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Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing’s Disease: An Effective Second-Line Treatment

Departments of Endocrinology (H.L.S., P.V.C., G.M.B., A.B.G., M.O.S.), Radiotherapy (P.N.P.), and Neurosurgery (F.A.), St. Bartholomew’s and The Royal London School of Medicine and Dentistry, London EC1A 7BE, United Kingdom; Department of Paediatrics (I.F.), University of Leuven, Leuven 3000, Belgium; and Department of Endocrinology (G.E.K.), Pagania Hospital, 54622 Thessaloniki, Greece

Address all correspondence and requests for reprints to: Professor Martin O. Savage, Paediatric Endocrinology Section, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: m.o.savage{at}qmul.ac.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing’s disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4–17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269–900 nM during the immediate postoperative period (2–20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4–17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200–600 mg/d) (n = 4) and metyrapone (750 mg–3 g/d) ± aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT.

The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25–2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150–300 nM) occurred at mean 1.16 yr (0.40–2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6–2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0–17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4–12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
PITUITARY-DEPENDENT CUSHING’S SYNDROME, Cushing’s disease (CD), is characterized by hypersecretion of ACTH from a pituitary corticotroph adenoma. The resulting hypercortisolemia causes considerable morbidity in childhood and adolescence (1, 2). Although rare in the pediatric age range, CD accounts for approximately 75% of pediatric Cushing’s syndrome (1, 2, 3). Transsphenoidal surgery (TSS) with selective microadenomectomy is now established as the primary treatment for both pediatric and adult patients with CD.

Remission or cure of CD after TSS is reported to vary from 50 to more than 90% (3, 4, 5, 6). However, successful transsphenoidal microadenomectomy in children is a highly skilled and technically difficult procedure. Most published series report a significant percentage of failure, even by the most experienced surgeons (5, 6). Consequently, a proportion of children will require alternative or second-line therapy. There is, however, no clear agreement on optimal therapy after unsuccessful TSS. The options are: repeat TSS, pituitary radiotherapy (RT), or unilateral or bilateral adrenalectomy.

Pituitary RT has been demonstrated to be effective treatment for adult (7, 8) and pediatric (9, 10) CD. However, there are few published series of short- and long-term outcome after this treatment in children and adolescents with CD. We report our experience with pituitary RT in seven pediatric patients with CD after failed TSS. We describe the response times between RT and cure of CD and recovery of the pituitary-adrenal axis. We also describe the effect of RT on long-term pituitary function.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Eighteen pediatric patients (11 males and 7 females; mean age, 12.8 yr; range, 6.4–17.8) with CD were investigated and treated at St. Bartholomew’s Hospital, London, United Kingdom, from 1983–2000. Transsphenoidal microadenomectomy was attempted in all 18 patients, and 11 achieved postoperative cure. Seven patients (6 males and 1 female; mean age, 11.7 yr; range, 6.4–17.8 yr; 3 pubertal; 4 prepubertal) had persisting hypercortisolemia in the immediate postoperative period, indicating lack of cure. These patients received direct pituitary irradiation. The patients were followed up for a mean time of 6.9 yr (1.4–12.0 yr). Clinical details of the patients are given in Table 1.

CD was diagnosed in the seven patients who received pituitary RT, on the basis of a detectable serum ACTH (mean 0900-h value, 54 ng/liter; range, 29–125 ng/liter; normal range, 10–50 ng/liter); loss of serum cortisol circadian rhythm, i.e. elevated sleeping midnight cortisol of more than 50 nM (mean, 586 nM; range, 263–930 nM); and failure of serum cortisol to suppress to <50 nM during a low-dose dexamethasone suppression test (LDDST; 0.5 mg, 6 hourly for 48 h) (11). In addition, the patients showed suppression of serum cortisol to more than 50% of the baseline value in a high-dose dexamethasone suppression test (2 mg, 6 hourly for 48 h) (11) and an exaggerated response of serum cortisol during a CRH test (1 µg/kg iv) ranging from 119–290% (12).

Radiological imaging

Preoperative pituitary imaging with computed tomography or magnetic resonance imaging scan was performed in all patients but demonstrated a surgically proven microadenoma in only one of seven patients. As previously reported, pituitary imaging provided a low rate of microadenoma detection in our patients with pediatric CD (4).

Simultaneous bilateral inferior petrosal sinus sampling

IPPS for ACTH, after iv CRH, was performed preoperatively in two of seven patients. In both patients, central-to-peripheral ACTH ratios after CRH were more than 3.0 (13.5 and 28.1), indicating a central etiology (11). Interpetrosal ACTH ratios were more than 1.4, indicating lateralization of the microadenoma (13).

TSS

Transsphenoidal microadenomectomy was attempted as first-line therapy in all patients. This was performed using the transnasal approach (13), by the same surgeon (F.A.), in 16 of 18 patients. Hydrocortisone was given for a minimum of 24 h postoperatively. After TSS, serum cortisol levels were measured daily at 0900 h, at least 12 h after the last dose of hydrocortisone.

Seven patients were not cured by surgery, having detectable postoperative serum cortisol more than 50 nM (14). These patients received pituitary RT.

Pituitary RT

RT consisted of external beam irradiation, using a 6-MV linear accelerator to deliver 45 Gy, in 25 fractions, over 35 d (15). This treatment was delivered at a mean interval of 2.8 months post TSS (range, 0.7–8.0 months). The technique consisted of immobilization of the head, in an individually constructed, tight-fitting full-head plastic shell. A three-field technique (two lateral and one superior oblique) was used to target irradiation to the pituitary and therefore minimize the dose to other brain structures.

Medical treatment

Persisting postoperative hypercortisolemia, defined as mean serum cortisol more than 300 nM (14), was treated with ketoconazole (dose, 200–600 mg/d; n = 4) and metyrapone (750 mg–3 g/d) ± aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d; n = 3) (8 ; see Table 1).

Definition of cure of CD

Cure of CD, after RT, was defined as mean serum cortisol on a 5-point day curve of less than 150 nM after discontinuation of medical therapy, in addition to a midnight serum cortisol less than 50 nM and suppression of serum cortisol to less than 50 nM on the LDDST (11). When cure occurred before recovery of the pituitary-adrenal axis, corticosteroid replacement treatment was given.

Recovery of the pituitary-adrenal axis

A mean serum cortisol on a 5-point day curve of 150–300 nM was taken as normalization of cortisol secretion (14), indicating recovery of the normal pituitary–adrenal axis.

Evaluation of GH secretion

GH secretion was assessed as the peak GH response to glucagon stimulation (15 µg/kg im; n = 2) or insulin-induced hypoglycemia (0.15 U/kg iv; n = 5). GH deficiency (GHD) was defined as peak GH less than 20 mU/liter; and severe GHD, as less than 9 mU/liter (16). GH secretion was assessed at a mean interval of 1.5 yr (range, 0.6–2.5 yr) after completion of RT. Long-term GH status was also assessed in two patients at 7.6 and 9.5 yr post RT.

Pubertal staging

Puberty was staged, at presentation, according to Tanner’s criteria (17, 18). Four patients were prepubertal and three were pubertal at diagnosis (Table 1).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Postoperative serum cortisol level

Seven of the 18 patients (39%) treated by TSS had 0900-h serum cortisol levels with a mean of 444 nM (range, 269–900 nM) in the immediate postoperative period (2–20 d), indicating lack of cure (14) (Table 2). Hypercortisolemia was controlled with medical treatment, as described above, until cure, after RT.

All seven patients achieved cure after RT. The mean interval between the end of RT and cure was 0.94 yr (range, 0.25–2.86 yr) (Table 2). At the time of cure, the mean serum cortisol level on a day curve was 93 nM; range, 57–138 nM (Table 2). Medical adrenal suppressive treatment was stopped for at least 1 month, in all patients, before assessment of endogenous cortisol secretion.

Interval from RT to recovery of pituitary adrenal axis

Recovery of normal pituitary-adrenal function occurred at a mean of 1.16 yr (range, 0.4–2.86 yr) post RT (Table 2). Three patients received steroid replacement from the time of cure until recovery of the pituitary-adrenal axis.

In six of seven patients, recovery of mean serum cortisol levels (mean, 218 nM; range, 162–296 nM) and restoration of normal serum cortisol circadian rhythm (sleeping midnight cortisol, <50 nM) occurred within 1.19 yr (mean, 0.87 yr). The remaining patient had a mean serum cortisol level, on a day curve, of 160 nM, at 15 months post RT, and midnight cortisol levels persistently more than 50 nM (105 nM), despite remaining in clinical remission. Undetectable midnight cortisol levels and normal suppression of serum cortisol to less than 50 nM on LDDST occurred at 2.86 yr post RT, suggesting cure (mean on cortisol day curve, 138 nM). Therefore, cure coincided with recovery.

Assessment of GH secretion

The peak serum GH response to provocative testing was assessed at 0.6–2.5 yr after RT in all patients (Table 2). Six (86%) had GHD (mean peak GH, 9.6 mU/liter; range, <1.0–17.9 mU/liter). Of these, three patients had severe GHD (GH < 1.0–6.5 mU/liter). All six patients received human GH (hGH) replacement. We have previously reported long-term growth after TSS and pituitary RT for CD (19). In two patients, GH was assessed 7.6 and 9.5 yr after RT. They showed changes of peak GH levels from 16.6–29.7 mU/liter and from 6.5–19.2 mU/liter, respectively. Of the remaining four GHD patients, two remain on hGH treatment 2.1 and 2.4 yr post RT, one has not commenced hGH yet, and one patient was not retested.

Gonadotropin, ACTH, TSH, and prolactin (PRL) secretion

In the three patients who were pubertal at diagnosis, puberty proceeded normally post RT. In one male patient, who was prepubertal at the time of RT, puberty occurred early, at age 9.8 yr (2 yr post RT), with genital development stage 2, pubic hair stage 2, and testicular volumes of 6 ml bilaterally. Bone age had also advanced from 6.5 yr (at chronological age 8.5 yr) to 9.9 yr. A GnRH test showed pubertal increases of LH and FSH, and serum testosterone was 1.5 nM (normal prepubertal range, <0.8 nM). A GnRH analog was commenced to suppress gonadotropin secretion and maximize linear growth potential. This case has been previously reported in detail (20).

At follow-up intervals of 1.4 to 12.0 yr in all seven patients, clinical and biochemical signs of gonadotropin secretion were normal. Serum cortisol day curves were performed regularly and showed no evidence of ACTH deficiency. Serum T₄, TSH, and PRL levels remained within the normal reference ranges throughout follow-up.

Long-term outcome

All patients were cured of their CD, both clinically and biochemically. At latest assessment, no patient showed evidence of recurrence of CD. Two patients were investigated for possible relapse, because of detectable midnight cortisol levels. One had persistently raised midnight serum cortisol (135 nM, 5 yr post RT) but with normal suppression on the LDDST. In the other patient, the abnormal serum cortisol circadian rhythm was related to excessive alcohol consumption, with an abnormal LDDST and elevated midnight cortisol (360 nM); however, both normalized after abstinence.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
CD is rare in childhood and adolescence (2) and presents a considerable therapeutic challenge to the pediatric endocrinologist. Transsphenoidal microadenomectomy has become accepted as first-line treatment of choice in children and adolescents (2, 4). Cure or remission rates after TSS for pediatric CD have been reported as 98% (2), 90% (21), 73% (5), 69% (22), and 45% (6). In our hospital, the cure rate for pediatric CD after TSS, defined strictly as an undetectable postoperative cortisol (14), is currently 66% (4). These findings indicate that a significant number of pediatric patients will require additional treatment after surgical failure. Repeat TSS is practiced in some neurosurgical centers (22), but this carries a risk of permanent pituitary deficiency.

Formerly, bilateral adrenalectomy was widely practiced (23). The potential development of Nelson’s syndrome, however, remains a major complication, with reported incidence in children of 25–67% (1, 23, 24).

External-beam pituitary RT has been demonstrated to be effective treatment for pediatric CD in children. It was initially suggested as primary therapy (9), before the development of TSS, but is now preferred as second-line treatment after unsuccessful TSS. Cure rates of 80–88% have been reported in small series (9, 10). Our findings support the efficacy of RT, because all our patients were cured, with no evidence of recurrence. A relatively rapid response time of 0.8–1.0 yr in childhood CD treated with RT has been reported (9, 10). In our study, cure was achieved at less than 1 yr after RT in 86% of patients. These data compare favorably with responses in adults, in whom cure occurs in 56–83% patients after RT as first- or second-line therapy, at a mean time interval of 1.5–4 yr (7, 8, 25).

There are no previously reported data on interval from RT to recovery of normal pituitary-adrenal function in children with CD cured by pituitary RT. We have demonstrated that this occurs at a mean of 1.16 yr (range, 0.40–2.86 yr), which is approximately the same time interval as cure after RT.

Hypopituitarism has been recognized as a potential complication of external RT for pituitary adenomas (7, 26). GHD is a well-recognized complication of pituitary irradiation (1, 7, 15, 16, 27). In adults, GHD is reported in 36% and 68% of patients post pituitary RT for CD (7, 16) and 79% in the treatment of prolactinomas (27). In our series, GHD was diagnosed in all but one patient, at a mean of 1.5 yr after RT. Early diagnosis of GHD and replacement with hGH ensures satisfactory growth acceleration and good catch-up growth in these patients (3, 19). GHD also occurs after TSS for pediatric CD (19, 28) and may be transient in adults (16). However, a recent analysis of our adult patients, who presented with CD in childhood, suggests that GHD persists for more than 5 yr after cure by TSS (29). Hence, it is difficult to distinguish the relative contribution of TSS or RT to the GHD in our patients. During the period of follow-up in this series, GHD was the only endocrine deficiency that occurred after RT, and some recovery of GH secretion was demonstrated at completion of linear growth in two patients, as is known to occur in idiopathic GHD (30).

Gonadotropin secretion may be disturbed after whole-brain or pituitary irradiation, puberty being either early or delayed. Early onset of puberty has been reported after whole-brain irradiation for childhood leukemias (31). With the exception of early puberty in one of our patients (20), no abnormalities of gonadal function were observed. Similarly, no abnormalities of TSH or PRL secretion were seen.

Our data provide evidence that pituitary RT is a safe and effective treatment for childhood and adolescent CD after failed transsphenoidal microadenomectomy. All of our patients were cured, and the response time was relatively rapid. This therapeutic modality can therefore be recommended as second-line treatment of choice in the management of pediatric CD.

	Acknowledgments

 

	Footnotes

 
Abbreviations: CD, Cushing’s disease; GHD, GH deficiency; hGH, human GH; LDDST, low-dose dexamethasone suppression test; PRL, prolactin; TSS, transsphenoidal surgery; RT, radiotherapy.

Received July 5, 2002.

Accepted September 19, 2002.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Storr, H. L. Articles by Savage, M. O. Search for Related Content PubMed PubMed Citation Articles by Storr, H. L. Articles by Savage, M. O.