During the last 10 to 15 years, RS has emerged as an important treatment modality in the management of nonresectable pituitary adenomas. The majority of these patients has been treated with the γ-knife technique.3, 18–39 Until now, to our knowledge, only 3 groups have reported regarding the treatment of patients with hormone-secreting (48 patients) and nonsecreting adenomas (30 patients) with LINAC-RS.40–42 The follow-up periods in those studies were 12 to 18 months,41 47 months,40 and 49.2 months.42 With 142 patients evaluated and a mean follow-up of 81.9 ± 3.1 months, the current analysis, to our knowledge, represents the largest data base of patients with pituitary macroadenomas who were treated prospectively in a single center with LINAC-RS. Because approximately 40% of those patients had an actual follow-up that exceeded 5 years, we were able to assess long-term effects in a significant number of patients.
LINAC-RS with a mean therapeutic dose of 15.3 Gy (range, 8–20 Gy) produced local tumor control in 96.5% of patients and tumor response in 34.4% of patients. This tumor control rate is comparable to the data reported by others, which varied from 92% to 100%.10, 20–22, 24–26, 29–33, 35–38, 40, 42 According to the literature, local tumor control does not depend on the prescribed therapeutic dose and the type of adenoma. There was no difference between patients with hormone-inactive adenomas who received an average therapeutic dose of 17.8 ± 3.2 Gy (range, 14–25 Gy)10, 20, 22, 25, 29–31, 35, 36, 38, 40, 42, 43 and patients with hormone-secreting adenomas who, on average, received a radiation dose of 22.2 ± 5.5 Gy (range, 15–34 Gy).10, 20–22, 24–26, 29–33, 35–38, 40, 42
In contrast to tumor control, the prescribed therapeutic dose seems to determine tumor regression. When the prescribed therapeutic dose was kept below 20 Gy, according to the literature, tumor regression rates ranged from 17% to 46%,31, 35–37, 40, 41 rates that are comparable to the findings of the current study (tumor regression rate, 32.4%). In most series in which patients received a mean therapeutic dose that exceeded 20 Gy, tumor regression rates tended to be higher (range, 58–100%).10, 24, 27–29, 33, 34, 43
In the current study, 48 of 105 patients (45.7%) who were treated for a hormone-active adenoma experienced hormone normalization within a mean of 36 months after RS. The cure rate was 35.2% (37 of 105 patients), and the mean ± standard deviation time from LINAC-RS to a cure was 42.1 ± 25.0 months. ACTH-secreting adenomas (cure rate, 52.9%) and TSH-secreting adenomas (a cure was achieved in 1 of 2 patients) were the most responsive adenoma types followed by GH-secreting adenomas (cure rate, 37.5%), prolactin-secreting adenomas (cure rate, 15.4%), and Nelson tumors (cure rate, 11.1%). According to the univariate analysis, the diagnosis of Cushing disease was associated significantly with a high cure rate (P = .001). Considering studies that used definitions and cut-off levels comparable to those used in our protocol, the cure rates varied considerably. Specifically, the cure rate for patients with GH-secreting adenomas ranged from 17% to 82%.10, 18, 19, 24, 32 With almost identical follow-up intervals, however, in 2 of those studies, the cure rates were lower (17%18 and 23%19) than that in the current study (37.5%); and, in 1 study, the cure rate was comparable (42%10). In patients with Cushing disease, the cure rate ranged from 10% to 83%3, 10, 22, 23, 27, 34, 36 (current study, 52.9%); and in patients with prolactin-secreting tumors, the cure rate ranged from 15% to 84%3, 10, 27–29, 31, 33, 42 (current study, 15.4%).
Data from the literature support the findings of the current study, i.e., that the type of adenoma determines the degree of hormone response after RS. The best results were reported for patients who had ACTH-secreting tumors (average cure rate, 54.7%),3, 10, 22, 23, 27, 34, 36 followed by GH-secreting adenomas (average cure rate, 40%),3, 10, 21, 24, 32, 37 and prolactin-secreting tumors (average cure rate, 24.3%).3, 10, 27–29, 31, 33, 42
In the majority of patients who received treatment with the γ-knife, remission or cure occurred within 2 years after RS.3, 10, 23, 27, 33, 34, 37 Pollock et al. calculated cure rates at 1 year, 2 years, and 4 years on the order of 20%, 32%, and 61%, respectively.10 In the current analysis, the overall time from RS to cure was longer (mean ± standard deviation, 42.1 ± 25.0 months). The probability of achieving a cure was 19.3% at 3 years and 36.6% at 5 years. Taking into consideration both the comparably higher therapeutic dose and the higher maximum dose applied in γ-knife treatments, these parameters may have influenced the time lag of hormone response. This conclusion is in line with the results from Pollock and coworkers, who reported that, in addition to the absence of hormone-suppressive medication, a maximum radiation dose >40 Gy was correlated significantly with a cure.10
Four patients who received treatment before 1993 presented with radiation-induced brain damage. Intensified dose confirmation according to a risk-prediction paradigm,15 however, could prevent this side effect of RS completely during the following years. Brain damage also was reported after γ-knife RS of pituitary adenomas with a frequency that ranged from 1.6% to 4.7%.10, 22, 25, 37 In the series by Witt and coworkers, 1 of 58 patients (1.7%) presented with contrast enhancement in the hypothalamus, suggesting a radiation-induced blood-brain barrier breakdown 12 months after therapy, and the patient died after an epileptic attack 4 months later.37
Even though, in our protocol, the maximum tolerated dose prescribed to the optic system was set at 9 Gy, we observed radiation-induced neuropathy (RON) in 2 patients (1.4%). Because these patients were treated prior to the integration of MRI into our treatment-planning analyses, RON most probably was caused by the limited anatomic information from CT images. Only 1 group that used LINAC-RS observed RON with a significantly higher incidence of 38.7%.41 However, in the series by Rocher and coworkers, 10 of 36 tumors were treated with a therapeutic dose of 20 Gy, even though there was close contact with the chiasm. Consequently, many of their patients were at risk a priori for radiation-induced damage of the anterior optic pathway, which significantly exceeded the risk for patients who had a sufficient distance between tumor and these structures.
In an extensive review of the literature on γ-knife-based RS for 1255 patients with pituitary adenomas, the frequency of RON was 0.9%,44 which is comparable the frequency of RON in our population. In the same review, the reported rate of permanent damage to cranial nerves III, IV, and VI was 0.4% (5 patients), and the reported rate of injury to the trigeminal nerve was 0.2% (2 patients).44 However, those structures were not affected in our patients.
In the current study, the total rate of developing hypopituitarism after LINAC-RS was 12.3% (14 of 114 analyzed patients), and the cumulative risk was 18.3% at 5 years. The reports after γ-knife RS have yielded wide variation in the incidence of radiation-induced hypopituitarism. Although, in some series, patients did not require new hormone replacement,25, 27, 36 others have reported that the incidence of requiring new hormone replacement varied from 1.5% to 29%.10, 29–32, 34, 38, 39 Feigl et al. observed the highest incidence reported to date of 49%.20 Other study groups that used LINAC-RS for pituitary adenomas reported shorter follow-up (12–49 months) than the current study but a higher incidence of radiogenic pituitary insufficiency (range, 22.6–29.1%).40–42 In contrast to the current study, which included a median of 3 isocenters per treatment, the radiation dose was applied in those other studies with only 1 isocenter. Because using more isocenters improves dose conformality, which, again reduces the dose delivered to the pituitary gland and/or pituitary stalk, the different outcomes between the current study and other LINAC series may be explained in part by the different irradiation strategies. This hypothesis is in accordance with factor analyses, which revealed a significant, direct relation between the radiation dose delivered to the pituitary gland45 or pituitary stalk20 and the occurrence of pituitary dysfunction after γ-knife RS.
According to a recently published review, local tumor control after XRT of pituitary adenomas varies from 67% to 98%,46 which is comparable to the control achieved with RS. On average, GH was controlled in 77.3% of patients (143 of 185 patients; range, 26–100%), and ACTH was controlled in 40.7% of patients with Cushing disease (109 of 268 patients; range, 0–100%). Although the endocrine response to XRT is comparable to the results gained with RS, the time to remission is significantly longer. In the series by Zierhut et al.,47 normalization of GH occurred within a mean of 53 months (range, 15–115 months), pathologically increased ACTH levels responded within 16 to 104 months, and 3 of 11 patients with a prolactin-secreting adenomas had normalized hormone values 37 months, 75 months, and 131 months after therapy.47 In another study, Epaminonda et al. also demonstrated that the time from XRT to normalization of IGF-1 (mean ± standard deviation, 12 ± 6 years) was considerably longer than after RS.48
When XRT is performed according to modern treatment guidelines (single dose, ≤2Gy; total dose, ≤50 Gy), the risk for RON ranges from 1% to 3%. In contrast to RS, however, XRT carries a higher risk for the development of hypopituitarism (range, 13–56%).46
During the last 5 years, the results from 2 larger studies (total, 172 treated patients) using stereotactic fractionated RT (SRT) have been published. Local tumor control rates from those studies were 95%49 and 98.7%.50 In the series by Milker-Zabel et al., 4 of 20 patients (25%) who had hormone-secreting adenomas had normalization of hormone hypersecretion within a median of 13.5 months.49 Colin et al. reported a cure rate after SRT of 42% (median time to cure, 80 months).50 Comparable to XRT, the time to cure is longer than after RS, but final cure rates obviously are in the same range. The risk for developing hypopituitarism after SRT was 40.7% at 4 years and 50.1% at 8 years,50 which similar to the data evaluated for XRT and, thus, higher than the risk after RS. Radiation damage of the anterior optic apparatus was reported differently for the 2 SRT series: Whereas Colin et al. observed no vision impairment caused by SRT,50 Milker-Zabel et al.49 reported an incidence of reduced visual acuity of 7%.
In conclusion, LINAC-RS performed with a therapeutic radiation dose of 20 Gy is safe and highly effective in patients with small and surgically inaccessible pituitary macroadenomas. Compared with RS studies that used higher radiation doses, local tumor control rates and cure rates of hormone hypersecretion were similar. Although, in the current study, the reduced therapeutic dose delayed the time from RS to a cure, it still was significantly shorter than the time from XRT or SRT to a cure.
In the current series, the rate of therapy-related hypothalamopituitary dysfunction was low compared with early RS series or with data from other series using either LINAC-RS or fractionated radiotherapy (XRT, SRT). Most probably, this is the result of both reduced therapeutic dose and improved imaging techniques, as anticipated. In summary, LINAC-RS with a reduced radiation dose achieved local tumor control and normalization or cure of hormone secretion comparable to that achieved using γ-knife RS.