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Fractionated proton beam irradiation of pituitary adenomas
Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 2, pp. 425– 434, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter
doi:10.1016/j.ijrobp.2005.07.978
CLINICAL INVESTIGATION
Brain
FRACTIONATED PROTON BEAM IRRADIATION OF PITUITARY ADENOMAS BRIAN B. RONSON, M.D., REINHARD W. SCHULTE, M.D., KHANH P. HAN, M.D., LILIA N. LOREDO, M.D., JAMES M. SLATER, M.D., F.A.C.R., AND JERRY D. SLATER, M.D. Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA Purpose: Various radiation techniques and modalities have been used to treat pituitary adenomas. This report details our experience with proton treatment of these tumors. Methods and Materials: Forty-seven patients with pituitary adenomas treated with protons, who had at least 6 months of follow-up, were included in this analysis. Forty-two patients underwent a prior surgical resection; 5 were treated with primary radiation. Approximately half the tumors were functional. The median dose was 54 cobalt-gray equivalent. Results: Tumor stabilization occurred in all 41 patients available for follow-up imaging; 10 patients had no residual tumor, and 3 had greater than 50% reduction in tumor size. Seventeen patients with functional adenomas had normalized or decreased hormone levels; progression occurred in 3 patients. Six patients have died; 2 deaths were attributed to functional progression. Complications included temporal lobe necrosis in 1 patient, new significant visual deficits in 3 patients, and incident hypopituitarism in 11 patients. Conclusion: Fractionated conformal proton-beam irradiation achieved effective radiologic, endocrinological, and symptomatic control of pituitary adenomas. Significant morbidity was uncommon, with the exception of postradiation hypopituitarism, which we attribute in part to concomitant risk factors for hypopituitarism present in our patient population. © 2006 Elsevier Inc. Proton, Pituitary, Radiation, Fractionated, Adenoma.
INTRODUCTION Pituitary adenomas comprise 10% to 12% of all intracranial tumors (1). They are classified as benign histologically but can cause morbidity and occasional mortality; these conditions may occur through hormonal imbalances and functional deficits via compression of adjacent structures, such as the optic chiasm and hypothalamus. For non–prolactinsecreting microadenomas, treatment has consisted primarily of surgery, usually via transsphenoidal resection (2–5). Prolactin-secreting microadenomas are treated primarily with bromocriptine (6, 7). Macroadenomas are treated optimally with a multimodality approach, including postoperative radiotherapy and hormonal suppression for secreting tumors (8). Treatment of pituitary adenomas with radiation dates back to the early 1900s (9). Although reports of good tumor control with primary radiotherapy exist in the literature (10), radiation is now more commonly used in a postoperative setting for macroadenomas that feature either macroscopic residuum or a high risk of recurrence (11). Various radiation
techniques have been employed to treat these tumors, including external photon-beam irradiation by use of conventional fractionation regimens, (12–16) gamma knife and linear accelerator– based stereotactic radiosurgery or radiotherapy (17–19), and charged-particle radiosurgery (20 –23). Comparative dosimetry studies have demonstrated that proton irradiation of small intracranial and paranasal sinus tumors can achieve greater target-dose conformity and sparing of organs at risk than can photon techniques (24, 25). One of these studies also found that proton irradiation achieved better target-dose uniformity than did 3D conformal, stereotactic arc, and intensity-modulated radiotherapy of a variety of small, benign intracranial tumors, including meningiomas, acoustic neuromas, and pituitary adenomas (24). From the late 1950s to the 1980s, pituitary adenomas were treated with proton and heavy-ion radiosurgery at several laboratory-based treatment centers abroad and in the United States, the latter at Harvard Cyclotron Laboratory and Lawrence Berkeley Laboratory (20 –23). However, with the advent of hospital-based proton treatment centers capable of treating large numbers of patients, treatment of pitu-
Reprint requests to: Jerry D. Slater, M.D., Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson St., Loma Linda, CA 92354. Tel: (909) 558-4258; Fax: (909) 558-0295; E-mail: [email protected] Acknowledgments—The authors extend special thanks to Roger I.
Grove, M.P.H., William Preston, Ed.D., Richard P. Levy, M.D., Ph.D., and Sandra Teichman, R.N., B.S.N. for their assistance in preparing this document. Received Feb 4, 2005, and in revised form July 22, 2005. Accepted for publication July 26, 2005. 425
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itary adenomas and other small intracranial tumors with protons in standard fractionation regimens over 5 to 6 weeks has become practical. From the outset of clinical proton treatments at Loma Linda University Medical Center in 1991, our practice has been to treat pituitary adenomas and other intracranial benign tumors with standard fractionation regimens (1.8 –2 Gy per fraction). We have previously reported on our experience in the treatment of intracranial and base-of-skull tumors, including pituitary adenomas, with proton irradiation in pediatric patients (26). In this retrospective review, we detail the first reported clinical series of patients with pituitary adenomas treated with fractionated proton radiation over a period of 10 years. METHODS AND MATERIALS Patient population Forty-seven patient records were eligible for retrospective analysis. Eligible patients included those with nonmetastatic primary pituitary adenomas, with or without 1 or more prior surgical
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procedures, who had at least 6 months of follow-up. Patients completed treatment between January 31, 1991 and March 2, 2001. The treatment group included 25 males (53.2%) and 22 females (46.8%). Median age at the time of treatment was 50 years (range, 15–79 years). Five patients (10.6%) received no prior surgery, 30 patients (63.8%) underwent prior transsphenoidal resection, and 12 patients (25.5%) underwent prior craniotomy. Six patients had 2 surgeries; in each of these instances, the most recent was scored. Adenoma types based upon serologies and symptoms were as follows: 24 nonsecreting adenomas (51%), 4 adrenocorticotropic hormone (ACTH)-secreting adenomas (8.5%), 11 growth hormone (GH)-secreting adenomas (23.4%), 6 prolactin-secreting adenomas (12.8%), 1 thyroid stimulating hormone (TSH)-secreting adenoma (2.1%), and 1 GH-and-prolactin–secreting mixed tumor (2.1%). Pathology reports that detailed hormone stains were available in 28 patients (59.6%) but did not always concur with the clinical or laboratory impression. The following discrepancies were noted: 1 patient with elevated prolactin and 2 patients with elevated growth hormone levels had adenomas that immunohistochemically stained negative for hormones; 1 patient without signs or symptoms of hormone elevation had a tumor that stained positive for GH and TSH; 1 patient with elevated GH and prolactin levels had an
Table 1. Patient characteristics
Number of patients Age when irradiated ⬍20 20–40 41–60 ⱖ60 Sex Male Female Adenoma subtype* Nonsecreting ACTH GH Prolactin TSH Mixed Preirradiation median tumor size (⫾1 SD) Presenting symptoms/signs‡ Headache visual field deficit neurologic deficit symptoms of hormonal excess symptoms of hormonal deficit metro/menorrhagia Indication for Radiation postoperative residual postoperative local recurrence postoperative serologic recurrence postoperative symptom persistence postoperative hormone elevation primary treatment
All adenomas
Nonsecreting adenomas*
Secreting adenomas*
47
24
23
2 (4.3%) 13 (27.7%) 15 (31.9%) 17 (36.2%)
0 4 (16.7%) 10 (41.7%) 10 (41.7%)
2 (8.7%) 9 (39.1%) 5 (21.7%) 7 (30.4%)
25 (53.2%) 22 (46.8%)
15 (62.5%) 9 (37.5%)
10 (43.5%) 13 (56.5%)
23 (48.9%) 18 (38.3%) 9 (19.1%) 15 (32%) 7 (14.9%) 2 (4.3%)
11 (45.8%) 13 (54.2%) 7 (29.2%) 0 6 (25.0%) 1 (4.2%)
12 (52.2%) 5 (21.7%) 2 (8.7%) 15 (65.2%) 1 (4.3%) 1 (4.3%)
25 (53.2%) 6 (12.8%) 4 (8.5%) 1 (2.1%) 6 (12.8%) 5 (10.6%)
17 (70.8%) 5 (20.8%) 0 1 (4.2%) 0 1 (4.2%)
8 (34.8%) 1 (4.4%) 4 (17.4%) 0 6 (26.1%) 4 (17.4%)
24 (51%) 4 (8.5%) 11 (23.4%) 6 (12.8%) 1 (2.1%) 1† (2.1%) 2.35 ⫾ 2.05 cm (range 0.8–8 cm)
Abbreviations: ACTH ⫽ adrenocorticotropic hormone; GH ⫽ growth hormone; TSH ⫽ thyroid-stimulating hormone; SD ⫽ standard deviation. * As per serologies and symptoms. † Postoperative tumor volume in patients undergoing initial surgery. ‡ One or more per patient.
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Table 2. Dosimetric data 1 Dosimetric parameter
All adenomas
Nonsecreting adenomas
Secreting adenomas
Adenomas ⬍2 cm
Adenomas ⱖ2 cm
Mean target volume (cc) ⫾ 1 SD (range) Mean minimal GTV dose (CGE) ⫾ 1 SD (range) Mean maximal optic chiasm dose (CGE) ⫾ 1 SD (range) Number of patients receiving ⬎50 CGE to optic chiasm Relative median volume (%) of optic chiasm receiving ⬎50 CGE in the above group (range)
8.09 ⫾ 8.95 (1–36) 48.93 ⫾ 2.56 (42–54) 45.33 ⫾ 7.28 (20 –54)
7.73 ⫾ 5.26 (2–18) 48.70 ⫾ 2.20 (44 –53.3) 48.61 ⫾ 2.70 (43–53.5)
8.36 ⫾ 11.09 (1–36) 48.17 ⫾ 2.88 (42–54) 42.23 ⫾ 8.85 (20 –54)
2.9 ⫾ 1.8 (1– 6) 48.85 ⫾ 1.67 (46 –51) 44.32 ⫾ 8.65 (20 –51.5)
10.16 ⫾ 9.83 (1–36) 48.97 ⫾ 2.96 (42–54) 45.9 ⫾ 6.52 (24 –54)
7
5
2
2
5
10 (3–100)
53.5 (12–95)
12 (4–100)
12 (3–100)
adenoma that stained positive only for GH. Of the 23 patients with secreting tumors, 15 received antihormonal medications (bromocriptine, octreotide, or both) before and during radiation. Preirradiation tumor-size data based on computed tomography (CT) or magnetic resonance imaging (MRI) scans was available for 35 patients, with the single longest dimension averaging 2.35 ⫾ 2.05 cm (range, 0.8 –9 cm) in those with visible tumor; 3 patients had no visible tumor before irradiation. Twenty-three patients (48.9%) were demonstrated to have 1 or more hormonal deficiencies before radiation. Presenting symptoms at the time of radiation were distributed as follows (1 or more symptoms per patient): 23 patients (48.9%) with headache, 18 patients (38.3%) with visual field deficit, 9 patients (19.1%) with neurologic deficit, 15 patients (32.0%) with symptoms of hormonal excess, 7 patients (14.9%) with symptoms of hormonal deficit, and 2 patients (4.3%) with metro/menorrhagia. Reasons for radiation included postoperative residual tumor for 26 patients (55.3%), local recurrence after surgery for 6 patients (12.8%), serologic recurrence after surgery for 4 patients (8.5%), persistent symptoms after surgery for 1 patient (2.1%), persistent hormone elevation after surgery for 6 patients (12.8%), and primary treatment for 4 patients (8.5%). Patient and disease characteristics are summarized in Table 1, which includes an additional subset analysis based upon adenoma secretory status.
Treatment All patients were treated with conformal proton irradiation. Each underwent a planning CT scan in a custom-made mask or with a custom-made bite block before radiation. An appropriate range shifter was chosen, and customized cerrobend blocks and tissue compensators were fabricated for each patient before treatment. Radiation fields were designed to encompass all gross visible tumor (or all intrasellar contents with microadenomas) with a 5-mm margin (planning target volume [PTV]) by the 90% isodose surface; this margin was occasionally reduced to prevent the optic chiasm from receiving the full dose. The sella was targeted if no macroscopic tumor was visible. When extrasellar extension was suspected without gross extrasellar disease, the clinical target volume (CTV) was designed to encompass this feature in addition to the gross tumor volume (GTV). Orthogonal radiographs were obtained daily to assess and adjust patient position. Proton-beam energies of either 155 or 200 MeV were chosen, depending on the
9 (3–15)
required beam penetration. An appropriate modulator wheel was chosen to spread out the proton Bragg peak to the required size, and a computer-milled wax bolus was used to tailor the distal edge of the beam to the target. Doses specified at the treatment isocenter ranged from 5,040 to 5,593 cobalt-gray equivalent (CGE), with 34 patients (72.3%) receiving a dose of 5,400 CGE to the GTV; the CTV, when utilized, received 45 CGE. Thus, the total number of treatment days ranged from 28 (50.4 CGE) to 30 (54 CGE). Forty patients (85.1%) received 1.8 CGE daily fractions; 7 patients (14.9%) received 2 CGE daily fractions. The total number of treatment fields varied from 2 to 7 over the treatment course; the most common arrangement included 4 fields, used for 21 patients (44.7%). This treatment was followed by 3 fields in 9 patients (19.1%), 5 fields in 5 patients (10.6%), 2 fields in 5 patients (10.6%), 6 fields in 4 patients (8.5%), 8 fields in 2 patients (4.3%), and 7 fields in 1 patient (2.1%). Fields were alternated daily; most patients were treated with 1 field per day. Dosimetric data were available for a subset of our patients (Table 2). GTVs were retrievable from a dose–volume histogram (DVH) for 36 patients; these volumes averaged 8.09 ⫾ 8.95 cc (⫾ 1 SD) (range, 1–36 cc). Minimal GTV doses were retrievable for 40 patients and averaged 48.93 ⫾ 2.56 CGE (⫾1 SD) (range, 42–54). Optic chiasm doses could be retrieved from a DVH in 39 patients; in 32 individuals, no portion of the optic chiasm received more than 50 CGE. In the remaining 7 patients, the relative median volume of optic chiasm that received a dose greater than 50 CGE was 12% (range, 3–100%); in 5 of these latter patients, 15% or less of the optic chiasm volume received this dose. The mean maximal optic chiasm dose in both groups combined was 45.33 ⫾ 7.28 CGE. Table 2 also features an additional subset analysis based upon adenoma secretory status and size. A sample isodose colorwash with dose–volume histograms of a patient treated in this series is shown in Fig. 1.
Follow-up and definition of response Radiographic follow-up was MRI-based in all but 2 cases, which were CT-based. Response was scored according to whether residual tumor remained and, if so, the extent to which regression or progression had occurred as evidenced by the most recent scan. An actuarial analysis (Kaplan-Meier method) of complete tumor regression was performed. Endocrinologic follow-up was primarily based on all available
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Fig. 1. Sagittal isodose colorwash and dose–volume histograms from a patient who received 54 CGE to the target isocenter with the optic apparatus restricted to receive no more than 45 CGE. Isodose-color relationships are keyed on left of colorwash figure. Abbreviations: RON ⫽ right optic nerve; LON ⫽ left optic nerve; CGE ⫽ cobalt-gray equivalent. in-house and outside laboratory reports. Because of the multiple testing facilities involved, we deferred to the normal ranges of the individual laboratories when we assessed normalization for secreting tumors. Improvement or worsening of hypersecretion was based on any change of the most recent laboratory value compared with the preirradiation value. Scoring of hormonal deficits in the thyroid, adrenal, somatotropic, and gonadal axes was based upon laboratory reports that documented lower than normal hormonal levels or documented use of hormone supplements. Finally, actuarial analysis of hormone normalization was performed. Subjective evaluations were based on in-house follow-up, outside follow-up notes, or follow-up questionnaires sent to patients. Scoring of clinical symptoms was based solely on changes in the presenting symptoms. Complications were divided into the following categories: (nonvisual) CNS complications, visual complications, and endocrinologic complications (hypopituitarism). CNS complications were evaluated by review of all follow-up MRI reports and correlation of these reports with subjective follow-up data. The temporary or permanent nature of the lesion, and whether symptoms were associated with it, was noted. Visual follow-up was based upon both subjective symptoms and objective findings or reports, as available. Visual complications were scored as major or minor. Major deficits were defined as progressive visual loss or blindness, or new significant (symptomatic) visual field deficits. All other complications were considered minor, including worsening of a preexisting visual-field deficit. Hormonal deficits were scored as complications when they were discovered after radiation that followed documented normal preirradiation values. Worsening of preexisting deficits was not assessed in this study. Patients with hypopituitarism often took supplemental hor-
monal medications and frequently had their hormone levels tested at more than 1 laboratory, which, thus, confounded the issue. Actuarial analysis of incident hypopituitarism was performed. Incidents of postirradiation surgery were scored separately. Observations were recorded as to whether recurrent tumor, radiation necrosis, or another known or unknown cause was the inciting factor. The survival status of all patients was assessed. Time to death after treatment and cause of death (when known) were also reported.
RESULTS Radiographic response Radiographic follow-up was available in 41 of the 44 patients (93.2%) who had visible tumor before radiation and in all 3 patients without visible tumor before radiation. The median follow-up time was 47 months (range, 6 –139 months). In all patients, tumors had regressed or stabilized in size at the time of most recent radiographic follow-up: 10 patients (24.4%) had complete tumor regression; 12 (29.3%) demonstrated partial tumor regression; 19 (46.3%) had tumor stabilization (Table 3). The actuarial rate of complete tumor regression was 22% ⫾ 7.7% (⫾ 1 SD) at 5 years (Fig. 2). Although the 3 patients without visible tumor before radiation were not included in this analysis, none had evidence of recurrence, according to the most recent follow-up scan, with a median follow-up time of 35 months (range, 17–123 months). Radiographic response outcomes based upon secretory
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Table 3. Radiographic response
Radiographic response Tumor resolution Tumor regression Tumor stabilization
Secretory status (n ⫽ 41)
Adenoma size (n ⫽ 33)*
All adenomas (n ⫽ 41)
Nonsecreting vs. secreting
⬍2 cm vs. ⱖ2 cm
10/41 (24.4%) 12/41 (29.3%) 19/41 (46.3%)
4/23 (17.4%) vs. 6/18 (33.3%) 10/23 (43.5%) vs. 12/18 (66.7%) 12/23 (52.2%) vs. 7/18 (38.9%)
4/12 (33.3%) vs. 1/21 (4.8%)† 6/12 (50%) vs. 10/21 (47.6%) 6/12 (50.0%) vs. 13/21 (61.9%)
* Preirradiation tumor-size data available for 33 of 41 patients with radiographic follow-up. † Statistically significant (p ⫽ 0.047 by Fisher’s exact test).
Endocrinological response Of the 23 patients with secreting adenomas, endocrinologic follow-up was available for 21 (91.3%). The median follow-up time was 83 months (range, 9 –139 months). Eighteen patients (85.7%) had normalized or decreased hormone levels and, thus, achieved biochemical control. Eight patients (38.1%) had hormonal normalization; 10 patients (47.6%) had decreased levels. The actuarial rate of hormonal normalization was 22.8% ⫾ 9.2% at 5 years (Fig. 3). Three patients (14.3%) had increased hormone levels compared with pretreatment values, including 2 of 4 patients (50%) with ACTH-secreting adenomas and 1 patient with a TSH-secreting adenoma. Endocrinologic response outcomes are summarized in Table 4, which includes further subset analysis based upon the major adenoma subtypes.
months). Thirty patients (71.4%) reported subjective improvement of their presenting symptoms; 5 patients (11.9%) reported no overall change. Subjective improvement occurred in 15 of 22 patients (68.2%) who had nonsecreting adenomas and in 15 of 20 patients (75%) who had secreting adenomas. Among the latter, improvement occurred in 1 of 3 patients (33.3%) with ACTH-secreting adenomas, 8 of 10 patients (80%) with GH-secreting tumors, and 4 of 5 patients (80%) with prolactin-secreting adenomas. No differences reached statistical significance. Seven patients (16.6%) reported worsened symptoms. Two patients experienced progressive headaches without radiographic evidence for tumor regrowth or treatment complication; 1 patient underwent surgery, as described below. Two patients had progressive visual field deficits; an additional patient, who had progressive Cushing’s disease, developed progressive bilateral visual loss. These patients are discussed in greater detail below. Worsening of endocrinologic symptoms occurred in 2 patients, 1 of whom had progressive symptoms of Cushing’s disease and 1 of whom demonstrated symptomatic worsening of a preexisting hypothyroidism.
Subjective response Subjective follow-up was available for 42 patients (89.4%); median follow-up time was 90 months (range, 8 –143
Postradiation surgery Four patients (8.5%) underwent additional surgery after radiation. One patient had a salvage transsphenoidal resec-
Fig. 2. Actuarial incidence of complete tumor regression. Dot symbols indicate censored events.
Fig. 3. Actuarial incidence of hormonal normalization. Dot symbols indicate censored events.
status and tumor size are detailed in Table 3. Of note, a statistically significant difference was seen in complete tumor resolution for tumors less than 2 cm when compared with those greater than or equal to 2 cm (33.3% vs. 4.8%; p ⫽ 0.047 by Fisher’s exact test). None of the other subanalyses reached statistical significance.
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Table 4. Endocrinologic response Endocrinologic response Hormonal normalization Decreased hormone levels Hormonal progression
All secreting adenomas (n ⫽ 21)
ACTH-secreting adenomas (n ⫽ 4)
8/21 (38%) 10/21 (47.6%) 3/21 (14.3%)
tion of an initially unresectable ACTH-secreting adenoma; this patient not only demonstrated some tumor regression after primary radiation but also had persistent Cushing’s disease. One patient required resection of an area of temporal lobe necrosis, as detailed below in the Complications section. Two patients had additional surgical procedures that appeared not to be related to tumor progression or radiation treatment. One patient had surgery for intractable headaches after radiation, albeit tumor progression or evidence of radiation necrosis were not evident. The headaches continued after surgery; no apparent cause was found. Another patient developed a CSF leak years after treatment that required surgical correction; the cause was not apparent from our records.
Complications One patient had a (nonvisual) CNS complication caused by radiation. Nineteen months after radiation, she developed progressive headaches and was found to have necrosis of the tip of the right anterior mesial temporal lobe. Symptomatic resolution was obtained after a craniotomy-based resection. No radiation-related secondary tumors or vascular injuries occurred in our series, although our follow-up may be too short to assess the incidence of these late complications of pituitary irradiation. Visual follow-up was available for 43 patients (91.5%). The median follow-up duration for these patients was 80 months (range, 10 –143 months). Thirty-three patients (76.7%) reported no visual worsening secondary to radiation; 7 (23.3%) reported new minor deficits. Two of the latter patients had new objective findings. One patient was noted by his endocrinologist to have an asymptomatic minimal visual field cut. Another patient developed temporary visual worsening associated with bilateral optic nerve enhancement on MRI (T2-lengthening), which has since both clinically and radiographically resolved. Two patients (4.6%), both with Cushing’s disease, noted new major visual complications. One of theses patients developed an inferior right quadrantanopsia after radiation; the other developed a bilateral optic nerve atrophy. This woman suffered from progressive Cushing’s disease after primary radiation for an initially unresectable tumor and underwent salvage resection 8 months later. She began to experience visual loss immediately after surgery that progressed to near blindness within 3 months. An MRI examination performed at that time demonstrated bilateral optic nerve atrophy. Maximal optic chiasm doses for these 2 patients were 42 Gy
1/4 (25%) 1/4 (25%) 2/4 (50%)
GH-secreting adenomas (n ⫽ 11) 5/11 (45%) 4/11 (36%) 0/11
Prolactinomas (n ⫽ 6) 2/6 (33%) 4/6 (66%) 0/6
and 47 Gy; both were well within 1 standard deviation of the group mean (45.33 ⫾ 7.28 Gy). Endocrinological follow-up to assess for posttherapy hypopituitarism was available in 37 patients (80.9%); median follow-up for these patients was 74 months (range, 7–139 months). Eleven patients (29.7%) developed hormonal deficiencies that were not present before radiation and required hormone supplements; 2 (5.4%) developed panhypopituitarism. Incident deficiencies in 1 or several of the 3 major hormonal axes are diagrammed in Fig. 4. The actuarial rate of developing any new hormonal deficiency was 21.7% ⫾ 7.3% at 5 years and 44.2% ⫾ 11.3% at 10 years. Hypopituitarism as a complication of radiation was noted in 4 of 20 patients (20%) with nonsecreting adenomas and in 7 of 20 patients (35%) with secreting adenomas. Among those with secreting tumors, incident hypopituitarism occurred in none of 4 patients with ACTH-secreting tumors, in 2 of 10 patients (20%) with GH-secreting tumors, in 3 of 5 patients (60%) with prolactin-secreting adenomas, and in the 2 patients with TSH-secreting and mixed (GH-andprolactin–secreting) adenomas, respectively. None of these differences reached statistical significance. Survival status Six patients (12.8%) died after treatment. Average time to death was 93.3 ⫾ 35.6 months (range, 52–149 months).
Fig. 4. Actuarial incidence of new hypopituitarism. Dot symbols indicate censored events.
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Two patients’ deaths (4.3%) were secondary to the effects of persistent Cushing’s disease. One patient died 52 months after treatment of intractable Cushing’s disease secondary to an ACTH-secreting adenoma that was functionally uncontrolled with primary radiation and salvage resection. A second patient died 59 months after treatment; this patient’s ACTH-secreting adenoma was managed initially with bilateral adrenalectomy, which resulted in Nelson’s syndrome. She was then salvaged with surgery and proton radiation 39 years later, after a large tumor mass with bilateral cavernous sinus invasion was found on MRI and increased cortisol levels were present. She was noted to have decreased, yet persistently elevated, ACTH levels from her ACTH-secreting adenoma 45 months after treatment, but she also experienced multiple strokes within 1 year of her death. Tumor growth was not present in either case. Three patients’ deaths (6.4%) were unrelated to tumor or treatment factors. One patient developed renal carcinoma and died of metastatic disease. Another, who developed liver failure and grand mal seizures, died 106 months after treatment; this man had a stable adenoma and no evidence of radiation-related complications at 44 months after treatment. Another patient died 106 months after treatment from an acute cardiopulmonary arrest, attributed in part to a seizure disorder. She was asymptomatic from tumor or treatment 77 months after treatment and had a stable adenoma without evidence of radiation-related complications 22 months after treatment. In 1 patient (2.1%), cause of death is unknown to us. She died 149 months after treatment. Ninety months after treatment, she had no evidence of adenoma and was asymptomatic. DISCUSSION Pituitary adenomas are benign tumors that can cause considerable morbidity and occasional mortality when they are not controlled. Tumors with a high risk of recurrence are frequently treated with postoperative radiation; common modalities have included fractionated photon external-beam irradiation (10 –16), stereotactically guided radiosurgery and radiotherapy techniques with photons or gamma knife (17–19), and charged-particle radiosurgery techniques with either protons or helium ions (20 –23). Although the experience with stereotactically guided photon radiation and gamma knife is limited to the past 2 decades, chargedparticle radiosurgery was performed starting in the late 1950s until the late 1980s at high-energy physics accelerator laboratories and was mostly limited to the treatment of hypersecreting microadenomas. In the early 1990s, fractionated precision-proton radiation therapy became available at our center; we are the first to report on a clinical experience in the treatment of pituitary adenomas with this technique. The rationale for use of heavy charged particles such as protons or helium ions for irradiation of any site in the body is based upon the superior depth-dose characteristics of such particles that result from their Bragg peak. This feature
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allows one to achieve high-dose conformity with relatively few beams, which permits dose escalation while minimizing integral dose. Dosimetric studies have demonstrated that protons offer a therapeutic advantage in the treatment of small intracranial tumors such as pituitary adenomas (24, 25). Charged-particle radiosurgical experiences published in the late 1970s and 1980s from Lawrence Berkeley Laboratory (LBL), Harvard Cyclotron Laboratory at Massachusetts General Hospital (MGH), the Burdenko Neurosurgical Institute in Moscow, and the Leningrad Institute of Nuclear Physics demonstrated excellent results in the treatment of hypersecreting microadenomas (22, 27). Doses and techniques ranged from single-fraction proton radiosurgery to 100 to 120 CGE (20) to 4-fraction helium-based radiosurgery to total doses that ranged from 30 to 150 CGE (28). Best results were reported in acromegalics, who achieved remission in 80% to 90% of cases. Cushing’s disease and prolactinoma patients had normalization in up to 65% of the cases. In Nelson’s syndrome, hormonal normalization rarely occurred. Complications were reported: at LBL, with helium radiosurgery, about one third of patients had developed some form of hypopituitarism at the time of analysis (22). Similar incidence rates were also reported from MGH, and these rates increased with time of follow-up (29). Focal temporal-lobe injury and injury to the cranial nerves were rare in these series (less than 1% of patients). Our rationale for fractionating treatment with protons was to maximize the therapeutic ratio and to permit treatment of larger pituitary tumors, both functional and nonfunctional, in which dose to the optics could not practically be kept below 40% of the prescribed dose, as is required with single-fraction radiosurgery. Thus, the patient population in our series differs significantly when compared with patients in the early charged-particle radiosurgery series. The range of tumor sizes and tumor histologies in our series is comparable to those in which conventionally fractionated photon therapy has been used. Overall local control of pituitary adenomas in these series exceeds 90%, with doses in the range of 45 to 50 Gy (12–15). In general, when matched for other risk factors, including size, nonsecreting adenomas have higher local-control rates than do secreting adenomas, which have control rates that range from 82% to 98% (12, 13, 30 –32) for nonsecreting adenomas and 67% to 85% (15) for secreting adenomas. Control was usually defined as absence of progressive clinical symptoms in older series and absence of tumor growth documented by imaging studies in more recent series. Our series demonstrated 100% radiographic local control of adenomas (without regard to biochemical outcomes) at a median follow-up time of 47 months (range, 6 –139 months). We attribute this excellent control rate to the fact that most of our patients received a dose of 54 Gy, which is 10% to 20% higher than doses reported in historic series with fractionated photon radiotherapy. However, several reports demonstrate gradually decreasing local-control rates of radiated pituitary adenomas when patients are followed
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for 10 years or more; (30, 33) our control rates may, therefore, decrease with further follow-up. Our series demonstrated complete regression in a larger percentage of tumors less than 2 cm than in those 2 cm or more (33.4 vs. 4.8%, p ⫽ 0.047). Other series have also found tumor size to be a prognostic factor (13, 14). However, in contrast to the literature, we found slightly higher rates of complete and partial regression in our secreting adenomas than in our nonsecreting adenomas, albeit this difference never reached statistical significance. At least 1 other study has challenged the literature on this premise as well (12). Our series demonstrated crude rates of 85% biochemical control and 40% hormonal normalization; the actuarial rate of hormonal normalization was 22.8% ⫾ 9.2% at 5 years. Biochemical control of functional adenomas has been reported after fractionated photon radiotherapy and varies from 45% to 90%, depending on intrinsic tumor factors that include size and functional subtype. Variation also depends on the operational definition of control; hormonal normalization has generally been reported to occur in 35% to 50% of patients (12, 14). Studies that examine primary radiation therapy suggest that biochemical control rates differ for the various common functional subtypes, with approximately 80% control in GH-secreting adenomas, 50% to 80% control in ACTH-secreting adenomas, and 30% to 35% control in prolactinomas (34). Other series suggest that ACTHsecreting adenomas are most difficult to control (12, 17). Certain studies suggest that prolactinomas and GH-secreting adenomas may require more than 5 years to normalize biochemically after conventionally fractionated radiation; (14) the normalization and control rates we observed may, therefore, still improve with time and become comparable with the radiosurgical series that achieve more rapid biochemical responses. In our series, 3 functional adenomas progressed, including 1 TSH-secreting adenoma and 2 ACTH-secreting adenomas. This result is consistent with reports that suggest ACTH-secreting adenomas in adults are more difficult to control (12, 17). Other factors may also account for our findings in these patients. One of these patients received primary radiation therapy rather than surgery. In the 2 other patients, large tumor size (4.2 and 8 cm) placed portions of these tumors adjacent to the optic chiasm, and, thus, these portions received less than the prescribed dose to reduce chiasm dose. Relatively few series reported the response of presenting symptoms after radiation treatment. A single study reported subjective improvement in 67% to 80% of symptoms because of mass effect and endocrine hypersecretion (15). In line with that study, we noted subjective improvement in the presenting symptoms in 71.4% of our patients. Brain necrosis that results from pituitary radiation is rare with conventional radiation doses, with the estimated risk of 0.04% for doses in the range of 45 to 50 Gy (34). Rates have been noted to increase at doses beyond 50 Gy. One of our patients developed temporal-lobe necrosis, and identifica-
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tion of the circumstances that may have led to this incident is a priority. This individual had a recurrent tumor with right cavernous sinus invasion and suprasellar extension, which required a relatively large target volume that encompassed much of the right temporal-lobe tip. She received a dose of 54 CGE in 2 Gy fractions. The treatment was delivered with 2 opposed lateral beams, and a small portion of the right temporal lobe received the full prescribed dose. Intravenous contrast was used for her planning CT and significant contrast uptake occurred in and around the target volume, which was not taken into account when the required beam penetration was calculated. Therefore, the actual beam range may have been a few millimeters larger than shown in the treatment isodose plan. This higher dose, in conjunction with the increased radiobiologic effect at the distal edge of the proton beam (1.2 to 1.3 vs. 1.1) (35) may have contributed to her necrosis. Subsequent to our experience with this patient, we use 1.8-Gy daily fractions on all of our pituitary patients treated with proton beams, generally correct for contrast enhancement, and frequently utilize superior oblique and superior beams for a significant portion of the treatment, to spare the temporal lobes. The incidence of radiation damage to the optic apparatus depends on fraction size and total dose. A large literature review found no cases of optic chiasm or nerve damage when doses of 45 Gy in 1.8 Gy fractions were used (36). Several series have shown a combined rate of 0.3% when less than 2-Gy fractions were used and 4% when 2-Gy or greater fractions were used; many of these patients received total doses of 50 Gy or more (33). Several series also note a dose response beyond 45 to 50 Gy for radiation damage to the optic apparatus (37–39). In our series, the majority of patients received a dose of 54 Gy in 1.8-Gy fractions; this dose and fractionation scheme is commonly quoted as the tolerance dose for the optic apparatus. In our series, 7 patients developed minor visual deficits and 2 patients developed major visual deficits that consisted of a new quadrantanopsia and bilateral optic nerve atrophy. Both of these patients had Cushing’s disease, which leads one to hypothesize that the longstanding effects of hypercortisolism predisposes the optic chiasm microvasculature of Cushinoid patients to radiation damage. This hypothesis is supported by reports of premature cerebral atrophy that occurred in patients with endogenous steroid production from Cushing’s syndrome or disease (40). With regard to the patient who developed optic nerve atrophy, the acute onset of symptoms immediately after a salvage resection 9 months after primary radiotherapy implicate surgical injury, possibly in addition to radiation and hypercortisolism, as causative factors. Finally, one must remember that fractionation permits treatment of larger target volumes that may be adjacent or even compressing the optics, which puts them at higher risk for injury. We concede that, despite their high degree of dose conformity, protons cannot completely prevent visual morbidity in patients with tumors close to the optic chiasm. This fact mandates a cautious approach in such patients, espe-
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cially when additional risk factors for radiation injury are present. Hypopituitarism is the most common side effect of pituitary radiation and, fortunately, is treatable by hormonal substitution. The rate of incident hypopituitarism after pituitary irradiation with fractionated photon therapy has been reported to range from 20% to 60% (14 –16), with somewhat higher rates noted for nonsecreting tumors (14). Approximately 30% of our patients developed 1 or more new hormonal deficits; the actuarial rate was just over 20% at 5 years and increased to over 40% at 10 years. Several factors put our patients at higher risk for incident hypopituitarism: large tumor size, nonsecreting adenomas in nearly 50% of our population, a surgical resection that preceded radiation in approximately 90%, and a somewhat higher median dose (54 Gy) than those in most other fractionated series. Although death from pituitary adenomas is uncommon, the long-standing effects of hormonal imbalance, in particular of ACTH, can be fatal. This circumstance was the case in 2 of our patients who had long-standing, uncontrolled Cushing’s disease. One of these patients had primary radiation therapy followed by salvage resection, which is presumably less effective than primary surgery with adjuvant radiation. The second patient had initially been managed with bilateral adrenalectomy followed by a prolonged interval (39 years) between diagnosis and definitive surgical and radiation therapy. She subsequently developed Nelson’s syndrome, which is clinically characterized by an aggressive local growth of the tumor (41, 42) and has shown disappointing results with both surgery and radiotherapy (27, 43– 45). None of our patients developed a secondary, radiationinduced tumor. Radiation-induced tumors of the skull base, mostly osteosarcomas and meningiomas, and brain have
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been reported after irradiation for pituitary adenomas, but the incidence or radiation-induced skull-base tumors appears to be very low (46). The latency of these tumors is longer than 3 years and typically exceeds 10 years. Therefore, possibly more time must pass before we can draw conclusions with regard to proton-radiation induced tumors based on our series. CONCLUSION Fractionated conformal proton-beam irradiation to doses of 50 to 54 Gy in 1.8-Gy to 2-Gy fractions appears to achieve effective radiologic, biochemical, and symptomatic control of pituitary adenomas. Long-term follow-up is required to determine whether this promising outcome persists. Average tumor size was much larger in our series than in the early charged-particle radiosurgical series, which precludes their direct comparison. In our experience with fractionated proton irradiation, fraction sizes of 1.8 Gy should be preferred to 2-Gy fractions to reduce late toxicity, and the higher RBE of protons may need to be taken into account when the number of treatment fields is kept small. Patients with long-standing Cushing’s disease may fare worse with regard to control and toxicity, and they may benefit from local radiation therapy early in the course of their disease. Patient access to hospital-based proton treatment centers for fractionated proton radiotherapy is expected to increase as more treatment centers become operational. On the basis of the dosimetric advantages of protons in the treatment of small intracranial tumors such as pituitary adenomas and our encouraging experience treating them in a fractionated matter, one may consider fractionated proton irradiation as a viable adjunctive treatment option for patients with pituitary adenomas.
REFERENCES 1. Kernohan JW, Sayer GP. Tumors of the pituitary gland and infundibulum. Atlas of tumor pathology, fasicle 36. Washington, DC: Armed Forces Institute of Pathology; 1956. 2. Ciric I, Mikhael M, Stafford T, et al. Transsphenoidal microsurgery of pituitary macroadenomas with long-term follow-up results. J Neurosurg 1983;59:395– 401. 3. Hardy J. Trans-sphenoidal microsurgical removal of pituitary micro-adenoma. In: Krayenbuhl H, Maspes PE, Sweet WH, editors. Progress in neurological surgery. 2nd ed. Basel: Karger; 1975. p. 200 –216. 4. Randall RV, Laws ER, Abboud CF, et al. Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas: Results in 100 patients. Mayo Clin Proc 1983;58: 108 –121. 5. Ross DA, Wilson CB. Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenoma in a series of 214 patients. J Neurosurg 1988;68:854 – 867. 6. Barrow DL, Tindall GT, Kovacs K, et al. Clinical and pathologic effects of bromocriptine on prolactin-secreting and other pituitary tumors. J Neurosurg 1984;60:1–7. 7. Benker G, Gieshoff B, Freundlieb O, et al. Parenteral bromocriptine in the treatment of hormonally active pituitary tumours. Clin Endocrinol 1986;24:505–513.
8. Henderson WR. Pituitary adenomata: A follow up study of the surgical results of 338 cases. Br J Surg 1939;26:811–921. 9. Gramegna A. Un cas d’acromegalie traité par la radiotherapie. Rev Neurol 1909;17:15. 10. Kramer S. The value of radiation therapy for pituitary and parapituitary tumors. Can Med Assoc J 1968;99:1120 –1127. 11. Salinger DJ, Brady LW, Miyamoto CT. Radiation therapy in the treatment of pituitary adenomas. Am J Clin Oncol 1992; 15:467– 473. 12. Zierhut D, Flentje M, Adolph J, et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33: 307–314. 13. Chun M, Masko G, Hetelekids S. Radiotherapy in the treatment of pituitary adenomas. Int J Radiat Oncol Biol Phys 1998;15:305–309. 14. Tsang R, Brierley J, Panzarella T, et al. Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiother Oncol 1996;41:45–53. 15. Sasaki R, Murakami M, Okamoto Y, et al. The efficacy of conventional radiation therapy in the management of pituitary adenoma. Int J Radiat Oncol Biol Phys 2000;47:1337–1345. 16. Shihadeh E, Ryu S, Bogart J, et al. Outcome of radiation therapy alone and post-operative radiation for non-functioning
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doi:10.1016/j.ijrobp.2005.07.978
CLINICAL INVESTIGATION
Brain
FRACTIONATED PROTON BEAM IRRADIATION OF PITUITARY ADENOMAS BRIAN B. RONSON, M.D., REINHARD W. SCHULTE, M.D., KHANH P. HAN, M.D., LILIA N. LOREDO, M.D., JAMES M. SLATER, M.D., F.A.C.R., AND JERRY D. SLATER, M.D. Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA Purpose: Various radiation techniques and modalities have been used to treat pituitary adenomas. This report details our experience with proton treatment of these tumors. Methods and Materials: Forty-seven patients with pituitary adenomas treated with protons, who had at least 6 months of follow-up, were included in this analysis. Forty-two patients underwent a prior surgical resection; 5 were treated with primary radiation. Approximately half the tumors were functional. The median dose was 54 cobalt-gray equivalent. Results: Tumor stabilization occurred in all 41 patients available for follow-up imaging; 10 patients had no residual tumor, and 3 had greater than 50% reduction in tumor size. Seventeen patients with functional adenomas had normalized or decreased hormone levels; progression occurred in 3 patients. Six patients have died; 2 deaths were attributed to functional progression. Complications included temporal lobe necrosis in 1 patient, new significant visual deficits in 3 patients, and incident hypopituitarism in 11 patients. Conclusion: Fractionated conformal proton-beam irradiation achieved effective radiologic, endocrinological, and symptomatic control of pituitary adenomas. Significant morbidity was uncommon, with the exception of postradiation hypopituitarism, which we attribute in part to concomitant risk factors for hypopituitarism present in our patient population. © 2006 Elsevier Inc. Proton, Pituitary, Radiation, Fractionated, Adenoma.
INTRODUCTION Pituitary adenomas comprise 10% to 12% of all intracranial tumors (1). They are classified as benign histologically but can cause morbidity and occasional mortality; these conditions may occur through hormonal imbalances and functional deficits via compression of adjacent structures, such as the optic chiasm and hypothalamus. For non–prolactinsecreting microadenomas, treatment has consisted primarily of surgery, usually via transsphenoidal resection (2–5). Prolactin-secreting microadenomas are treated primarily with bromocriptine (6, 7). Macroadenomas are treated optimally with a multimodality approach, including postoperative radiotherapy and hormonal suppression for secreting tumors (8). Treatment of pituitary adenomas with radiation dates back to the early 1900s (9). Although reports of good tumor control with primary radiotherapy exist in the literature (10), radiation is now more commonly used in a postoperative setting for macroadenomas that feature either macroscopic residuum or a high risk of recurrence (11). Various radiation
techniques have been employed to treat these tumors, including external photon-beam irradiation by use of conventional fractionation regimens, (12–16) gamma knife and linear accelerator– based stereotactic radiosurgery or radiotherapy (17–19), and charged-particle radiosurgery (20 –23). Comparative dosimetry studies have demonstrated that proton irradiation of small intracranial and paranasal sinus tumors can achieve greater target-dose conformity and sparing of organs at risk than can photon techniques (24, 25). One of these studies also found that proton irradiation achieved better target-dose uniformity than did 3D conformal, stereotactic arc, and intensity-modulated radiotherapy of a variety of small, benign intracranial tumors, including meningiomas, acoustic neuromas, and pituitary adenomas (24). From the late 1950s to the 1980s, pituitary adenomas were treated with proton and heavy-ion radiosurgery at several laboratory-based treatment centers abroad and in the United States, the latter at Harvard Cyclotron Laboratory and Lawrence Berkeley Laboratory (20 –23). However, with the advent of hospital-based proton treatment centers capable of treating large numbers of patients, treatment of pitu-
Reprint requests to: Jerry D. Slater, M.D., Department of Radiation Medicine, Loma Linda University Medical Center, 11234 Anderson St., Loma Linda, CA 92354. Tel: (909) 558-4258; Fax: (909) 558-0295; E-mail: [email protected] Acknowledgments—The authors extend special thanks to Roger I.
Grove, M.P.H., William Preston, Ed.D., Richard P. Levy, M.D., Ph.D., and Sandra Teichman, R.N., B.S.N. for their assistance in preparing this document. Received Feb 4, 2005, and in revised form July 22, 2005. Accepted for publication July 26, 2005. 425
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itary adenomas and other small intracranial tumors with protons in standard fractionation regimens over 5 to 6 weeks has become practical. From the outset of clinical proton treatments at Loma Linda University Medical Center in 1991, our practice has been to treat pituitary adenomas and other intracranial benign tumors with standard fractionation regimens (1.8 –2 Gy per fraction). We have previously reported on our experience in the treatment of intracranial and base-of-skull tumors, including pituitary adenomas, with proton irradiation in pediatric patients (26). In this retrospective review, we detail the first reported clinical series of patients with pituitary adenomas treated with fractionated proton radiation over a period of 10 years. METHODS AND MATERIALS Patient population Forty-seven patient records were eligible for retrospective analysis. Eligible patients included those with nonmetastatic primary pituitary adenomas, with or without 1 or more prior surgical
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procedures, who had at least 6 months of follow-up. Patients completed treatment between January 31, 1991 and March 2, 2001. The treatment group included 25 males (53.2%) and 22 females (46.8%). Median age at the time of treatment was 50 years (range, 15–79 years). Five patients (10.6%) received no prior surgery, 30 patients (63.8%) underwent prior transsphenoidal resection, and 12 patients (25.5%) underwent prior craniotomy. Six patients had 2 surgeries; in each of these instances, the most recent was scored. Adenoma types based upon serologies and symptoms were as follows: 24 nonsecreting adenomas (51%), 4 adrenocorticotropic hormone (ACTH)-secreting adenomas (8.5%), 11 growth hormone (GH)-secreting adenomas (23.4%), 6 prolactin-secreting adenomas (12.8%), 1 thyroid stimulating hormone (TSH)-secreting adenoma (2.1%), and 1 GH-and-prolactin–secreting mixed tumor (2.1%). Pathology reports that detailed hormone stains were available in 28 patients (59.6%) but did not always concur with the clinical or laboratory impression. The following discrepancies were noted: 1 patient with elevated prolactin and 2 patients with elevated growth hormone levels had adenomas that immunohistochemically stained negative for hormones; 1 patient without signs or symptoms of hormone elevation had a tumor that stained positive for GH and TSH; 1 patient with elevated GH and prolactin levels had an
Table 1. Patient characteristics
Number of patients Age when irradiated ⬍20 20–40 41–60 ⱖ60 Sex Male Female Adenoma subtype* Nonsecreting ACTH GH Prolactin TSH Mixed Preirradiation median tumor size (⫾1 SD) Presenting symptoms/signs‡ Headache visual field deficit neurologic deficit symptoms of hormonal excess symptoms of hormonal deficit metro/menorrhagia Indication for Radiation postoperative residual postoperative local recurrence postoperative serologic recurrence postoperative symptom persistence postoperative hormone elevation primary treatment
All adenomas
Nonsecreting adenomas*
Secreting adenomas*
47
24
23
2 (4.3%) 13 (27.7%) 15 (31.9%) 17 (36.2%)
0 4 (16.7%) 10 (41.7%) 10 (41.7%)
2 (8.7%) 9 (39.1%) 5 (21.7%) 7 (30.4%)
25 (53.2%) 22 (46.8%)
15 (62.5%) 9 (37.5%)
10 (43.5%) 13 (56.5%)
23 (48.9%) 18 (38.3%) 9 (19.1%) 15 (32%) 7 (14.9%) 2 (4.3%)
11 (45.8%) 13 (54.2%) 7 (29.2%) 0 6 (25.0%) 1 (4.2%)
12 (52.2%) 5 (21.7%) 2 (8.7%) 15 (65.2%) 1 (4.3%) 1 (4.3%)
25 (53.2%) 6 (12.8%) 4 (8.5%) 1 (2.1%) 6 (12.8%) 5 (10.6%)
17 (70.8%) 5 (20.8%) 0 1 (4.2%) 0 1 (4.2%)
8 (34.8%) 1 (4.4%) 4 (17.4%) 0 6 (26.1%) 4 (17.4%)
24 (51%) 4 (8.5%) 11 (23.4%) 6 (12.8%) 1 (2.1%) 1† (2.1%) 2.35 ⫾ 2.05 cm (range 0.8–8 cm)
Abbreviations: ACTH ⫽ adrenocorticotropic hormone; GH ⫽ growth hormone; TSH ⫽ thyroid-stimulating hormone; SD ⫽ standard deviation. * As per serologies and symptoms. † Postoperative tumor volume in patients undergoing initial surgery. ‡ One or more per patient.
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Table 2. Dosimetric data 1 Dosimetric parameter
All adenomas
Nonsecreting adenomas
Secreting adenomas
Adenomas ⬍2 cm
Adenomas ⱖ2 cm
Mean target volume (cc) ⫾ 1 SD (range) Mean minimal GTV dose (CGE) ⫾ 1 SD (range) Mean maximal optic chiasm dose (CGE) ⫾ 1 SD (range) Number of patients receiving ⬎50 CGE to optic chiasm Relative median volume (%) of optic chiasm receiving ⬎50 CGE in the above group (range)
8.09 ⫾ 8.95 (1–36) 48.93 ⫾ 2.56 (42–54) 45.33 ⫾ 7.28 (20 –54)
7.73 ⫾ 5.26 (2–18) 48.70 ⫾ 2.20 (44 –53.3) 48.61 ⫾ 2.70 (43–53.5)
8.36 ⫾ 11.09 (1–36) 48.17 ⫾ 2.88 (42–54) 42.23 ⫾ 8.85 (20 –54)
2.9 ⫾ 1.8 (1– 6) 48.85 ⫾ 1.67 (46 –51) 44.32 ⫾ 8.65 (20 –51.5)
10.16 ⫾ 9.83 (1–36) 48.97 ⫾ 2.96 (42–54) 45.9 ⫾ 6.52 (24 –54)
7
5
2
2
5
10 (3–100)
53.5 (12–95)
12 (4–100)
12 (3–100)
adenoma that stained positive only for GH. Of the 23 patients with secreting tumors, 15 received antihormonal medications (bromocriptine, octreotide, or both) before and during radiation. Preirradiation tumor-size data based on computed tomography (CT) or magnetic resonance imaging (MRI) scans was available for 35 patients, with the single longest dimension averaging 2.35 ⫾ 2.05 cm (range, 0.8 –9 cm) in those with visible tumor; 3 patients had no visible tumor before irradiation. Twenty-three patients (48.9%) were demonstrated to have 1 or more hormonal deficiencies before radiation. Presenting symptoms at the time of radiation were distributed as follows (1 or more symptoms per patient): 23 patients (48.9%) with headache, 18 patients (38.3%) with visual field deficit, 9 patients (19.1%) with neurologic deficit, 15 patients (32.0%) with symptoms of hormonal excess, 7 patients (14.9%) with symptoms of hormonal deficit, and 2 patients (4.3%) with metro/menorrhagia. Reasons for radiation included postoperative residual tumor for 26 patients (55.3%), local recurrence after surgery for 6 patients (12.8%), serologic recurrence after surgery for 4 patients (8.5%), persistent symptoms after surgery for 1 patient (2.1%), persistent hormone elevation after surgery for 6 patients (12.8%), and primary treatment for 4 patients (8.5%). Patient and disease characteristics are summarized in Table 1, which includes an additional subset analysis based upon adenoma secretory status.
Treatment All patients were treated with conformal proton irradiation. Each underwent a planning CT scan in a custom-made mask or with a custom-made bite block before radiation. An appropriate range shifter was chosen, and customized cerrobend blocks and tissue compensators were fabricated for each patient before treatment. Radiation fields were designed to encompass all gross visible tumor (or all intrasellar contents with microadenomas) with a 5-mm margin (planning target volume [PTV]) by the 90% isodose surface; this margin was occasionally reduced to prevent the optic chiasm from receiving the full dose. The sella was targeted if no macroscopic tumor was visible. When extrasellar extension was suspected without gross extrasellar disease, the clinical target volume (CTV) was designed to encompass this feature in addition to the gross tumor volume (GTV). Orthogonal radiographs were obtained daily to assess and adjust patient position. Proton-beam energies of either 155 or 200 MeV were chosen, depending on the
9 (3–15)
required beam penetration. An appropriate modulator wheel was chosen to spread out the proton Bragg peak to the required size, and a computer-milled wax bolus was used to tailor the distal edge of the beam to the target. Doses specified at the treatment isocenter ranged from 5,040 to 5,593 cobalt-gray equivalent (CGE), with 34 patients (72.3%) receiving a dose of 5,400 CGE to the GTV; the CTV, when utilized, received 45 CGE. Thus, the total number of treatment days ranged from 28 (50.4 CGE) to 30 (54 CGE). Forty patients (85.1%) received 1.8 CGE daily fractions; 7 patients (14.9%) received 2 CGE daily fractions. The total number of treatment fields varied from 2 to 7 over the treatment course; the most common arrangement included 4 fields, used for 21 patients (44.7%). This treatment was followed by 3 fields in 9 patients (19.1%), 5 fields in 5 patients (10.6%), 2 fields in 5 patients (10.6%), 6 fields in 4 patients (8.5%), 8 fields in 2 patients (4.3%), and 7 fields in 1 patient (2.1%). Fields were alternated daily; most patients were treated with 1 field per day. Dosimetric data were available for a subset of our patients (Table 2). GTVs were retrievable from a dose–volume histogram (DVH) for 36 patients; these volumes averaged 8.09 ⫾ 8.95 cc (⫾ 1 SD) (range, 1–36 cc). Minimal GTV doses were retrievable for 40 patients and averaged 48.93 ⫾ 2.56 CGE (⫾1 SD) (range, 42–54). Optic chiasm doses could be retrieved from a DVH in 39 patients; in 32 individuals, no portion of the optic chiasm received more than 50 CGE. In the remaining 7 patients, the relative median volume of optic chiasm that received a dose greater than 50 CGE was 12% (range, 3–100%); in 5 of these latter patients, 15% or less of the optic chiasm volume received this dose. The mean maximal optic chiasm dose in both groups combined was 45.33 ⫾ 7.28 CGE. Table 2 also features an additional subset analysis based upon adenoma secretory status and size. A sample isodose colorwash with dose–volume histograms of a patient treated in this series is shown in Fig. 1.
Follow-up and definition of response Radiographic follow-up was MRI-based in all but 2 cases, which were CT-based. Response was scored according to whether residual tumor remained and, if so, the extent to which regression or progression had occurred as evidenced by the most recent scan. An actuarial analysis (Kaplan-Meier method) of complete tumor regression was performed. Endocrinologic follow-up was primarily based on all available
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Fig. 1. Sagittal isodose colorwash and dose–volume histograms from a patient who received 54 CGE to the target isocenter with the optic apparatus restricted to receive no more than 45 CGE. Isodose-color relationships are keyed on left of colorwash figure. Abbreviations: RON ⫽ right optic nerve; LON ⫽ left optic nerve; CGE ⫽ cobalt-gray equivalent. in-house and outside laboratory reports. Because of the multiple testing facilities involved, we deferred to the normal ranges of the individual laboratories when we assessed normalization for secreting tumors. Improvement or worsening of hypersecretion was based on any change of the most recent laboratory value compared with the preirradiation value. Scoring of hormonal deficits in the thyroid, adrenal, somatotropic, and gonadal axes was based upon laboratory reports that documented lower than normal hormonal levels or documented use of hormone supplements. Finally, actuarial analysis of hormone normalization was performed. Subjective evaluations were based on in-house follow-up, outside follow-up notes, or follow-up questionnaires sent to patients. Scoring of clinical symptoms was based solely on changes in the presenting symptoms. Complications were divided into the following categories: (nonvisual) CNS complications, visual complications, and endocrinologic complications (hypopituitarism). CNS complications were evaluated by review of all follow-up MRI reports and correlation of these reports with subjective follow-up data. The temporary or permanent nature of the lesion, and whether symptoms were associated with it, was noted. Visual follow-up was based upon both subjective symptoms and objective findings or reports, as available. Visual complications were scored as major or minor. Major deficits were defined as progressive visual loss or blindness, or new significant (symptomatic) visual field deficits. All other complications were considered minor, including worsening of a preexisting visual-field deficit. Hormonal deficits were scored as complications when they were discovered after radiation that followed documented normal preirradiation values. Worsening of preexisting deficits was not assessed in this study. Patients with hypopituitarism often took supplemental hor-
monal medications and frequently had their hormone levels tested at more than 1 laboratory, which, thus, confounded the issue. Actuarial analysis of incident hypopituitarism was performed. Incidents of postirradiation surgery were scored separately. Observations were recorded as to whether recurrent tumor, radiation necrosis, or another known or unknown cause was the inciting factor. The survival status of all patients was assessed. Time to death after treatment and cause of death (when known) were also reported.
RESULTS Radiographic response Radiographic follow-up was available in 41 of the 44 patients (93.2%) who had visible tumor before radiation and in all 3 patients without visible tumor before radiation. The median follow-up time was 47 months (range, 6 –139 months). In all patients, tumors had regressed or stabilized in size at the time of most recent radiographic follow-up: 10 patients (24.4%) had complete tumor regression; 12 (29.3%) demonstrated partial tumor regression; 19 (46.3%) had tumor stabilization (Table 3). The actuarial rate of complete tumor regression was 22% ⫾ 7.7% (⫾ 1 SD) at 5 years (Fig. 2). Although the 3 patients without visible tumor before radiation were not included in this analysis, none had evidence of recurrence, according to the most recent follow-up scan, with a median follow-up time of 35 months (range, 17–123 months). Radiographic response outcomes based upon secretory
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Table 3. Radiographic response
Radiographic response Tumor resolution Tumor regression Tumor stabilization
Secretory status (n ⫽ 41)
Adenoma size (n ⫽ 33)*
All adenomas (n ⫽ 41)
Nonsecreting vs. secreting
⬍2 cm vs. ⱖ2 cm
10/41 (24.4%) 12/41 (29.3%) 19/41 (46.3%)
4/23 (17.4%) vs. 6/18 (33.3%) 10/23 (43.5%) vs. 12/18 (66.7%) 12/23 (52.2%) vs. 7/18 (38.9%)
4/12 (33.3%) vs. 1/21 (4.8%)† 6/12 (50%) vs. 10/21 (47.6%) 6/12 (50.0%) vs. 13/21 (61.9%)
* Preirradiation tumor-size data available for 33 of 41 patients with radiographic follow-up. † Statistically significant (p ⫽ 0.047 by Fisher’s exact test).
Endocrinological response Of the 23 patients with secreting adenomas, endocrinologic follow-up was available for 21 (91.3%). The median follow-up time was 83 months (range, 9 –139 months). Eighteen patients (85.7%) had normalized or decreased hormone levels and, thus, achieved biochemical control. Eight patients (38.1%) had hormonal normalization; 10 patients (47.6%) had decreased levels. The actuarial rate of hormonal normalization was 22.8% ⫾ 9.2% at 5 years (Fig. 3). Three patients (14.3%) had increased hormone levels compared with pretreatment values, including 2 of 4 patients (50%) with ACTH-secreting adenomas and 1 patient with a TSH-secreting adenoma. Endocrinologic response outcomes are summarized in Table 4, which includes further subset analysis based upon the major adenoma subtypes.
months). Thirty patients (71.4%) reported subjective improvement of their presenting symptoms; 5 patients (11.9%) reported no overall change. Subjective improvement occurred in 15 of 22 patients (68.2%) who had nonsecreting adenomas and in 15 of 20 patients (75%) who had secreting adenomas. Among the latter, improvement occurred in 1 of 3 patients (33.3%) with ACTH-secreting adenomas, 8 of 10 patients (80%) with GH-secreting tumors, and 4 of 5 patients (80%) with prolactin-secreting adenomas. No differences reached statistical significance. Seven patients (16.6%) reported worsened symptoms. Two patients experienced progressive headaches without radiographic evidence for tumor regrowth or treatment complication; 1 patient underwent surgery, as described below. Two patients had progressive visual field deficits; an additional patient, who had progressive Cushing’s disease, developed progressive bilateral visual loss. These patients are discussed in greater detail below. Worsening of endocrinologic symptoms occurred in 2 patients, 1 of whom had progressive symptoms of Cushing’s disease and 1 of whom demonstrated symptomatic worsening of a preexisting hypothyroidism.
Subjective response Subjective follow-up was available for 42 patients (89.4%); median follow-up time was 90 months (range, 8 –143
Postradiation surgery Four patients (8.5%) underwent additional surgery after radiation. One patient had a salvage transsphenoidal resec-
Fig. 2. Actuarial incidence of complete tumor regression. Dot symbols indicate censored events.
Fig. 3. Actuarial incidence of hormonal normalization. Dot symbols indicate censored events.
status and tumor size are detailed in Table 3. Of note, a statistically significant difference was seen in complete tumor resolution for tumors less than 2 cm when compared with those greater than or equal to 2 cm (33.3% vs. 4.8%; p ⫽ 0.047 by Fisher’s exact test). None of the other subanalyses reached statistical significance.
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Table 4. Endocrinologic response Endocrinologic response Hormonal normalization Decreased hormone levels Hormonal progression
All secreting adenomas (n ⫽ 21)
ACTH-secreting adenomas (n ⫽ 4)
8/21 (38%) 10/21 (47.6%) 3/21 (14.3%)
tion of an initially unresectable ACTH-secreting adenoma; this patient not only demonstrated some tumor regression after primary radiation but also had persistent Cushing’s disease. One patient required resection of an area of temporal lobe necrosis, as detailed below in the Complications section. Two patients had additional surgical procedures that appeared not to be related to tumor progression or radiation treatment. One patient had surgery for intractable headaches after radiation, albeit tumor progression or evidence of radiation necrosis were not evident. The headaches continued after surgery; no apparent cause was found. Another patient developed a CSF leak years after treatment that required surgical correction; the cause was not apparent from our records.
Complications One patient had a (nonvisual) CNS complication caused by radiation. Nineteen months after radiation, she developed progressive headaches and was found to have necrosis of the tip of the right anterior mesial temporal lobe. Symptomatic resolution was obtained after a craniotomy-based resection. No radiation-related secondary tumors or vascular injuries occurred in our series, although our follow-up may be too short to assess the incidence of these late complications of pituitary irradiation. Visual follow-up was available for 43 patients (91.5%). The median follow-up duration for these patients was 80 months (range, 10 –143 months). Thirty-three patients (76.7%) reported no visual worsening secondary to radiation; 7 (23.3%) reported new minor deficits. Two of the latter patients had new objective findings. One patient was noted by his endocrinologist to have an asymptomatic minimal visual field cut. Another patient developed temporary visual worsening associated with bilateral optic nerve enhancement on MRI (T2-lengthening), which has since both clinically and radiographically resolved. Two patients (4.6%), both with Cushing’s disease, noted new major visual complications. One of theses patients developed an inferior right quadrantanopsia after radiation; the other developed a bilateral optic nerve atrophy. This woman suffered from progressive Cushing’s disease after primary radiation for an initially unresectable tumor and underwent salvage resection 8 months later. She began to experience visual loss immediately after surgery that progressed to near blindness within 3 months. An MRI examination performed at that time demonstrated bilateral optic nerve atrophy. Maximal optic chiasm doses for these 2 patients were 42 Gy
1/4 (25%) 1/4 (25%) 2/4 (50%)
GH-secreting adenomas (n ⫽ 11) 5/11 (45%) 4/11 (36%) 0/11
Prolactinomas (n ⫽ 6) 2/6 (33%) 4/6 (66%) 0/6
and 47 Gy; both were well within 1 standard deviation of the group mean (45.33 ⫾ 7.28 Gy). Endocrinological follow-up to assess for posttherapy hypopituitarism was available in 37 patients (80.9%); median follow-up for these patients was 74 months (range, 7–139 months). Eleven patients (29.7%) developed hormonal deficiencies that were not present before radiation and required hormone supplements; 2 (5.4%) developed panhypopituitarism. Incident deficiencies in 1 or several of the 3 major hormonal axes are diagrammed in Fig. 4. The actuarial rate of developing any new hormonal deficiency was 21.7% ⫾ 7.3% at 5 years and 44.2% ⫾ 11.3% at 10 years. Hypopituitarism as a complication of radiation was noted in 4 of 20 patients (20%) with nonsecreting adenomas and in 7 of 20 patients (35%) with secreting adenomas. Among those with secreting tumors, incident hypopituitarism occurred in none of 4 patients with ACTH-secreting tumors, in 2 of 10 patients (20%) with GH-secreting tumors, in 3 of 5 patients (60%) with prolactin-secreting adenomas, and in the 2 patients with TSH-secreting and mixed (GH-andprolactin–secreting) adenomas, respectively. None of these differences reached statistical significance. Survival status Six patients (12.8%) died after treatment. Average time to death was 93.3 ⫾ 35.6 months (range, 52–149 months).
Fig. 4. Actuarial incidence of new hypopituitarism. Dot symbols indicate censored events.
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Two patients’ deaths (4.3%) were secondary to the effects of persistent Cushing’s disease. One patient died 52 months after treatment of intractable Cushing’s disease secondary to an ACTH-secreting adenoma that was functionally uncontrolled with primary radiation and salvage resection. A second patient died 59 months after treatment; this patient’s ACTH-secreting adenoma was managed initially with bilateral adrenalectomy, which resulted in Nelson’s syndrome. She was then salvaged with surgery and proton radiation 39 years later, after a large tumor mass with bilateral cavernous sinus invasion was found on MRI and increased cortisol levels were present. She was noted to have decreased, yet persistently elevated, ACTH levels from her ACTH-secreting adenoma 45 months after treatment, but she also experienced multiple strokes within 1 year of her death. Tumor growth was not present in either case. Three patients’ deaths (6.4%) were unrelated to tumor or treatment factors. One patient developed renal carcinoma and died of metastatic disease. Another, who developed liver failure and grand mal seizures, died 106 months after treatment; this man had a stable adenoma and no evidence of radiation-related complications at 44 months after treatment. Another patient died 106 months after treatment from an acute cardiopulmonary arrest, attributed in part to a seizure disorder. She was asymptomatic from tumor or treatment 77 months after treatment and had a stable adenoma without evidence of radiation-related complications 22 months after treatment. In 1 patient (2.1%), cause of death is unknown to us. She died 149 months after treatment. Ninety months after treatment, she had no evidence of adenoma and was asymptomatic. DISCUSSION Pituitary adenomas are benign tumors that can cause considerable morbidity and occasional mortality when they are not controlled. Tumors with a high risk of recurrence are frequently treated with postoperative radiation; common modalities have included fractionated photon external-beam irradiation (10 –16), stereotactically guided radiosurgery and radiotherapy techniques with photons or gamma knife (17–19), and charged-particle radiosurgery techniques with either protons or helium ions (20 –23). Although the experience with stereotactically guided photon radiation and gamma knife is limited to the past 2 decades, chargedparticle radiosurgery was performed starting in the late 1950s until the late 1980s at high-energy physics accelerator laboratories and was mostly limited to the treatment of hypersecreting microadenomas. In the early 1990s, fractionated precision-proton radiation therapy became available at our center; we are the first to report on a clinical experience in the treatment of pituitary adenomas with this technique. The rationale for use of heavy charged particles such as protons or helium ions for irradiation of any site in the body is based upon the superior depth-dose characteristics of such particles that result from their Bragg peak. This feature
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allows one to achieve high-dose conformity with relatively few beams, which permits dose escalation while minimizing integral dose. Dosimetric studies have demonstrated that protons offer a therapeutic advantage in the treatment of small intracranial tumors such as pituitary adenomas (24, 25). Charged-particle radiosurgical experiences published in the late 1970s and 1980s from Lawrence Berkeley Laboratory (LBL), Harvard Cyclotron Laboratory at Massachusetts General Hospital (MGH), the Burdenko Neurosurgical Institute in Moscow, and the Leningrad Institute of Nuclear Physics demonstrated excellent results in the treatment of hypersecreting microadenomas (22, 27). Doses and techniques ranged from single-fraction proton radiosurgery to 100 to 120 CGE (20) to 4-fraction helium-based radiosurgery to total doses that ranged from 30 to 150 CGE (28). Best results were reported in acromegalics, who achieved remission in 80% to 90% of cases. Cushing’s disease and prolactinoma patients had normalization in up to 65% of the cases. In Nelson’s syndrome, hormonal normalization rarely occurred. Complications were reported: at LBL, with helium radiosurgery, about one third of patients had developed some form of hypopituitarism at the time of analysis (22). Similar incidence rates were also reported from MGH, and these rates increased with time of follow-up (29). Focal temporal-lobe injury and injury to the cranial nerves were rare in these series (less than 1% of patients). Our rationale for fractionating treatment with protons was to maximize the therapeutic ratio and to permit treatment of larger pituitary tumors, both functional and nonfunctional, in which dose to the optics could not practically be kept below 40% of the prescribed dose, as is required with single-fraction radiosurgery. Thus, the patient population in our series differs significantly when compared with patients in the early charged-particle radiosurgery series. The range of tumor sizes and tumor histologies in our series is comparable to those in which conventionally fractionated photon therapy has been used. Overall local control of pituitary adenomas in these series exceeds 90%, with doses in the range of 45 to 50 Gy (12–15). In general, when matched for other risk factors, including size, nonsecreting adenomas have higher local-control rates than do secreting adenomas, which have control rates that range from 82% to 98% (12, 13, 30 –32) for nonsecreting adenomas and 67% to 85% (15) for secreting adenomas. Control was usually defined as absence of progressive clinical symptoms in older series and absence of tumor growth documented by imaging studies in more recent series. Our series demonstrated 100% radiographic local control of adenomas (without regard to biochemical outcomes) at a median follow-up time of 47 months (range, 6 –139 months). We attribute this excellent control rate to the fact that most of our patients received a dose of 54 Gy, which is 10% to 20% higher than doses reported in historic series with fractionated photon radiotherapy. However, several reports demonstrate gradually decreasing local-control rates of radiated pituitary adenomas when patients are followed
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for 10 years or more; (30, 33) our control rates may, therefore, decrease with further follow-up. Our series demonstrated complete regression in a larger percentage of tumors less than 2 cm than in those 2 cm or more (33.4 vs. 4.8%, p ⫽ 0.047). Other series have also found tumor size to be a prognostic factor (13, 14). However, in contrast to the literature, we found slightly higher rates of complete and partial regression in our secreting adenomas than in our nonsecreting adenomas, albeit this difference never reached statistical significance. At least 1 other study has challenged the literature on this premise as well (12). Our series demonstrated crude rates of 85% biochemical control and 40% hormonal normalization; the actuarial rate of hormonal normalization was 22.8% ⫾ 9.2% at 5 years. Biochemical control of functional adenomas has been reported after fractionated photon radiotherapy and varies from 45% to 90%, depending on intrinsic tumor factors that include size and functional subtype. Variation also depends on the operational definition of control; hormonal normalization has generally been reported to occur in 35% to 50% of patients (12, 14). Studies that examine primary radiation therapy suggest that biochemical control rates differ for the various common functional subtypes, with approximately 80% control in GH-secreting adenomas, 50% to 80% control in ACTH-secreting adenomas, and 30% to 35% control in prolactinomas (34). Other series suggest that ACTHsecreting adenomas are most difficult to control (12, 17). Certain studies suggest that prolactinomas and GH-secreting adenomas may require more than 5 years to normalize biochemically after conventionally fractionated radiation; (14) the normalization and control rates we observed may, therefore, still improve with time and become comparable with the radiosurgical series that achieve more rapid biochemical responses. In our series, 3 functional adenomas progressed, including 1 TSH-secreting adenoma and 2 ACTH-secreting adenomas. This result is consistent with reports that suggest ACTH-secreting adenomas in adults are more difficult to control (12, 17). Other factors may also account for our findings in these patients. One of these patients received primary radiation therapy rather than surgery. In the 2 other patients, large tumor size (4.2 and 8 cm) placed portions of these tumors adjacent to the optic chiasm, and, thus, these portions received less than the prescribed dose to reduce chiasm dose. Relatively few series reported the response of presenting symptoms after radiation treatment. A single study reported subjective improvement in 67% to 80% of symptoms because of mass effect and endocrine hypersecretion (15). In line with that study, we noted subjective improvement in the presenting symptoms in 71.4% of our patients. Brain necrosis that results from pituitary radiation is rare with conventional radiation doses, with the estimated risk of 0.04% for doses in the range of 45 to 50 Gy (34). Rates have been noted to increase at doses beyond 50 Gy. One of our patients developed temporal-lobe necrosis, and identifica-
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tion of the circumstances that may have led to this incident is a priority. This individual had a recurrent tumor with right cavernous sinus invasion and suprasellar extension, which required a relatively large target volume that encompassed much of the right temporal-lobe tip. She received a dose of 54 CGE in 2 Gy fractions. The treatment was delivered with 2 opposed lateral beams, and a small portion of the right temporal lobe received the full prescribed dose. Intravenous contrast was used for her planning CT and significant contrast uptake occurred in and around the target volume, which was not taken into account when the required beam penetration was calculated. Therefore, the actual beam range may have been a few millimeters larger than shown in the treatment isodose plan. This higher dose, in conjunction with the increased radiobiologic effect at the distal edge of the proton beam (1.2 to 1.3 vs. 1.1) (35) may have contributed to her necrosis. Subsequent to our experience with this patient, we use 1.8-Gy daily fractions on all of our pituitary patients treated with proton beams, generally correct for contrast enhancement, and frequently utilize superior oblique and superior beams for a significant portion of the treatment, to spare the temporal lobes. The incidence of radiation damage to the optic apparatus depends on fraction size and total dose. A large literature review found no cases of optic chiasm or nerve damage when doses of 45 Gy in 1.8 Gy fractions were used (36). Several series have shown a combined rate of 0.3% when less than 2-Gy fractions were used and 4% when 2-Gy or greater fractions were used; many of these patients received total doses of 50 Gy or more (33). Several series also note a dose response beyond 45 to 50 Gy for radiation damage to the optic apparatus (37–39). In our series, the majority of patients received a dose of 54 Gy in 1.8-Gy fractions; this dose and fractionation scheme is commonly quoted as the tolerance dose for the optic apparatus. In our series, 7 patients developed minor visual deficits and 2 patients developed major visual deficits that consisted of a new quadrantanopsia and bilateral optic nerve atrophy. Both of these patients had Cushing’s disease, which leads one to hypothesize that the longstanding effects of hypercortisolism predisposes the optic chiasm microvasculature of Cushinoid patients to radiation damage. This hypothesis is supported by reports of premature cerebral atrophy that occurred in patients with endogenous steroid production from Cushing’s syndrome or disease (40). With regard to the patient who developed optic nerve atrophy, the acute onset of symptoms immediately after a salvage resection 9 months after primary radiotherapy implicate surgical injury, possibly in addition to radiation and hypercortisolism, as causative factors. Finally, one must remember that fractionation permits treatment of larger target volumes that may be adjacent or even compressing the optics, which puts them at higher risk for injury. We concede that, despite their high degree of dose conformity, protons cannot completely prevent visual morbidity in patients with tumors close to the optic chiasm. This fact mandates a cautious approach in such patients, espe-
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cially when additional risk factors for radiation injury are present. Hypopituitarism is the most common side effect of pituitary radiation and, fortunately, is treatable by hormonal substitution. The rate of incident hypopituitarism after pituitary irradiation with fractionated photon therapy has been reported to range from 20% to 60% (14 –16), with somewhat higher rates noted for nonsecreting tumors (14). Approximately 30% of our patients developed 1 or more new hormonal deficits; the actuarial rate was just over 20% at 5 years and increased to over 40% at 10 years. Several factors put our patients at higher risk for incident hypopituitarism: large tumor size, nonsecreting adenomas in nearly 50% of our population, a surgical resection that preceded radiation in approximately 90%, and a somewhat higher median dose (54 Gy) than those in most other fractionated series. Although death from pituitary adenomas is uncommon, the long-standing effects of hormonal imbalance, in particular of ACTH, can be fatal. This circumstance was the case in 2 of our patients who had long-standing, uncontrolled Cushing’s disease. One of these patients had primary radiation therapy followed by salvage resection, which is presumably less effective than primary surgery with adjuvant radiation. The second patient had initially been managed with bilateral adrenalectomy followed by a prolonged interval (39 years) between diagnosis and definitive surgical and radiation therapy. She subsequently developed Nelson’s syndrome, which is clinically characterized by an aggressive local growth of the tumor (41, 42) and has shown disappointing results with both surgery and radiotherapy (27, 43– 45). None of our patients developed a secondary, radiationinduced tumor. Radiation-induced tumors of the skull base, mostly osteosarcomas and meningiomas, and brain have
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been reported after irradiation for pituitary adenomas, but the incidence or radiation-induced skull-base tumors appears to be very low (46). The latency of these tumors is longer than 3 years and typically exceeds 10 years. Therefore, possibly more time must pass before we can draw conclusions with regard to proton-radiation induced tumors based on our series. CONCLUSION Fractionated conformal proton-beam irradiation to doses of 50 to 54 Gy in 1.8-Gy to 2-Gy fractions appears to achieve effective radiologic, biochemical, and symptomatic control of pituitary adenomas. Long-term follow-up is required to determine whether this promising outcome persists. Average tumor size was much larger in our series than in the early charged-particle radiosurgical series, which precludes their direct comparison. In our experience with fractionated proton irradiation, fraction sizes of 1.8 Gy should be preferred to 2-Gy fractions to reduce late toxicity, and the higher RBE of protons may need to be taken into account when the number of treatment fields is kept small. Patients with long-standing Cushing’s disease may fare worse with regard to control and toxicity, and they may benefit from local radiation therapy early in the course of their disease. Patient access to hospital-based proton treatment centers for fractionated proton radiotherapy is expected to increase as more treatment centers become operational. On the basis of the dosimetric advantages of protons in the treatment of small intracranial tumors such as pituitary adenomas and our encouraging experience treating them in a fractionated matter, one may consider fractionated proton irradiation as a viable adjunctive treatment option for patients with pituitary adenomas.
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