Introduction

Gamma Knife radiosurgery is a method for delivering focused radiation therapy to a variety of tumors and lesions in the brain and to pituitary tumors. This discussion will address the use of Gamma Knife in patients with Cushing’s Disease, excess cortisol production by the adrenal glands because of a pituitary adenoma producing an excessive amount of ACTH.

Pituitary radiation is usually administered as adjunctive (additional) therapy in patients who have a residual tumor and persistent Cushing’s Disease after surgery. This residual tumor produces an excessive amount of a hormone, ACTH. The size of the residual tumor is the limiting factor in selecting a patient for this treatment, the tumor cannot be too close to the optic chiasm (eye nerves) because of the risk of damage to vision. The treatment is usually administered in one setting, the patient has a stereotactic frame placed on the head, and an MRI scan is used to plan the precise field which will be exposed to radiation. Because most pituitary adenomas are benign (non-cancerous), it is thought that a single dose of focused radiation is adequate therapy. Administering the radiation in one session is more convenient for the patient and may be more cost effective. Another advantage is that focused radiation should avoid damage to the hypothalamus (the portion of the brain which regulates the pituitary gland) and other parts of the brain. Focused radiation with the Gamma Knife exposes a much smaller amount of the brain to radiation, thus decreasing the risks. Because this method of delivering radiation has a very steep fall off of radiation, the optic nerves and optic chiasm are spared from receiving harmful doses of radiation. In some patients, a discrete tumor can be targeted and the normal gland can be spared from receiving significant radiation.

Candidates for Gamma Knife Treatment

Gamma Knife radiation treatment for a pituitary tumor is most often used as secondary therapy after surgery. The size of the residual tumor is the limiting factor in selecting a patient for this treatment. A large pituitary tumor is not appropriate for treatment with the Gamma Knife. In some cases, no obvious tumor is seen on the postoperative MRI scan, but the patient still has excessive hormone production which should be reduced to normal. In this situation, the entire pituitary gland is usually targeted for treatment. Because approximately 20% of patients with Cushing’s Disease have persistent excessive hormone production after surgery, every effort should be made to reduce ACTH (and thus cortisol production) to normal. Gamma Knife treatment may also be appropriate for patients who have an initial remission after surgery and then develop a recurrence which occurs in approximately 8 to 12% of patients with Cushing’s Disease.

Results: Cushing’s Disease

At the University of Virginia, we have treated 260 patients with pituitary tumors with the Gamma Knife; 54 patients had Cushing’s Disease. Follow-up information is available in 38, and we have observed that 24 of these 38 (63%) achieved a normal 24-hour urine cortisol level after Gamma Knife treatment. The average time to achieving a normal 24-hour urine free cortisol level was 13 months, and the range was 2 to 48 months. In contrast, a study of conventional (fractionated) radiation in 30 patients with Cushing’s Disease found that 25 achieved a remission within 18 to 114 months. New hormone deficiency developed in 17 of 30 patients. In our patients, 8 of the 38 developed a new pituitary hormone deficiency after Gamma Knife radiation which required hormone replacement (oral medication).

As is evident, no method of radiation treatment to the pituitary gland cures the disease instantly. For this reason, we recommend that our patients be treated medically with a drug to lower cortisol production while awaiting the effect of the Gamma Knife radiation treatment. Most commonly, our patients are treated with ketoconazole (Nizoril) tablets to reduce the adrenal gland production of cortisol while awaiting the effect of radiation. Every six months, the medication is discontinued for two weeks, and the patient collects another 24-hour urine specimen for measurement of free cortisol. If the cortisol is normal, the patient is considered to be in remission, and the medication is discontinued. If the urine cortisol level is elevated, then the medication is restarted. Additionally, other hormone levels are measured to determine if the patient has developed any hormone deficiencies. For example, it is important to measure the thyroid hormone level to determine if the patient requires thyroid hormone replacement.

Limitations of the Gamma Knife

As mentioned above, a large tumor or a tumor that is close to the optic chiasm is probably not a tumor which can be treated with the Gamma Knife because of the risk of damaging vision. In this situation, additional surgery to remove as much of the tumor as possible may be indicated. If there is persistent disease (excess hormone production), then a Gamma Knife treatment may be indicated. Of course, each patient must be evaluated completely, including the blood hormone tests, the 24-hour urine cortisol, and an MRI scan must be reviewed before deciding if surgery or Gamma Knife is indicated. In the meantime, all efforts must be made to control the excessive cortisol production by the adrenal glands since high cortisol levels result in the numerous medical problems of Cushing’s, including weight gain, hypertension, diabetes, depression, osteoporosis and muscle weakness. It is important to emphasize the medical treatment only controls excess cortisol production, it does not have any effect on the pituitary gland itself.

Conclusion

Gamma Knife radiation has become an integral part of our combined treatment program for the management of pituitary adenomas. Our preliminary results indicate that it is a safe treatment, is convenient for the patient, and produces remission in some patients earlier than conventional fractionated radiation treatment. We plan to continue our efforts in assessing the benefits and risks of this treatment for Cushing’s Disease and for other types of pituitary adenomas.

Author: Dr. Mary Lee Vance MD (Spring, 1999)

Editor’s Note: Dr. Mary Lee Vance is a Professor of Medicine and Neurosurgery at the University of Virginia Health Sciences Center in Charlottesville, Virginia. Dr. Vance has been involved in the treatment of pituitary tumors and Cushing’s Disease for many years.