiting the effects of RT [
10]. Long-term treatment may not be effective because of oversecretion of corticotrophin [
2].
There are several drugs that can be used: Ketoconazole and other adrenal enzyme inhibitors: metyrapone, aminoglutethimide and trilostane may be used alone or in combinations to control hypercortisolism but they do not destroy adrenocortical cells that secrete cortisol [
20]. None of these drugs is approved by the FDA (US Food and Drug Administration) for CD treatment [
80]. Ketoconazole is an agent that affects many P450 enzymes (depending on the dose used) blocking adrenal steroidogenesis. Ketoconazole therapy requires liver function monitoring [
81]. The dose is 300 to 1200 mg/day [
81,
82] and 45–50% of patients show long-term control with continued use [
81]. Ketoconazole has not been approved by the FDA for CD treatment neither in children nor in adults [
80], because of the risk of severe liver injury and harmful interactions with other medications [
80]. The European Agency EMA had recommended a permission of a marketing authorization for KCN (HRA Pharma) in the treatment of CS [
83]. Metyrapone increases cortisol metabolites in the serum and urine due to the predominant inhibition of 11-hydroxylase (also the other steroidogenesis enzymes but to a lesser extent) [
84]. Metyrapone has been used safely in children awaiting for RT results [
10], the recommended dosage is 750–2250 mg/day [
81]. Metyrapone is approved for the treatment of CS in the European Union in adults. Mitotane decreases cortisol by direct inhibition of steroidogenesis at a few enzymatic steps [
85]. It also destroys adrenocortical cells secreting cortisol. Therapy with mitotane alone can be successful in up to 72% of patients with CD [
86]. Mitotane (3 mg/day) can be used also as an additional drug with metyrapone [
10]. Aminoglutethimide blocks the conversion of cholesterol to pregnenolone in the adrenal cortex, inhibiting the synthesis of cortisol, aldosterone, and androgens. Aminoglutethimide can be used in a combine therapy with metyrapone (the dosage is 1 g/day) [
10]. Trilostane inhibits the conversion of pregnenolone to progesterone. Storr et al. described in their study successful use of oral drugs (ketoconazole, metyrapone, aminoglutethimide or mitotane) to control hypercortisolemia in 8 patients after pituitary RT [
10].
Another pharmaceutical drug—etomidate has been occasionally used in the treatment of CD [
87,
88]. Greening et al. described a 6.2-year-old male patient with severe hypercortisolemia and life-threatening complications (respiratory failure, severe psychosis) of CD in whom the therapy with metyrapone and ketoconazole was ineffective. Intravenous administration of etomidate had successfully lowered the cortisol level before bilateral adrenalectomy was done [
88].
There are also newer therapies for patients unsuccessfully treated by surgery that directly affect the pituitary tumor: cabergoline and pasireotide [
89,
90]. Cabergoline is a dopamine agonist and its role in CD treatment has been debated. Pivonello in his study [
89] has shown that cabergoline treatment is effective in controlling cortisol secretion for at least 1–2 yrs in more than 33% of a limited population of patients with CD (20 patients in the age 24–60 yrs with persistent CD after unsuccessful surgery). Currently, cabergoline is not approved by FDA for CD treatment.
Specific somatostatin analogs are promising in achieving CD therapeutic goals. Tumors corticotroph cells have on their surface somatostatin receptors (SSTR), mainly SSTR5 and SSTR2 [
91‐
93]. The SSTR subtype 5 has become a therapeutic target in patients with CD thanks to the use of the somatostatin analog—pasireotide that has the highest affinity for this receptor subtype [
89,
90,
94]. Both subtypes: SSTR5 and SSTR2 have been shown to be involved in the regulation of ACTH release [
86,
95]. Several studies (including large phase III clinical trial) have proven that pasireotide causes normalization of urinary cortisol in 25–30% of CD adult patients [
90,
93,
96,
97]. Pasireotide (Signifor) has been approved for adult CD treatment by the FDA and the European Commission [
80]. The use of pasireotide in children is limited to single cases and there are no studies summarizing the effects of treatment in this group of patients. Yordanova et al. describes 1 female patient diagnosed with CD at the age of 13.8 yrs, who had relapse of CD 6 years after TSS [
25]. The patient refused BA and was being managed with pasireotide with good control of hypercortisolemia.
Recently, mifepristone (a progesterone receptor antagonist with glucocorticoid receptor antagonist activity at higher doses) was approved by FDA for treatment of adults with CS to control hyperglycemia [
98]. Improvement in clinical, metabolic, and psychosocial outcome in adults has been documented [
97]. Data on the use of medical therapies to treat CS in children and adolescents are limited [
99]. At present, mifepristone is the promising option for long-term medical treatment of refractory CD in children. Unfortunately the clinical trial “Mifepristone in children with refractory Cushing’s disease”, which was to be the largest study on the effects of mifepristone in children gave no results because of lack of patients enrollment.
Bilateral adrenalectomy
Bilateral adrenalectomy is the treatment option for CD patients who have either failed surgery or RT or where TSS is not possible or available. If performed properly, BA provides immediate relief from hypercortisolism. A laparoscopic approach is the preferred method as is associated with reduced morbidity. There are some disadvantages of BA for the patients: 1. a necessity of lifelong replacement with glucocorticoids and mineralocorticoids; 2. BA does not eliminate the cause underlying the hypersecretion of ACTH; 3. the perioperative mortality is approximately 3 times higher than that of TSS (3% vs. 1% in TSS); 4. recurrences can (rarely) occur (as the result of the growth of adrenal rest tissues) [
20]; 5. the risk of Nelson’s syndrome (NS)—an important complication of BA when the patient develops macroadenomas that secrete ACTH [
100].
NS was documented months or years in up to 15% of children with CD after BA [
20,
24]. NS appears to be more frequent in children than in adults (an incidence of 8–43% in adults [
101] and 25–75% in children [
102‐
104] and often requires pituitary surgery or RT [
105]. Children after BA seem to have higher risk of NS in comparison to adults—for this reason they should be carefully monitored—they require annual monitoring with MRI and assessment of plasma ACTH values [
102‐
104].