Adrenocorticotropic Hormone-Producing Tumors

Cushing’s disease is associated with significant morbidity and premature death. Up to 30% of patients may experience persistent or recurrent disease after trans-sphenoidal surgery.¹ Most studies define remission as normalization of 24-hour, urine-free cortisol (UFC) in the absence of medical suppression. Remission rates after radiotherapy reported in literature vary widely from 17% to 83% due to varying indications for radiosurgery, dosing, definitions of remission, and follow-up length. The time to remission also varies widely, from 2 months to 8 years,² although the majority occur within 2 years of radiosurgery.¹

Jagannathan et al.³ reviewed the GK radiosurgery experience in 90 patients with Cushing’s disease treated between 1990 and 2005, all of whom either had at least 12 months of follow-up postirradiation or experienced remission within 12 months of treatment. Patients presenting with Nelson’s syndrome were not included in this study. Indication for GK radiosurgery in all patients was persistent elevation of 24-hour UFC following surgical resection. The mean follow-up length post-GK was 45 months (range 12–132 months), and the mean marginal dose was 23 Gy (median 25 Gy). At the time of treatment, only 49 patients (54%) had tumors that were visible on magnetic resonance imaging (MRI). Remission was defined as normalized 24-hour UFC without concomitant medical therapy. Remission was achieved in 54% of patients at an average time of 13 months after radiosurgery (range 2–67 months). In patients with MRI-evident tumors, tumor volume decreased in 80%, remained constant in 14%, and increased in 6%. Of the patients who experienced biochemical remission, 20% suffered relapse at a mean time of 27 months (range, 6–60) after remission. Radiosurgical complications included hormone deficiencies in 22% of patients diagnosed at a mean time of 16 months (range, 4–36 months) after GKS and cranial nerve (CN) and visual field deficits in 5% of patients.

In the above study, no correlation between either maximum dose, marginal dose, or treatment volume and biochemical remission or tumor control was found, consistent with findings from another recent study.⁴ In two other studies,^5,6 however, the authors found the maximum dose and prescription isodose volume to be significantly correlated with hormone response, although it is worth noting that when analyzing hormone response, these two studies lumped all functioning adenomas, and therefore the specific applicability of the conclusions to Cushing’s disease may be brought into question. Indeed, as mentioned previously, functioning adenomas show differential responses to irradiation as reflected by their differential response rates.⁷ To maximize the likelihood of treatment success, many authors^3,5 advocate the use of more than 20 Gy at the 50% prescription isodose line when safe to do so.

Endocrinologic relapse after initial remission is an important problem in Cushing’s disease and, in some series,^3,4,7 occurs in approximately 20% of patients cured by radiosurgery. In the Jagannathan et al. study,³ recurrence occurred at a mean time of 27 months after radiosurgery and 43% had their disease brought into remission again after a second radiosurgery treatment. In the study with the longest follow-up to date (mean follow-up of 94 months), Castinetti et al.⁴ observed a 50% cure rate in 18 patients with Cushing’s disease and recurrence in two patients (11%) at 6 and 8 years after initial treatment. Therefore, long-term endocrinologic follow-up is recommended.

Patients undergoing bilateral adrenalectomy due to persistent Cushing’s disease risk the development of Nelson syndrome, characterized by aggressive growth of the residual ACTH-secreting adenoma due to a reduced feedback inhibition by cortisol. Periodic imaging and monitoring of plasma ACTH levels have allowed early detection and treatment of these tumors. Corticotroph growth is rare in radiated patients, but may occur in up to 50% of nonradiated patients within 3 years of adrenalectomy.⁸ Few studies have been conducted to specifically investigate the safety and efficacy of stereotactic radiosurgery for Nelson syndrome. Nonetheless, GKSRS seems to offer a favorable tumor control rate of 82% to 100% and some authors have reported endocrinologic remission rates of up to 36%.^9–11

Growth Hormone–Producing Tumors

Biochemical remission for growth hormone (GH)–producing pituitary adenomas is commonly defined as normalization of age- and sex-adjusted serum level of insulin-like growth factor-1 (IGF-1) in the absence of medical therapy, as well as a basal GH level of less than 2.5 μg/L or less than 1 μg/L after glucose challenge (see Figs. 101B and 102A).^1,4,12–14 In general, GH-secreting adenomas are particularly resistant to the effects of radiation. In a retrospective study¹³ of 83 patients with GH-secreting pituitary adenomas and acromegaly who received stereotactic radiosurgery as treatment for residual or recurrent disease following trans-sphenoidal surgery, biochemical remission was achieved in 60% of patients with a median follow-up of 69 months. The 5-year remission rate was 52%. Two patients experienced tumor progression, which occurred outside the treated volume. The median marginal dose at the 50% prescription isodose line was 21.5 Gy, no patients suffered CN toxicities, and hypopituitarism occurred in 8.5% of patients. Biochemical recurrence occurred in 1 patient and was managed medically. For patients with somatostatin analog-resistant tumors (n = 13), the authors found a much lower 16% remission rate.

In GH-secreting tumors lower basal GH levels are associated with increased rate of cure after radiosurgery. Losa et al.,¹³ using multivariate analysis, found increased likelihood of remission when basal GH levels were below 7.0 μg/L and basal multiples of upper limit (mUNL) IGF-1 levels were below 1.83 times UNL, with hazard ratios of 2.7 (95% confidence interval [CI] = 1.4–5.3) and 2.6 (95% CI = 1.3–5.1), respectively. This finding has since been replicated by Castinetti et al.⁴ in a series of 43 acromegalic patients with a mean follow-up of 102 months (42% remission). In these studies, radiation dose did not have a statistically significant impact.

There is emerging evidence that somatostatin analogs, when present at the time of radiosurgery, have a detrimental effect on achieving biochemical remission. In the initial study by Landolt et al.,¹⁵ 9 patients treated with octreotide at time of radiosurgery were compared to 22 patients who did not receive octreotide at time of radiosurgery but had baseline characteristics with respect to age, sex, GH and IGF-1 levels at time of radiosurgery, treatment volume, and radiation dose. While patients who did not receive octreotide achieved a remission rate of 60%, patients who received octreotide achieved a remission rate of only 20% at 3-year follow-up. The radioprotective effect of octreotide has since been observed in other studies as well,^12,16 albeit inconsistently.^4,13 It is hypothesized¹⁵ that antisecretory agents such as octreotide may exert a radioprotective effect by decreasing cell cycling and thereby render cells less vulnerable to radiation-induced DNA damage. Based on these data, it is recommended that patients undergoing stereotactic radiosurgery for GH-releasing pituitary adenomas discontinue somatostatin-analogs at least 2 months prior to, and not resume them until 6 weeks after, radiosurgery. It is important to note however, that patients in these studies were not randomized and therefore selection biases, such as patients on octreotide were likely to have more severe and intractable disease, cannot be excluded.

Prolactin-Producing Tumors

Due to prolactin-secreting tumors’ robust response to dopamine-agonists, radiosurgery is commonly the last-line treatment, reserved for tumors that fail medical management and trans-sphenoidal resection (see Fig. 101A). In a retrospective study¹⁷ of 23 patients with medically and surgically refractory prolactinomas treated by GK, biochemical remission was achieved in 26% of patients with an average time of 24.5 months. Remission was defined as normalized serum prolactin without concomitant dopamine-agonist therapy. Volumetric control of tumors was achieved in 89% of patients with shrinkage in 46%. The mean marginal dose was 18.6 Gy. Pituitary insufficiency occurred in 28% of patients with an average time to onset of 44 months. Moreover, one patient developed a 3rd CN palsy and another patient a 6th CN palsy. Both patients suffered from tumors with cavernous sinus extension and were treated with a maximum dose of 50 Gy. The remission rate reported here is consistent with other series.^4,7,18,19 Among functional adenomas, prolactin-secreting tumors have been reported in a study to be the least responsive to irradiation.⁷ However, the study with the longest follow-up⁴ showed similar remission rates for secretory tumors (42%, 46%, and 50% of patients with GH-, PRL-, and ACTH-secreting adenomas, respectively). The difference was the mean time to remission (50, 24, and 28 months for GH-, PRL-, and ACTH-secreting adenomas, respectively), suggesting again that GH-secreting adenomas are more resistant to the effects of radiosurgery. Although no study has specifically addressed the issue of fertility after radiosurgery for prolactin-secreting adenomas, Landolt and Lomax¹⁸ observed that 2 out of 11 patients with normalized serum prolactin became pregnant spontaneously.

It has been found¹⁷ that biochemical remission was significantly associated with a tumor volume of less than 3 cc. Moreover, analogous to GH-secreting adenomas, dopamine-agonist therapy at the time of radiosurgery decreases the likelihood of achieving biochemical remission.^17,18