Treatment Options for Cushing Disease After Unsuccessful Transsphenoidal Surgery

James K. Liu, M.D.; Maria Fleseriu, M.D.; Johnny B. Delashaw Jr., M.D.; Ivan S. Ciric, M.D.; William T. Couldwell, M.D., Ph.D.


Neurosurg Focus. 2007;23(3):E8 

In This Article

Radiation Therapy

Pituitary irradiation has been used for several decades as an adjunctive therapy in treating pituitary tumors, particularly for residual or recurrent tumors after resection. The goals of this radiation therapy are to control pituitary hypersecretion associated with minimal hypopituitarism, prevent future tumor growth, and possibly diminish tumor size. Radiation therapy may serve as a primary treatment in some patients who cannot medically tolerate resection or who have tumors in a surgically inaccessible location, such as the cavernous sinus.[55] Conventional fractionated radiation therapy has historically been the primary radiation treatment in Cushing disease, but in the last decade or so, SRS has emerged as the primary modality for radiation therapy for pituitary tumors. There is a delay from the time radiation therapy is initiated until the time it takes effect on hypercortisolemia; therefore, medical therapy is initiated and continued for some time until the radiation therapy takes effect during the lag period.

The remission rates after conventional fractionated radiation therapy have been reported to range from 56 to 84% in patients with Cushing disease.[25,46] Minniti and colleagues[46] treated 40 patients with persistent or recurrent Cushing disease after transsphenoidal surgery with conventional fractionated radiation therapy (45–50 Gy in 25–28 fractions) with a median follow-up of 9 years; the 10-year survival rate in this study was 95%. The percentage of patients with normalization of plasma cortisol was 73% at 3 years, 78% at 5 years, and 84% at 10 years. The average time to remission was 2 years. Hypopituitarism was present in 62 and 76% of patients at 5 and 10 years after radiation therapy, respectively. Estrada and associates[25] reported similar results, with a remission rate of 83% in 30 patients after a median follow-up of 42 months (range 18–114 months). The time to remission in this study ranged from 6 to 60 months after radiation therapy, with the majority of remissions occurring in the first 2 years. There were no relapses in the patients who achieved remission. Hypopituitarism was present in 57% of the patients, and no other adverse effects were seen.

Although conventional radiation therapy has demonstrated effectiveness in controlling ACTH secretion, its related complications have limited its usefulness.[55] The incidence of hypopituitarism after fractionated radiation therapy to the pituitary varies between 50 and 100% several years after treatment.[7,67] Additional complications associated with conventional radiation therapy to the sella include radiation necrosis, cerebral vasculopathy, damage to surrounding sellar and parasellar structures (including visual damage), and the development of radiation-induced neoplasms.[11,21,28,56] There is often a delay of several years between treatment and effective control of tumor growth and hormone production. Failures of conventional fractionated radiotherapy have been attributed, in part, to an inability to deliver adequate doses accurately to a small tumor volume while sparing the surrounding structures.[31,55] These concerns have resulted in increased use of SRS for refractory Cushing disease. In a large review of 35 studies in which SRS was used to treat pituitary tumors, Sheehan et al.[55] concluded that SRS appeared to lead to faster normalization of hormone levels than fractionated radiotherapy with apparently lower risk of hypopituitarism, visual deterioration, and radiation-induced neoplasms.

As reported by Sheehan and coworkers,[55] the rates of remission for Cushing disease after SRS have ranged from 17 to 83% in series with more than 10 patients and a median follow-up of 2 years. The variability in reported remission rates is due in part to differing criteria for defining an endocrinological cure by different authors. At most centers, endocrinological remission is generally defined as a normal urinary free cortisol level in conjunction with resolution of clinical signs or a series of normal postoperative serum cortisol levels obtained throughout the day.[55]

In one of the largest SRS series to date, Jagannathan and coworkers[31] evaluated 90 patients with Cushing disease who underwent Gamma knife SRS at a mean dose of 23 Gy to the tumor margin with a mean follow-up of 45 months (range 12–132 months). All but one patient had unsuccessful prior transsphenoidal surgery. One patient who had a cavernous sinus tumor underwent SRS as the primary treatment without resection. Biochemical remission (defined as normalization of 24-hour urinary free cortisol levels) was achieved in 49 patients (54%), with a mean time to remission of 13 months. Ten patients (20%) who achieved remission after SRS experienced relapse, with a mean time to recurrence of 27 months. This rate of relapse after initial remission emphasizes the importance of long-term, and perhaps lifelong, follow-up. Sixty-nine percent of patients had a decrease in tumor size, and 22% suffered a new hormone deficit. The most common newly developed deficit was hypothyroidism, followed by growth hormone deficiency. Five patients experienced ophthalmoplegia from a third, fourth, or sixth cranial nerve deficit, and of these, four had additional visual deficits. Of these five patients, two had previous conventional fractionated radiation therapy and four had previous SRS. One patient who had previous conventional radiation therapy and two SRS treatments developed blindness in both eyes. These results suggest that repeated radiation treatments increase the risk of optic neuropathy and cranial nerve deficit.

Although SRS appears to be a promising modality for adjunctive therapy, longer-term follow-up is necessary to determine the durability of initial remission as well as the true percentage of delayed complications from SRS, such as hypopituitarism, visual and cranial nerve neuropathy, and radiation-induced tumors. It is also important to keep in mind that if the tumor is in close proximity to the optic nerves, fractionated radiation therapy, rather than SRS, may offer a more suitable dose plan that is tolerated by the optic nerves.


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