Radiation Tech

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Radiation therapy in acromegaly

Helen A. Shih &Jay S. Loeffler

Published online: 14 December 2007# Springer Science + Business Media, LLC 2007

Abstract Radiation therapy is generally not a primary

treatment modality for growth hormone-secreting pituitaryadenomas. However, in patients with acromegaly refractory

to medical and/or surgical interventions, radiation can offer

durable tumor control and often biochemical remission.

Technique of radiation therapy delivery and dose vary by

adenoma size and extrasellar extension. Radiation can be

delivered in a single sitting by stereotactic radiosurgery or

in fractionated form of smaller doses delivered over

typically 56 weeks in 2530 treatments. A brief overview

of forms of radiation modalities is reviewed followed by

discussion of the role for radiation therapy, rationale of

delivery method, and potential adverse effects.

Keywords Radiation . Radiation therapy. Stereotactic

radiotherapy . Stereotactic radiosurgery. Gamma knife .

Proton radiation

1 Introduction

Modern radiotherapy for pituitary adenomas, including the

setting of acromegaly, utilize CT +/ MR scan-based

treatment planning. Equipment used and number of planned

treatments define the specific form of therapeutic radiation.

The term radiosurgery is used to define radiation delivered

at a high dose to a typically small target in a single or few

sittings. In contrast, fractionated radiotherapy refers to

radiation therapy delivered over multiple smaller doses inmultiple sittings. In order to minimize the dose to

surrounding tissue, techniques for stereotactic localization

can be employed such that the target is localized in a

coordinate reference system, usually by means of a frame

affixed to the head. There are a number of different forms

of radiosurgery in use, with radiation delivered as photons

(Gamma Knife, Linac, CyberKnife) or charged particles

(protons). Stereotactic radiotherapy (SRT) is a hybrid form

that has been developed which employs stereotactic

localization techniques with fractionated therapy.

2 Modalities of radiation therapy

2.1 Stereotactic radiosurgery

2.1.1 Gamma knife radiation therapy

The first form of stereotactic radiosurgery to be developed

is the Gamma Knife (GK; Elekta, Stockholm, Sweden).

High dose radiation is delivered with fine precision to an

intracranial target in a single sitting. This treatment unit

was first envisioned by Lars Leksell, MD, a Swedish

neurosurgeon in 1951, who opened the first clinical

treatment facility in 1968. Although its initial indica-

tion was to treat vascular lesions in the brain by a

nonsurgical method, its use has expanded to include

treatment of other small intracranial targets such as brain

metastases and pituitary adenomas. GK utilizes cobalt-60, a

radioactive isotope, as its radiation source. In its most

common design, a total of 201 sources of 60Co are

distributed in a hemisphere. A metal frame for the patients

head provides a bridge between the radioactive sources and

Rev Endocr Metab Disord (2008) 9:5965

DOI 10.1007/s11154-007-9065-x

H. A. Shih (*) :J. S. Loeffler

Department of Radiation Oncology,

Massachusetts General Hospital,

100 Blossom St, Cox 3,

Boston, MA 02114, USA

e-mail: [email protected]

J. S. Loeffler

e-mail: [email protected]


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the patient. The bores in the metal frame vary in size and

determine the width of the radiation beams. 60Co has a half-

life of 5.25 years and emits photons of an average energy of

1.25 MV. Its low megavoltage energy is ideal for limited

tissue penetration such as in the head. The dose gradient

between high and low doses is very narrow such that small

targets can be treated to high doses yet may be adjacent to

radiation-sensitive structures that will receive a negligibledose. These high dose spots permit delivery of highly

conformal treatments by treating clusters of spots that create

the shape of the target. The dose heterogeneity between the

edge of the treatment margin and the center of each

pinpointed target is typically a 50% dose gradient and this

can be either very useful or sometimes harmful depending

upon the irradiated tissue. GK is the most widely published

radiosurgical methodology used to treat pituitary adenomas.

2.1.2 Linear accelerator-based stereotactic radiosurgery

The most common technological equipment used today todeliver therapeutic radiation is the linear accelerator (linac).

Energy is accelerated, shaped, and delivered in the form of

electrons. More commonly, the energy is converted to

photons. Linacs have been adapted to deliver stereotactic

treatments using small beams of photon radiation delivered

in arcs to a fixed target of limited size in the head [1].

Linac-based SRS in the treatment of pituitary adenomas has

been reported with comparable efficacy to GK in the

literature [2, 3]. In this system, an adapted form of a

neurosurgical stereotactic frame is used and involves

stabilization pins that fix the halo-shaped frame to the

cranium, typically using four pins above the level of the

brow. Local anesthesia is administered to ease the discom-

fort of pin placement. Frame placement can be performed in

the outpatient setting with the patient sitting upright. A

radiation treatment planning CT scan is subsequently

obtained with the frame now fixed to the patients head.

The frame attaches to the CT scanner patient platform in

similar manner as it does to the linear accelerator during

treatment. In SRS planning, MRI scans are frequently used

to facilitate treatment planning by fusing the images to the

CT data set, although this is rarely necessary when

targeting the pituitary. Radiation delivered by linac-based

SRS is more homogeneous in dose as compared to GK; this

is helpful in avoiding high dose heterogeneity when

irradiated targets include radiation-sensitive normal tissues.

Because treatment is delivered as moving arcs of radiation

beams around a central axis, the treatment volume is quasi-

spherical or elliptoid and can have an inferior conformality

when treating irregularly shaped targets as compared to GK.

This has been partially resolved by dividing the focus of

treatment into targeting multiple adjacent spots (isocenters)

in linac-based SRS delivery.

2.1.3 CyberKnife radiosurgery

CyberKnife (CK; Accuray, Sunnyvale, CA) is a relatively

new technological advancement in radiation therapy in

which a miniaturized low energy linear accelerator is

mounted on a robotic arm. It allows for frameless image-

guided radiation treatments in either single or multiple

fractions. Unlike GK and standard linac-based radiosurgery,it has the capacity to deliver large doses of radiation to

extracranial targets due to the real time image-guided

treatment delivery. Treatment times are lengthened with

complexity and size of the target thus it is best suited for

small lesions to be treated in one or few fractions.

2.2 Stereotactic radiotherapy

Stereotactic radiotherapy (SRT) is linac-based stereotactic

treatment modified to deliver fractionated doses. SRT

commonly utilizes the same planning system as SRS but

with the primary difference of an alternate form ofimmobilization technique. Instead of the SRS frame that

involves invasive pins fixed to the head, SRT most

commonly uses a dental mold attached to a stereotactic

frame. This set up can be replicated daily with no

discomfort to the patient. Customized head molds can also

be made in the cases of edentulous patients. Fractionation

schedules most commonly used to treat pituitary adenomas

are 1.82.0 Gy per treatment, similar to other fractionated

radiation therapy although hypofractionated schemes (e.g.,

5 Gy for sev en fractio ns) can also b e u sed when

appropriately medically indicated.

2.3 3D-conformal radiation therapy

Conventional linear accelerator-based treatment has long

been used to treat pituitary adenomas. Most centers without

stereotactic capabilities will use 3D-conformal radiation

therapy (3D-CRT), the most widely available form of

radiation treatment. It utilizes CT-based planning methods

similar to stereotactic forms of delivery but employs

immobilization and planning systems that have slightly

less stringency in set up replication. A custom mask of the

head is made during the planning process that utilizes a

thermoplastic mesh that molds to the patients facial

contour and attaches directly to the treatment machine. As

with other forms of immobilization, the mask serves to

keep the head in the same position for each treatment and

minimizes head rotation and chin tilt variation. It provides

an easy and replicable method for patient positioning; this

technique is widely used but does not yield the same degree

of firm immobilization as the techniques used in GK or

linac-based SRS or SRT. To account for the potentially

larger variation in positioning in 3D-CRT, a set up error

60 Rev Endocr Metab Disord (2008) 9:5965


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margin is included into the planned treatment volume that

results in a significantly larger radiation target as compared

to stereotactic methods. A variety of treatment beam

directions can be used with two to four fields most

commonly employed. Volume of neighboring tissue irradi-

ated and dose to these areas are higher as compared to

stereotactic methods. Because of the larger treatment

volume, treatment delivery is always fractionated. Totaldoses required to control pituitary adenomas are generally

within the accepted tolerances of the surrounding normal

tissues. Thus, 3D-CRT is a very effective and acceptable

alternative therapy when more advanced technological

alternatives are not available.

2.4 Intensity modulated radiation therapy

Intensity modulated radiation therapy (IMRT) is another

relatively recent technological advancement in radiation

therapy delivery. It also relies on 3D-based image planning.

Linear accelerators are adapted to delivering variableradiation dose to each point within a radiation field. While

the radiation output from the machine is still constant, there

are active moving slivers of heavy metal in the path of the

radiation beam that will determine the shape of the

radiation field by blocking transmission in the area it

extends. These leaves of metal can entirely block the path

of the beam when closed together. By opening to

predetermined settings, variable amounts of radiation can

pass through and thereby shape the radiation field and the

dose delivered at any given spatial point. The result is a

more highly conformal treatment to the target and compar-

atively much lower radiation exposure to adjacent tissues

which may be particularly critical when irradiating lesions

adjacent to radiation-sensitive tissues. This technique is

thus useful in treating lesions in the region of the sella for

avoidance of excess dose to the optic chiasm, optic nerves,

and brainstem.

2.5 Proton radiation therapy

Particle radiation has been also applied successfully in

treatment of pituitary adenomas. Proton radiation has

similar biological effects to photon administration, but has

a distinct benefit in physical properties enabling far less

excess radiation deposition to surrounding non-target

tissues. Due to the complexity and expense of building

and maintaining such facilities, there are limited clinical

proton treatment facilities in the USA, although this number

has growing to five centers as of 2007 and is continuing to

increase. Proton radiation can be delivered in a single

fraction as proton stereotactic radiosurgery, or in multiple

fractions depending upon the clinical indication. While the

pattern of dose distribution is inherently more conformal

than photon-based systems and inherently felt to translate

into reduced treatment-related adverse effects, scarce

resources limit its current widespread use. The greatest

benefit of using protons in the treatment of pituitary

adenomas is in cases with larger target volumes, such as

in the presence of a macroadenoma that fills the sella or in

the setting of extrasellar extension. In such incidences,

similar radiation doses are administered with significantlyless radiation delivered to the surrounding normal tissues

as compared to photon-based methods.

3 Treatment of acromegaly with radiation

Radiation therapy provides a useful third line therapy for

acromegaly where surgery and medical therapy are unable

to achieve adequate hormonal response. However, efficacy

rates of treatments have seemingly decreased over the years

with the recognition of more stringent biochemical criteria

for curative acromegaly. This has likewise affected thereported complete response rates of radiation therapy in the

recent literature as compared to older reports.

3.1 Stereotactic radiosurgery for acromegaly

Efficacy of radiosurgery in the management of growth

hormone-secreting tumors is variable in the literature but

generally felt to be favorable [4]. A recent review of the

published radiosurgical literature that included 22 GK

series and three linac SRS reports cumulated a total of

420 patients with acromegaly who received marginal tumor

doses of 1534 Gy [4]. Definitions of endocrinologic cure

varied between studies and ranged between 0 and 100%.

One of the largest series consisted of 68 patients treated

with a mean margin dose of 31 Gy [5]. Normalization of

growth hormone level was achieved in 96% of patients at

24 months. This was more than double of their 12 months

response rate of 40%, indicating that endocrine response

following radiation therapy may require years to achieve its

full effect. Castinetti et al. [6] report on 82 patients with

acromegaly also treated with GK with tumor margin dose

range of 1240 Gy at mean follow up of 49.5 months and

achieved a 40% hormonal response in which either

complete remission was achieved or decreased GH secre-

tion could be effectively controlled by medical therapy.

Across multiple similar series, reported hormonal response

is variable whereas tumor growth local control is generally

95100% [4, 68].

Initial experiences with the application of CyberKnife

(CK) radiosurgery or hypofractionated radiotherapy in

treating patients with acromegaly are also promising. The

first report by Kajiwara et al. [9] included 21 patients with

pituitary adenomas of which seven patients had hormone-

Rev Endocr Metab Disord (2008) 9:5965 61


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secreting tumors. With a mean follow up of 35 months for

all patients, tumor control rate was 95.2%. Hormone

function improvement was documented in all seven patients

with functional adenomas and this included two patients

with acromegaly. Similarly, in a report of nine patients with

acromegaly that were all treated with CK to doses of 18

24 Gy in one to three fractions, four patients had already

achieved biochemical complete remission at a mean followup of 25.4 months [10]. An additional patient obtained

biochemical control with the addition of medical therapy.

Overall, these limited but initial CK experiences are

promising of not only the role for CK in the management

of acromegaly, but also the efficacy of hypofractionated

treatment schedules which may offer a reduced risk of

radiation-related adverse effects as compared to single

fraction radiosurgery.

Experience from proton radiation therapy is sparse due

to the limited number of treatment facilities, but proton

administration is expected to have superior dose delivery

and normal tissue sparing based upon the inherent physicalproperties of protons. An early report of the Massachusetts

General Hospital proton experience in treating acromegaly

established the efficacy of proton radiosurgery based upon

follow up of 14 patients with acromegaly with available

follow up [11]. Nine of these patients showed clinical and/

or biochemical response. In a recent update of the use of

proton radiation in acromegaly, we reported results in 22

patients with persistent acromegaly who were treated with

single fraction proton radiosurgery at a median dose of

20 GyE [12]. Of these, 95% have achieved at least a partial

response at 6 years and 50% have had a complete response.

Median time to complete response in those who responded

was 30.5 months. One-third of patients developed at least

one new pituitary deficiency, requiring corrective supple-

mentation. These data support a role for use of proton

radiosurgery over photon-based techniques, and a generally

favorable role for stereotactic radiosurgical modalities

overall.

3.2 Fractionated radiation therapy for acromegaly

Reports from fractionated radiation series also suggest

variable hormonal control. In one series of 36 patients with

acromegaly treated with fractionated therapy to 40 Gy, 69%

achieved normalization of GH at 10 years [13]. Milker-

Zabel et al. [14] report that administration of SRT to a

median dose of 52.2 Gy in 20 subjects with acromegaly

resulted in 80% GH normalization, with local tumor control

in 100%. Another fractionated series that included 17

patients with acromegaly treated to a median dose of

51 Gy and followed for a median of 8.2 years showed 80%

symptomatic improvement [15]. In a study of 47 patients

treated with conventional fractionated radiation to 45

50 Gy, progressive response to radiation over time with

GH normalization was achieved in 29% at 5 years, 52% at

10 years, and 77% at 15 years [16]. Local tumor control

was achieved in 95% at 15 years. Despite the multiple

reports suggesting the efficacy of radiation therapy in the

management of acromegaly, at least one report differs. In a

study that evaluated random GH and IGF-1 levels among

38 patients with acromegaly treated with radiation therapy,65% of patients achieved random GH levels below 5 mcg/L

off medical therapy at 5 years but only two patients (5%)

achieved normalization of IGF-1 [17]. IGF-1 levels did not

change to correlate with the decrease in GH levels,

suggesting normalized GH levels may be overestimating

the effectiveness of radiation. Differences in results be-

tween these studies may reflect the significant variability in

methodology among published reports, including differ-

ences of each institutional biochemical assays of GH and

IGF-1, differences in radiation therapy as prescribed by

physicians or limitations of technological hardware. Varia-

tion in patient population or selection bias may alsocontribute to differences and are inherent limitations of

retrospective studies.

In regards to results from fractionated proton radiation

therapy, reported data are limited to the experience from the

proton facility at Loma Linda [18]. These investigators

report on the treatment of 21 patients with functional

adenomas treated to a median dose of 54 GyE and followed

for a median of 47 months. Biochemical control was

achieved in 86% of patients. By questionnaire, 71% of

patients reported symptomatic improvement. Despite the

limited data following proton radiation therapy, the existing

data suggest at least an equivalent biochemical response

between fractionated proton and photon radiation.

3.3 Single versus fractionated radiation therapy

Overall, local control of tumor growth is similar between

fractionated and single fraction radiation therapy with rates

of approximately 95% at 5 years, similar to nonfunctioning

adenomas [4, 19]. In contrast, stereotactic radiosurgery

appears to produce a faster hormonal ablative response than

fractionated radiation [3, 8, 20]. The mean t ime to

hormonal normalization varies by studies but all show the

same relative trend of quicker response with single fraction

treatments. Mitsumori et al. [3] report mean time to

hormonal normalization of 8.5 and 18 months for linac-

based SRS versus fractionated SRT, respectively. One

comparative experience of patients with acromegaly

reported a mean time to hormonal normalization of both

GH and IGF-1 of 1.4 years for GK radiosurgery and

7.1 years for fractionated radiation [20]. Similarly, a recent

report of 54 patients with hormone-secreting adenomas

treated with either GK radiosurgery or fractionated radia-



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tion found a median time of complete biochemical

remission of 26 and 63 months, respectively [8]. Thus, in

those patients with no residual tumor within 35 mm of the

optic chiasm, radiosurgery is usually the preferred option

and is more convenient for patients. When the tumor is

closer than 35 mm to the chiasm or other critical structures

such as brain parenchyma or other cranial nerves, fraction-

ated radiation offers therapy with lower treatment-relatedlate effects than radiosurgery [3]. Treatments are typically

once daily, five treatments per week for 2530 fractions,

equating to 56 weeks.

3.4 Predictors of radiation response

Predicting response to radiation therapy is not well

understood but some suggestions have been made based

upon existing data. Baseline GH and IGF-1 levels prior to

irradiation correlate negatively with treatment suggesting

that disease activity may impede radiation efficacy [6, 21

23]. Recently, several investigators have observed thatconcurrent medical therapy during the time of radiosurgery

may decrease the probability of radiation response [6, 23

24]. Of note, these studies are not prospective randomized

trials and thus are subject to multiple biases. In addition,

this effect was not found in another study [21]. Neverthe-

less, based upon these results, the common recommenda-

tion is to withhold medical therapy at the time of radiation.

Another potential predictor of response may be radiation

dose. Higher doses have been correlated with faster

response [5, 10]. With a mean follow up of 34 months in

one study, 10 of 11 patients with acromegaly achieved

normoglycemia when treated to a radiosurgery dose of

>30 Gy as compared to only two of ten patients treated to

lower doses [5]. In the same study, similar striking differ-

ences in time to response were found with endpoints of

resolution of hypertension and reduction of tumor size.

4 Adverse effects of radiation therapy in the treatment

of acromegaly

Despite the plethora of new radiation therapy delivery

systems that achieve increasing accuracy and conformality

of radiation delivery, radiation-related adverse effects still

occur. Many manifestations today are the result of treat-

ments from the past with antiquated treatment technique

that applied much larger radiation treatment fields due to

limited technology in localization by imaging and to less

conformal radiation delivery techniques. Others are un-

avoidable given the nature of pituitary adenomas. Under-

standing the risks of radiation-related adverse effects is

important for determining individualized care and for

optimizing future advancements in therapy.

4.1 Hypopituitarism

Irradiation of the pituitary gland may lead to a high risk of

causing the loss of one or more hypothalamicpituitary

functions. The importance of regular, serial endocrinologic

evaluation is very important for timely detection of

hypopituitarism. The risk for a new hormonal deficiency

of one or more axes increases with time. In a previouslymentioned report of 36 patients with acromegaly treated

with fractionated 40 Gy, rates of hypopituitarism requiring

replacement were 29% at 5 years, 54% at 10 years, and

58% at 15 years [13]. Similarly, a series of 47 patients with

GH-secreting tumors treated with standard fractionated 45

50 Gy and with otherwise normal pituitary function prior to

irradiation has been reported by Minniti et al. [16]. New

hypopituitarism developed following irradiation at a rate of

57% at 5 years, 78% at 10 years, and 85% at 15 years,

distributed over gonadal, thyroid, and cortisol insufficiency.

Similar rates of hypopituitarism develop with either radio-

surgery or fractionated therapy [3].In attempt to characterize susceptibility to radiation-

associated hypopituitarism, increased dose to the pituitary,

pituitary stalk, and hypothalamus appear to correlate with

an increased risk of post-radiation hypopituitarism [19,25

26]. The effects of hypothalamic and stalk irradiation

should be considered and minimized during radiation

planning. Nonetheless, since hormonal deficiency may be

unavoidable and is correctable with pharmacotherapy, the

importance of life-long close surveillance should be

discussed with patients with acromegaly who receive

pituitary irradiation.

4.2 Cranial nerve injury

With current careful use of radiation therapy, treatment-

induced vision injury or blindness is uncommon. The

generally accepted threshold of single fraction radiation

tolerance to the optic system is 810 Gy, with 8 Gy

considered as a safe threshold. Rare occurrences of optic

neuropathy have been detected at a dose of 10 Gy [2728].

Leber et al. [27] experienced no cases of optic neuropathy

following radiosurgery doses of


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safe. Fractionated radiation is associated with substantially

lower risk of optic pathway injury with an estimate of 1.5%

at 20 years in one large series of 411 patients and no visual

complications are often reported in smaller series [3, 29].

Although fractionation can reduce the rate of radiation side

effects, the historical use of substantially larger treatment

volumes likely accounts for the 2% treatment-related vision

impairment reported in some series [3031].Injury to other cranial nerves as a result of radiation

therapy for pituitary adenomas is far less likely but may

occur with irradiation of nerves in the cavernous sinus [4].

Symptoms are frequently transient and are generally

avoidable because of current understanding that injury is

associated with significantly high doses such as >18 Gy

[2728]. Tishler et al. [28] found eight cases of cranial

neuropathies of which, two occurred on the background of

prior high dose irradiation, all others occurring at doses

>18 Gy, and at least three cases with symptoms that were

either temporary or intermittent. Patients with prior irradi-

ation or with co-morbidities such as baseline cranial nerveinjury, diabetes mellitus, and vascular disease likely define

an inherently higher risk population for nerve injury.

Fractionation remains an important means of decreasing

this risk when a high dose is delivered to nerves that are

unavoidably in the treatment field.

4.3 Second tumors

Radiation-related second tumors are both a rare occurrence

and a significantly reduced risk with implementation of

modern methods of treatment delivery. Risk for radiation-

induced neoplasm is low, but can be devastating when it

occurs. Older radiation delivery techniques have resulted in

data suggesting a second tumor risk of 23% at 1020 years

following radiation treatment [29, 32]. Most common

histologies of second tumors have been gliomas or

meningiomas. Current radiation techniques expose an

exponentially smaller volume of cranial tissue to radiation

and this is expected to reduce the second tumor risk

significantly.

4.4 Other adverse events

Brain edema and frank necrosis of the flanking temporal

lobes has been seen after radiation therapy, particularly with

the use of old radiation techniques that utilize large

treatment fields and deliver substantial dose to the

neighboring brain tissue [15]. Although much less com-

monly seen, radiographic brain parenchymal injury follow-

ing modern SRS has been occasionally described but

collectively reported at a rate of less than one percent [4].

These cases may be both clinically asymptomatic and self-

resolving [3,33]. Patients with prior irradiation appear to be

more susceptible to radiation-induced brain necrosis [4,33

34]. With current technological advancements of radiother-

apy techniques, it is expected that the significant reduction

of radiation treatment fields will translate into brain

necrosis being a rare occurrence.

Internal carotid artery stenosis appears to be both an

uncommon occurrence and poorly documented event

reported in only few series [33, 3536]. One long-termanalysis of 331 pituitary patients treated with fractionated

radiation reported 5, 10, and 20-year risks for cerebrovas-

cular accident of 4, 11, and 21%, respectively [35]. This

rate of stroke was equivalent to a relative risk of 4.1 as

compared to the normal population. Another review of 211

patients with acromegaly treated with fractionated radiation

using a traditional three-field technique found a significant

increase in the standardized mortality ratio (4.42) among

this cohort as compared to the local population [37]. The

increased mortality was due to cerebrovascular accidents.

Despite these potentially worrisome data, the lack of other

substantial data to support these findings, the lack of detailof the study population in these studies, and the use of less

conformal radiation techniques suggest that the true

incidence of vascular stenosis is much lower. Nonetheless,

it is prudent to minimize unnecessary irradiation of

neighboring tissues when possible to reduce any risks of

treatment-related adverse events.

5 Conclusion

Modern radiation therapy has evolved into a variety of

treatment delivery mechanisms that can be effectively

employed in the setting of surgically and medically

refractory acromegaly. Stereotactic radiosurgery is generally

the preferred treatment of choice when possible because of

excellent response rates in tumor control, faster hormonal

response, and patient convenience. In contrast, fractionated

radiation appears to offer similar response rates over a longer

time period but with minimization of injury to critical

structures when the tumor is in physical close proximity to

radiation-sensitive structures. Choice of radiation therapy

technique and dose requires an understanding of the clinical

history, tumor extensions, potential risks, and patient

preferences.

6 Key unanswered questions

Although most available literature supports the adjuvant use

radiation therapy in the management of residual acromegaly

following surgery and pharmacological therapy, reported

hormonal response rates are widely discrepant. This may be

due to study heterogeneity of patient population, available



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imaging, radiation dose, radiation fractionation, or radiation

technique. These details are yet to be elucidated. Predictors

of response to radiation treatment are also still poorly

understood. Thus, there are multiple unclear aspects of

radiation therapy that remain to be clarified. With the

increasing number of proton radiation facilities becoming

available in this era, the promising superior role of proton

radiation in the management of GH-secreting adenomaswill hopefully be soon defined.

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