Rev Endocr Metab Disord (2008) 9:5965

DOI 10.1007/s11154-007-9065-x

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 pituitary
adenomas. 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.

sittings. In contrast, fractionated radiotherapy refers to

radiation therapy delivered over multiple smaller doses in
multiple 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.

Keywords Radiation . Radiation therapy . Stereotactic

radiotherapy . Stereotactic radiosurgery . Gamma knife .
Proton radiation

2 Modalities of radiation therapy

2.1 Stereotactic radiosurgery
2.1.1 Gamma knife radiation therapy

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
H. A. Shih (*) : J. S. Loeffler
Department of Radiation Oncology,
Massachusetts General Hospital,
100 Blossom St, Cox 3,
Boston, MA 02114, USA
e-mail: hshih@partners.org
J. S. Loeffler
e-mail: jloeffler@partners.org

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 indication 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

60

the patient. The bores in the metal frame vary in size and
determine the width of the radiation beams. 60Co has a halflife 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 negligible
dose. 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 to
deliver 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 discomfort 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 quasispherical 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.

Rev Endocr Metab Disord (2008) 9:5965

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 imageguided 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 of
immobilization 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 seven fractions) can also be used 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

Rev Endocr Metab Disord (2008) 9:5965

61

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 irradiated and dose to these areas are higher as compared to
stereotactic methods. Because of the larger treatment
volume, treatment delivery is always fractionated. Total
doses 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.

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 significantly
less radiation delivered to the surrounding normal tissues
as compared to photon-based methods.

2.4 Intensity modulated radiation therapy

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 the
reported complete response rates of radiation therapy in the
recent literature as compared to older reports.

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 variable
radiation 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 comparatively 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

3 Treatment of acromegaly with radiation

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 secretion 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-

62

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 follow
up 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 physical
properties 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 supplementation. 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]. MilkerZabel 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

Rev Endocr Metab Disord (2008) 9:5965

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 between these studies may reflect the significant variability in
methodology among published reports, including differences of each institutional biochemical assays of GH and
IGF-1, differences in radiation therapy as prescribed by
physicians or limitations of technological hardware. Variation in patient population or selection bias may also
contribute 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 time 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 linacbased 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-

Rev Endocr Metab Disord (2008) 9:5965

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, fractionated radiation offers therapy with lower treatment-related
late 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 that
concurrent 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]. Nevertheless, based upon these results, the common recommendation 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 differences 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 treatments 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 unavoidable given the nature of pituitary adenomas. Understanding the risks of radiation-related adverse effects is
important for determining individualized care and for
optimizing future advancements in therapy.

63

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 previously
mentioned 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 radiosurgery or fractionated therapy [3].
In attempt to characterize susceptibility to radiationassociated 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, treatmentinduced 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 <10 Gy exposure to the
optic nerves, whereas there was an incidence of 26.7% and
77.8% of optic neuropathy following nerve doses of 10
15 Gy and 15 Gy, respectively. Tishler et al. [28] report 4
of 17 cases of new optic neuropathy following single doses
higher than 8 Gy and no visual injury among 35 patients
with optic nerves exposed to lower doses. However, cases
of vision injury have been reported with doses to the optic
pathways ranging between 0.7 and 12 Gy [5]. This is an
important reminder that radiation-related neural tissue
injury is stochastic, meaning the risks decrease with lower
doses but with no true threshold below which is it entirely

64

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 irradiation or with co-morbidities such as baseline cranial nerve
injury, 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.

Rev Endocr Metab Disord (2008) 9:5965

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

34]. With current technological advancements of radiotherapy 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-term
analysis of 331 pituitary patients treated with fractionated
radiation reported 5, 10, and 20-year risks for cerebrovascular 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 detail
of 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.

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 radiationinduced 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 commonly seen, radiographic brain parenchymal injury following 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 selfresolving [3, 33]. Patients with prior irradiation appear to be

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

Rev Endocr Metab Disord (2008) 9:5965

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 adenomas
will hopefully be soon defined.

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