Proton Stereotactic Radiotherapy for Persistent Adrenocorticotropin ...

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Proton Stereotactic Radiotherapy for Persistent Adrenocorticotropin-Producing Adenomas Joshua H. Petit, Beverly M. K. Biller, Torunn I. Yock, Brooke Swearingen, John J. Coen, Paul Chapman, Marek Ancukiewicz, Marc Bussiere, Anne Klibanski, and Jay S. Loeffler Departments of Radiation Oncology (J.H.P., T.I.Y., J.J.C., M.A., M.B., J.S.L.), Neurosurgery (B.S., P.C.), and Medicine (Neuroendocrinology) (B.M.K.B., A.K.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Context: Radiation therapy is a potentially curative treatment for corticotroph adenomas refractory to surgery. Protons have an advantage over photons (x-rays) by depositing energy at the target with no exit dose, providing a lower dose to adjacent normal tissues. Until recently, proton stereotactic radiotherapy (PSR) was available at only two U.S. centers; use will increase as proton facilities are under development. Objective: Our objective was to evaluate the efficacy and safety of PSR for persistent Cushing’s disease (CD) and Nelson’s syndrome (NS). Design: This was a retrospective review of 38 patients (33 with CD and five with NS) treated between 1992 and 2005. Participants: All patients had transsphenoidal surgery without biochemical cure. Four had previous irradiation with photons. The patients with NS underwent bilateral adrenalectomy 29 –228 months (median 40) before PSR. Intervention: Single-fraction PSR was delivered at a median dose of 20 Cobalt Gray Equivalents (range 15–20) on 1 treatment day. Main Outcome Measures: Complete response (CR) was defined as sustained (ⱖ3 months) normalization of urinary free cortisol off medical therapy. CR in NS was based on normalization of plasma corticotropin. Results: At a median follow-up of 62 months (range 20 –136), CR was achieved in five patients (100%) with NS and 17 (52%) patients with CD. Among all patients with CR, median time to CR was 18 months (range 5– 49). No secondary tumors were noted on follow-up magnetic resonance imaging scans, and there was no clinical evidence of optic nerve damage, seizure, or brain injury. There were 17 patients (52%) who developed new pituitary deficits. Conclusions: PSR is effective for patients with persistent corticotroph adenomas with low morbidity after a median follow-up of 62 months; longer follow-up is warranted for late radiationrelated sequelae. (J Clin Endocrinol Metab 93: 393–399, 2008)

he first line of treatment for an ACTH-secreting pituitary adenoma is transsphenoidal resection of the tumor (TSS), which achieves an initial success rate of 78 –91% when performed by an experienced pituitary surgeon (1–5). Treatment options for patients with recurrent or persistent disease after

T

surgery include repeat TSS, medical management, bilateral adrenalectomy, radiation therapy, or a combination of these. Radiation therapy presents a potentially curative treatment option for patients with corticotroph adenomas who are not cured with initial surgery.

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Abbreviations: CD, Cushing’s disease; CGE, Cobalt Gray Equivalent; CR, complete response; CT, computed tomography; GKRS, Gamma Knife radiosurgery; MRI, magnetic resonance imaging; NS, Nelson’s syndrome; PSR, proton stereotactic radiotherapy; PSRS, proton stereotactic radiosurgery; SRS, stereotactic radiosurgery; TSS, transsphenoidal resection of the tumor; UFC, urinary free cortisol.

Printed in U.S.A. Copyright © 2008 by The Endocrine Society doi: 10.1210/jc.2007-1220 Received June 4, 2007. Accepted November 13, 2007. First Published Online November 20, 2007

J Clin Endocrinol Metab, February 2008, 93(2):393–399

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Proton Radiotherapy for ACTH-Producing Adenomas

Stereotactic radiosurgery (SRS), in which patients can be treated at a single sitting, has gained widespread use over the past decade. SRS can be performed using either photons [such as Gamma Knife (Center for Image-Guided Neurosurgery, University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, PA), CyberKnife (Accuracy, Sunnyvale, CA), or linear accelerator-based radiosurgery] or protons. The primary advantage of protons is their characteristic Bragg peak, which essentially eliminates exit dose to structures beyond the target (Fig. 1). This allows the treatment of an irradiated volume that conforms more closely with the actual target volume (6). Therefore, proton stereotactic radiotherapy (PSR), often referred to as proton SRS, achieves more selective treatment of the tumor mass while min-


imizing dose to surrounding tissues when compared with SRS using photons. Until recently, there were only two facilities in the United States where PSR was available. Given the theoretical advantages of protons, many centers are currently under development. As the practice of radiation oncology shifts toward the more widespread use of protons, data regarding the safety and efficacy of proton radiation will be critical to clinical practitioners treating patients with pituitary tumors. We report the first and only data on PSR for refractory ACTH-producing pituitary adenomas in the era of computed tomography (CT)/magnetic resonance imaging (MRI)-based treatment planning.

Patients and Methods Patient characteristics From 1992–2005, 38 patients (six males and 32 females) were treated with PSRS for ACTH-producing pituitary adenomas that were not cured after TSS. All patients had undergone one to four prior pituitary surgeries with a median of two surgical attempts for cure. All surgeries before PSR were transsphenoidal resections, and no patient underwent craniotomy. Two patients had been previously treated with fractionated radiotherapy: one with Cushing’s disease (CD) was treated 5 yr before PSR, and one with Nelson’s syndrome (NS) was treated 8 yr before PSR. Two other patients with CD had previously undergone Gamma Knife radiosurgery (GKRS) (3.5 and 4.5 yr before PSR). Patient and treatment characteristics for CD and NS are summarized in Tables 1 and Table 2, respectively.

CD For the 33 patients with CD, a pituitary etiology was confirmed by ACTH-positive staining cells in a surgical specimen for 25 patients (76%). The remaining eight (24%) without positive pathology all had findings consistent with ACTH-dependent pituitary CD and positive inferior petrosal sinus sampling, defined as a pituitary to peripheral ACTH ratio of two or more before ovine CRH and/or three or more after CRH 1 ␮g/kg. At PSR, three patients were refractory to adrenal blockade medication, six were controlled on medication, and 24 were uncontrolled but had not yet received medication. Medication was not withdrawn at PSR for the nine patients receiving adrenal-suppressive medication.

NS Five patients had undergone previous bilateral adrenalectomy between 29 and 228 months (median 40) before PSR and had developed NS. The patients with NS all had both elevated plasma ACTH levels and tumor growth demonstrated on imaging. None of these patients had neurological deficits at PSR.

Treatment parameters

FIG. 1. A, Dose distribution for a single right lateral 6 MV photon (x-ray) beam. B, Dose distribution for a single right lateral 230 MEV proton beam. Isodose lines are color coded and represent relative dose of radiation delivered to the area encompassed within each line.

All patients were treated with PSR using two to five convergent beams of 160 or 230 MEV protons. Treatment volumes were constructed using fused CT and MRI (7). The entire sella, medial walls of the cavernous sinuses, and inferior dura of the sella turcica were targeted in all patients. Additional residual tumor outside of the sella, visible on MRI, was also targeted in 12 patients (32%). Three fiducial markers were placed in the outer table of the skull before imaging to ensure accurate localization on the day of treatment (8). A stereotactic head frame was placed on the day of radiosurgery to obtain adequate immobilization. The median radiation dose was 20 Cobalt Gray Equivalents (CGEs) (range 15–20). The dose was prescribed at the 90% isodose line in 37 patients and the 100% line in one patient. The dose to the optic chiasm was limited to less than eight CGEs in all cases, and less than four CGEs



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TABLE 1. Patient parameters and treatment outcomes for CD Age (yr)/ sex 26/M 50/F 43/F 42/F 41/M 53/F 29/F 42/F 42/F 19/M 38/F 20/F 40/F 42/F 37/F 33/F 21/M 14/M 45/F 27/F 44/F 54/F 45/F 24/F 30/F 60/F 49/F 47/F 46/F 58/F 56/F 24/F 49/F

No. of prior TSSs

MRI residual

Size

Dose (CGE)

TV (cc)

Follow-up (months)

New HPa

CR

Time to CR (months)

4 2 2 2 2 2 1 2 2 2 2 2 2 1 2 2 2 2 2 2 1 2 2 1 1 1 1 2 2 2 1 2 1

No Yes No No No No No No No No No Yes No No No No No No No No Yes No No Yes No No No Yes No No Yes No Yes

NA MR NA NA NA NA NA NA NA NA NA MR NA NA NA NA NA NA NA NA MR NA NA MR NA NA NA MR NA NA MR NA MR

20 20 20 20 20 20 15 20 20 20 20 20 20 18 20 20 20 20 20 20 20 20 20 20 20 18 20 20 20 20 20 20 20

1.3 1.0 0.9 0.9 1.1 1.1 0.8 0.8 0.9 1.0 1.3 1.4 2.0 0.6 1.0 1.1 1.4 1.9 0.7 1.0 1.9 1.9 1.3 3.4 3.9 0.8 1.0 1.3 0.6 0.4 0.9 0.2 2.4

108 104 102 100 96 84 71 81 83 84 60 70 73 54 58 64 55 50 63 59 53 48 43 40 34 34 27 24 24 23 20 21 20

NA T No T, E A, GH, T No No No No No No No No GH T T GH, T No No E, GH No A, GH No T No GH No No No T GH A No

Yes No Yes No Yes Yes No Yes No Yes No No Yes Yes No Yes Yes Yes Yes No Yes No No No No No No Yes No No Yes Yes Yes

15 NA 23 NA 7 14 NA 21 NA 11 NA NA 29 7 NA 7 16 6 49 NA 7 NA NA NA NA NA NA 14 NA NA 14 17 5

A, Adrenal replacement; E, estrogen replacement; F, female; GH, GH replacement; M, male; NA, not applicable; T, thyroid replacement; TV, treatment volume; CGE, cobalt gray equivalents; CR, complete response; MR, minimal residual (⬍1 cm maximum diameter at time of PSRS). a

New hypopituitarism (HP) after PSRS.

for patients with a history of prior radiation treatment. All patients were treated to 20 CGEs except for three patients with a history of prior irradiation, for whom the prescription dose was reduced. One patient had previously been treated with GKRS (12 Gy minimum target dose) 3.5 yr before PSR, and the prescription dose was reduced to 15 Gy to keep the optic chiasm dose under four CGEs. The other two patients had previously received fractionated radiotherapy as described previously, and the prescription dose was reduced to 18 CGEs.

Follow-up evaluation The study was approved by the Massachusetts General Hospital Institutional Review Board. Retrospective chart review included follow-up obtained from referring endocrinologists, neurosurgeons, and primary care physicians. Some patients also continued to be seen regularly in the Radiation Oncology Clinic and/or the Neuroendocrine Clinical Center at the Massachusetts General Hospital. All patients were evaluated with

TABLE 2. Patient parameters and treatment outcomes for NS Age (yr)/ sex 34/M 52/F 29/F 53/M 41/M

No. of prior TSSs

MRI residual

Size (cm)a

Dose (CGE)

TV (cc)

Follow-up (months)

New HPb

CR

Time to CR (months)

4 2 2 1 2

Yes Yes Yes Yes Yes

MR 2.0 2.0 MR MR

20 20 20 17 20

0.18 1.5 0.5 1.8 0.5

136 108 106 92 103

NA GH T No No

Yes Yes Yes Yes Yes

17 22 27 19 25

F, Female; GH, GH replacement; M, male; NA, not applicable; T, thyroid replacement; TV, treatment volume. CGE, cobalt gray equivalents; CR, complete response; MR, minimal residual (⬍1 cm maximum diameter at time of PSRS). a

Maximum diameter of residual tumor on MRI at PSRS.

b

New hypopituitarism (HP) after PSRS.

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serial urinary free cortisol (UFC) levels, or plasma ACTH in patients with bilateral adrenalectomy. Medications that block adrenal production of cortisol were administered by the patient’s local physicians, with ketoconazole the most common choice, followed by metyrapone, and then aminoglutethimide. Attempts to wean cortisol-suppressive medications were made after patients had sustained normal UFC levels for at least 3 months. If discontinuation of medication resulted in high UFCs, medical treatment was resumed. Medications were permanently discontinued once complete remission, defined as successive normal UFCs on no medical treatment, was documented. Patients were screened for pituitary dysfunction at least annually by checking levels of free T4, prolactin (women), and testosterone (men), as well as documenting the menstrual status of women who were premenopausal at PSR. Early morning cortisol more than or equal to 18 ␮g/dl or cortisol more than equal to 18 ␮g/dl after Cortrosyn injection (Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA) was used to define normal glucocorticoid production. The years encompassed by the follow-up predated the Food and Drug Administration approval of GH replacement in adults, therefore, systematic evaluation for GH deficiency was not performed in all patients but was available in 23. Glucocorticoid replacement therapy was administered to patients with subsequent adrenal insufficiency. MRI scans of the pituitary were obtained regularly (at least annually for 2 yr and then at least every 3 yr) to follow for evidence of radiographic recurrence and screen for secondary tumors, or when prompted by clinical or biochemical findings.

Endpoints–CD Complete response (CR) was defined as sustained (ⱖ3 months) normalization of UFC after the completion of a washout period during which medical therapy was withdrawn. Local tumor control, defined as no tumor enlargement on imaging, was also required for the definition of CR.

Endpoints–NS CR was defined as normalization of plasma ACTH and local tumor control.

Endpoints–all patients


Results Complete endocrine and radiographic follow-up was available for all patients at a median of 62 months (range 20 –136) after PSR. CD A CR after PSR was achieved in 17 patients (52%) with CD. Among patients with CR, median time to CR was 14 months (range 5– 49). Actuarial rates of CR at 1– 6 yr were 21, 45, 49, 49, 55, and 55%, respectively (Fig. 2). During follow-up, 50% of the patients were in CR at 25 months after PSR. No complete responder developed recurrent CD at last follow-up. There were 12 (36%) additional patients with CD who had achieved stable, normal UFC levels but have not been weaned off medical therapy. None of the patients with normal UFC had evidence for tumor growth on follow-up imaging. Among the four patients (12%) with persistently elevated UFC levels, two developed radiographic evidence of local tumor progression and underwent subsequent TSS during the follow-up period. Seven of nine patients (78%) on adrenal suppressive medication at PSR achieved CR. Median treatment volume for patients with CR was 1.1 cc compared with 1.0 cc for patients who did not achieve CR. On univariate analysis, CR was not associated with any of the tested variables. NS A CR to PSR was achieved in all five patients (100%) with NS (Fig. 3). Median time to CR was 22 months (range 15–27). There has been no evidence for biochemical or radiographic progression after a median 9 yr (range 8 –11) of follow-up in these patients. Treatment morbidity No visual complications or clinical evidence of brain injury was observed. No patients had clinical or radiographic evidence suggestive of a cerebrovascular event during the follow-up pe-

Before PSR, 22 patients (58%) already required replacement of one or more pituitary hormones, whereas the remainder of patients had no deficit. New partial pituitary dysfunction was defined as the need for initiating replacement of any additional pituitary axis hormones, including thyroid hormone, GH, sex hormones, or glucocorticoids, after PSR. In patients who were menstruating at PSR, the onset of amenorrhea without elevated prolactin level or clear evidence of menopause based on clinical symptoms and elevated FSH was counted as a new pituitary deficit. New complete pituitary dysfunction was defined as the requirement of replacement of all of these hormones among patients who had two or less deficiencies before PSR. Patients were considered deficient at the point when replacement medication was initiated.

Statistical analysis Actuarial rates of CR to single dose PSR, and new pituitary deficiencies, were calculated using Kaplan-Meier estimates. Variables evaluated for statistical association with biochemical outcomes (CR and hypopituitarism) included age, sex, cavernous sinus invasion, visible MRI residual, treatment volume, pretreatment UFC or ACTH level, medical therapy at PSR, number of prior surgeries, history of prior radiation, and radiation dose. The group comparisons were performed using log-rank tests.

FIG. 2. Actuarial rate of CR, with 95% confidence interval, over time after PSRS. Parentheses show the number remaining at each time point.


riod. No secondary tumors were noted on MRI scans. MRI scans in two of the four previously irradiated patients demonstrated new temporal lobe enhancement that was not associated with any symptoms. Before PSR, both patients had been previously treated with fractionated radiotherapy for involvement of the cavernous sinus directly adjacent to the area of enhancement. There were no changes noted among patients with no history of prior radiation. Five patients had panhypopituitarism before PSR and, therefore, were not evaluated for new pituitary deficits. Of the 33 patients at risk, 17 (52%) developed new pituitary deficits during follow-up and were administered replacement hormones (Fig. 4): panhypopituitarism in two (6%), thyroid and GH in one (3%), adrenal and GH in one (3%), GH and estrogen in one (3%), thyroid hormone and estrogen in one (3%), thyroid only in six (18%), GH only in four (12%), and estrogen only in one (3%). The median time to pituitary hormone deficiency was 27 months (range 9 – 60) as seen in Fig. 5. On univariate analysis, the incidence of hypopituitarism was not associated with any of the tested variables.

Discussion The primary finding of this study was that single-dose PSR achieved CR in 58% of patients with ACTH-secreting adenomas after failed TSS over a median 62-month follow-up period. This included 52% of patients with active CD and 100% of patients with NS. An additional 32% of patients with CD have stable, normal UFC levels on medication and may achieve CR in the future. This represents the first report on the outcomes of PSR for ACTH-producing adenomas in the modern era during which CT, MRI, and other technical advances have substantially improved radiation therapy. Our findings are comparable with historical data for conventional fractionated radiotherapy and other forms of SRS (GKRS and linear accelerator-based SRS) regarding efficacy and timing of response. However, it is important to note the advantage of protons in achieving more precise dose delivery. Although historical data are discussed later for context, any direct comparison of these techniques should be considered with caution, given the potential for selection bias and the differences in follow-up among these series.

FIG. 3. Pretreatment (closed circles) and the most recent posttreatment (open circles) ACTH values for each NS patient treated with PSR.


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Most conventional fractionated radiotherapy series have reported CR and tumor control in 50 –57% of patients (9 –14); one study demonstrated a higher rate (15). Fractionated stereotactic radiotherapy, which delivers the same 6-wk daily treatment but uses improved patient positioning for tighter treatment margins, has achieved CR and tumor control in 54% of patients (16). Linear accelerator-based SRS and GKRS series showed CR and tumor control in 43–56% of patients (17–24) treated with a single large radiation dose. Median time to CR has been relatively similar, consistently between 6 months and 2 yr. Our findings indicate that PSR has similar efficacy and timing to other radiation techniques. This similarity demonstrates a fundamental concept in the field of radiation oncology: the ability to deliver an adequate radiation dose to a target volume can be achieved by different techniques. The challenge lies in reaching this goal while optimally reducing the radiation dose to the normal surrounding tissue. Based on the proton vs. photon dose characteristics, PSR has several potential advantages over other radiation techniques. Protons deposit a radiation dose over a finite distance (called the Bragg peak) with essentially no exit dose beyond this region. In contrast, photons (GKRS and linear accelerator-based SRS) deposit a maximum dose at a specific depth, then continue to deliver an attenuated but significant dose to the remainder of the tissue traversed before the photon exits the patient. Because of this difference, the irradiated volume conforms more closely to the target with protons than photons (6). This allows the delivery of a desired treatment dose to the target volume while optimally reducing radiation of surrounding normal tissues. This selectivity has several potential benefits in the treatment of pituitary tumors. First, by reducing the optic apparatus dose, PSR may provide a radiosurgical treatment option when the proximity of the target volume to the chiasm is dose limiting for other SRS techniques. Second, the dose to the adjacent medial temporal lobes and vascular structures of the cavernous sinus is also reduced with PSR. Studies have suggested that irradiation of these tissues with conventional fractionated radiation increases the risk of long-term neurocognitive and cerebrovascular sequelae (25–28). Limiting the radiation dose to these tissues by using PSR may

FIG. 4. Pretreatment (closed circles) and the most recent posttreatment (open circles) UFC values for each CD patient treated with PSR. Note the log scale; normal ranges differed somewhat among laboratories.

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lower the incidence of these complications. Finally, the most notable difference using PSR is the reduction in the integral dose. Integral dose represents the summation of radiation dose received by all tissues in the patient and is generally considered to relate to the risk of radiation-induced neoplasia. Reports have demonstrated an increase in the incidence of secondary brain tumors in areas previously irradiated using conventional fractionated radiotherapy for pituitary tumors (29 –33). The most common tumors described after pituitary irradiation include malignant gliomas and meningiomas. The significant reduction in volume of normal tissue irradiated using PSR may reduce the risk for secondary tumors in this patient population. However, the median follow-up of 62 months in this series is not sufficient to confirm this hypothesis, given that the latency ranges from 5–34 yr in the literature (30); longer follow-up is needed. Fractionated stereotactic radiotherapy and other forms of SRS also significantly reduce the exposure of normal structures to radiation when compared with conventional fractionated radiation. Although PSR achieves the least exposure of these tissues to radiation, and, thus, in theory should result in the lowest incidence of long-term sequelae, the difference between techniques may be small and could require large numbers of patients followed for long periods to demonstrate any clinically significant difference. New pituitary deficiencies developed in 52% of patients in this series. This is somewhat higher than previously published radiosurgical series (17–24). Differences in the percentage of patients developing hypopituitarism after radiation could result from a number of factors. One contributing factor is that 30 of 38 patients (79%) in this series had two or more surgeries, and 58% already required replacement of at least one pituitary hormone before PSR. Patients who have undergone more extensive surgical treatment may have less functional reserve and could be more likely to develop future deficits with or without radiation. In addition, at our institution the entire sellar contents, including the adjacent portions of the cavernous sinuses, are targeted in all patients treated with PSR for CD. This approach has been adopted based on the theory and literature suggesting that surgical recurrence may result from microscopic seeding in the medial wall of the cavernous sinuses or dural invasion. By design, we intentionally make no attempt to use the improved targeting possible with protons to reduce the dose to the pituitary gland. Instead, the selectivity of proton technique is used to deliver a high dose to this larger target area to ensure adequate treatment while reducing the dose to the optic apparatus, adjacent neurovascular structures, and temporal lobe. Another potential factor is that the median time to pituitary deficit was 27 months (range 9 – 60) in the current series. The shorter follow-up reported in most of the aforementioned series would be unlikely to have detected some of these events; the one study with longer follow-up noted deficits in 67% of patients, some occurring more than 10 yr after treatment (20). Two patients developed new temporal lobe enhancement without clinical symptoms. Both had received prior conventional radiotherapy. In the recent publication describing the largest GKRS series to date, Jagannathan et al. (23) reported that two of three patients with prior fractionated radiotherapy developed


FIG. 5. Actuarial incidence of new pituitary deficits over time after PSR. Parentheses show the number of patients remaining at risk for new deficits at each time point.

new cranial neuropathies after GKRS. Both neuropathies occurred within 15-month treatment. In contrast, the two patients who developed new temporal lobe enhancement in the current series have been followed for 92 and 108 months after PSR, respectively, with no clinical evidence for cranial neuropathy or other deficit thus far. This highlights the fact that administering a second course of radiation may carry more risk. In addition, it indicates that although protons allow for substantially reduced irradiation to surrounding tissues, this dose is not zero and must be considered carefully. One limitation of this study was the length of follow-up (median 62 months). Although this represents the longest follow-up for any cohort treated with radiosurgery for ACTH-secreting adenomas in the modern era, additional follow-up is required to evaluate the long-term sequelae of pituitary irradiation using PSR and all other radiotherapy techniques. One of the basic principles of radiation oncology is to reduce the volume of normal tissue exposed to ionizing radiation while ensuring adequate tumor dosing. In this respect, PSR currently provides the best technique for achieving this goal. As the number of proton facilities in this country continues to increase, further data on PSR will become important in guiding clinical practice. Conclusions These results demonstrate that PSR is effective for patients with persistent corticotroph adenomas, with 58% of patients attaining biochemical control off all medication after a median follow-up of 62 months. Our findings indicate that PSR achieves biochemical control with low morbidity; longer follow-up is warranted to assess for late radiation-related sequelae.

Acknowledgments Address all correspondence and requests for reprints to: Jay S. Loeffler, M.D., Department of Radiation Oncology, Massachusetts General Hos-


pital, 100 Blossom Street, Cox 347, Boston, Massachusetts 02114. Email: [email protected]. Results from this work were presented in part at the 88th Annual Meeting of The Endocrine Society, Boston, Massachusetts, 2006 (Abstract 2259). Disclosure Statement: The authors have nothing to disclose.

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