A significant proportion of patients with CD continue to have measurable cortisol levels after pituitary surgery, indicating total or partial failure in removing the adenoma. They may have invasive macroadenomas, and surgery was mandatory to reduce tumor bulk and correct visual failure from compression of the optic chiasm. After noncurative surgery, an immediate decision should be made as to whether a second surgical intervention is indicated. This may involve reexploration of the pituitary fossa or a full removal (total hypophysectomy) of remaining pituitary tissue. If a second procedure results in undetectable early morning cortisol concentrations, subsequent management is as outlined earlier.
In those with evidence of continuing ACTH hypersecretion, further measures to control cortisol levels are necessary. In most cases, medical management with adrenolytic drugs is indicated, with metyrapone, ketoconazole, and mitotane being the most widely used. When initiating metyrapone, a test dose (usually 750 mg by mouth) may be given as a metyrapone "sensitivity test" (see Appendix 1, p. 201). Maintenance treatment is then started with equal divided doses taken every 8 h. In the case of all adrenolytics, the response to treament may be assessed using a Cushing's "day-curve" (see Appendix 1, pp. 199-200), with doses titrated to achieve mean cortisol concentrations between 150 and 300 nmol/L (equivalent to the normal daily production rate).
The majority of patients with unsuccessful surgery for CD are considered for pituitary irradiation. Conventionally, this is delivered in fractions during a 5- to 7-wk period in the form of three-field external beam irradiation. Newer radiotherapy techniques include the Gamma Knife and X-knife (see Chapter 14), but we do not recommend these as initial treatment. In all cases, the ACTH time course response to treatment is variable, with 6 to 12 mo typically passing before significant benefits are seen. Patients may achieve remission within 1 yr after radiotherapy (21), particularly in childhood, but usually many years are required before medical therapy can be terminated. Periodic remeasurement of the CDC is required with careful titration of adrenolytic drugs.
In resistant cases where the combination of pituitary surgery and irradiation have failed to control CD and/or medical therapy is poorly tolerated, bilateral adrenalectomy should be considered. Provided all adrenal tissue is removed, satisfactory reduction in the circulating cortisol level is seen. This procedure is frequently performed by minimally invasive surgery or laparoscopy, but care is required because the adrenal glands are often large, vascular, and friable in CD. The presence of continuing cortisol excess after adrenalectomy raises the possibility of the presence of adrenal rests.
After bilateral adrenalectomy, all patients require both corticosteroid and mineralocorticoid replacement. Pituitary surveillance is mandatory in patients with CD who have undergone adrenalectomy. Nelson's syndrome of pituitary tumor enlargement in this situation results in marked elevation of circulating ACTH concentrations with resultant pigmentation of the skin (22). Regular imaging, combined with measurement of ACTH before and after the morning dose of glucocorticoids, facilitates monitoring for the development of Nelson's syndrome. It remains unclear whether and to what extent pituitary radiotherapy lessens this complication, but in general, advances in surgery have rendered early bilateral adrenalectomy less common.
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