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Modern Radiation Therapy for Pituitary
Adenoma: Review of Techniques and
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Outcomes
Tejpal Gupta1,2, Abhishek Chatterjee1,2
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Website:
www.neurologyindia.com

DOI: Abstract:
10.4103/0028-3886.287678
Pituitary adenomas are benign tumors arising in the adenohypophysis and comprise 8%–20% of all reported
PMID: primary brain tumors in the west. Transsphenoidal surgery with an aim to achieve complete tumor resection
xxxx is the recommended first‑line treatment for nonfunctioning as well as secretory pituitary adenoma. External
beam radiation therapy (RT) has been demonstrated to be an effective treatment modality for pituitary
adenoma, uncured by surgery and/or medical therapy, providing excellent long‑term local control (>90%),
but lower and variable rates (50%–80%) of biochemical remission in secretory tumors. The adoption of
pituitary RT in the community has been limited due to concerns regarding potential late toxicity and long
latency in normalization of hormonal hypersecretion. Over the years, technological advances in RT planning
and delivery have resulted in progressive conformation of high doses to the target tissues while sparing
adjacent neurovascular structures providing a favorable therapeutic index. The choice of RT technique
should be based on size, site, and availability of infrastructure and expertise, with no significant differences
between fractionated approaches and stereotactic radiosurgery (SRS). In contemporary clinical practice,
the recommended dose of fractionated RT for pituitary adenoma is 45–50.4Gy in 25–28 fractions delivered
over 5–6 weeks using modern high‑precision techniques. The recommended dose of SRS given in a single
fraction is 12–14Gy for nonfunctioning adenomas and 16–20Gy for secretory tumors. Late toxicity of pituitary
RT includes hypopituitarism, neurocognitive impairment, neuropsychological dysfunction, optic neuropathy,
cerebrovascular accidents, and second malignant neoplasms. Hence, RT in pituitary adenoma should be
offered only to patients with residual, recurrent, progressive, or high‑risk tumors with careful assessment of
the benefit‑risk ratio by an experienced multidisciplinary neurooncology team.
Key Words:
Pituitary adenoma, radiotherapy, secretory, stereotactic radiosurgery, toxicity

Key Messages:
Transsphenoidal surgery is recommended first-line treatment for pituitary adenoma. External beam radiation
therapy (RT) should be offered to patients with residual, recurrent, or progressive disease uncured by surgery
and/or medical therapy. RT is associated with excellent long-term local tumor control but somewhat lower and
variable rates of biochemical remission. Modern high-precision techniques have improved the therapeutic
index of irradiation.
Departments of
Radiation Oncology
1

and 2Neuro‑Oncology
Disease Management
Group, TMH/ACTREC,
Tata Memorial Centre,
Homi Bhabha National
Institute (HBNI),
Mumbai, Maharashtra,
India
Address for
correspondence:
Dr. Tejpal Gupta,
Radiation Oncology,
ACTREC, Tata
Memorial Centre, HBNI,
Kharghar - 410 210,
Navi Mumbai,
Maharashtra, India.
E‑mail: tejpalgupta@
rediffmail.com
P ituitary adenomas constitute a spectrum
of benign neoplasms arising in the
adenohypophysis that comprise nearly 8%–
20% of all reported primary tumors of the
brain and central nervous system in large
population databases from the west such
as the Central Brain Tumor Registry of the
United States (CBTRUS)[1] and Cancer Research
United Kingdom (CRUK). [2] Limited data
available from hospital‑based registry and large
single‑institution series suggest that pituitary
tumors comprise around 7%–10% of primary
brain tumors in India. [3] Although the new
This is an open access journal, and articles are distributed under the terms
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World Health Organization (WHO) system
provides a more refined and prognostically
relevant histological classification based on
the cell of origin, [4] traditionally they have
been broadly classified into nonfunctioning
pituitary adenomas (NFPA) without any
discernible hypersecretion of pituitary hormones
or functional/secretory pituitary adenomas with
evident hypersecretion of single or multiple
pituitary hormones (plurihormonal) for clinical
management. The disease primarily affects
adolescents and young adults in the prime
of their lives who remain at risk of several
side‑effects of the disease and its treatment with
How to cite this article: Gupta T, Chatterjee A.
Modern radiation therapy for pituitary adenoma:
review of techniques and outcomes. Neurol India
2020;68:S113-22.

© 2020 Neurology India, Neurological Society of India | Published by Wolters Kluwer - Medknow S113
 Gupta and Chatterjee: RT in pituitary adenoma
consequent negative impact upon health‑related quality of
life. Management of pituitary adenomas is best undertaken in
the context of a dedicated multidisciplinary neurooncology
team comprising neurosurgeons, radiation oncologists,
endocrinologists, and rehabilitation experts. Transsphenoidal
surgery with an aim to achieve complete tumor resection
and normalization of hormonal hypersecretion (biochemical
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remission) is the recommended first‑line treatment for pituitary
adenoma making it largely a neurosurgical disease with
relatively low incidence of surgical complications. However,
gross total resection can be achieved in only 50%–70% of patients
depending upon the size, location, tumor extensions, and
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 06/28/2024
available expertise and infrastructure. The rates of biochemical
remission can be lesser and even more variable necessitating
further adjuvant treatment for sustained cures. External
beam radiation therapy (RT) has been demonstrated to be an
effective treatment modality for pituitary adenoma, uncured
by surgery and/or medical therapy, irrespective of technique,
dose, or subtype, providing long‑term local tumor control
exceeding 90% at 5–10 years. However, time‑to‑normalization
of hormonal levels (ranging from several months to few
years) and biochemical remission rates in secretory adenomas
following RT have been reportedly variable (50%–80%) due
to differences in patient population, affected hormonal axes,
technique, dose, and changing definition of success. The
adoption of pituitary RT in the community has been limited
due to concerns regarding potential late toxicity and long
latency‑period in normalization of hormonal hypersecretion in
functional adenomas. Over the years, technological advances
in immobilization, imaging, treatment planning, delivery,
and verification have resulted in progressive conformation
of high‑doses of RT to the target tissues while sparing
adjacent neurovascular structures providing a favorable
therapeutic index. In parallel with these developments, medical
management of secretory pituitary adenomas has witnessed
remarkable advancements with availability of several newer
agents including dopamine agonists and somatostatin analogs
with promising rates of biochemical remission, particularly
in patients with prolactinoma and acromegaly. This article
provides an overview of current indications of RT, its biological
basis, contemporary RT workflow, and treatment planning
process followed by critical appraisal of the available evidence
of its efficacy and safety including author’s institutional
experience in pituitary adenoma.
Indications for radiation therapy
As stated before, the treatment of choice for NFPA remains
complete tumor excision followed by observation in case of no
radiologically discernible residual disease. The presence of a
small residue may also be amenable to close clinico‑radiological
surveillance with serial magnetic resonance imaging (MRI)
scans to potentially avoid or delay RT. However, such an
approach is associated with the risk of tumor progression in up
to 60% of cases, with profoundly increased risk of regrowth for
large tumors, tumors with extra‑sellar extension (particularly
into the cavernous sinus) and longer (15 years) follow‑up.[5‑7]
Upfront adjuvant RT in the setting of such subtotal resection
is associated with marked protection against tumor regrowth[5]
providing excellent long‑term local tumor control, [5,8] but
may be associated with increased risks of late morbidity
and mortality.[9] Careful and judicious case selection with
appropriate usage of optimal RT techniques is warranted
S114
to minimize irradiation of normal neurovascular structures
in the vicinity of the target volumes to achieve a favorable
benefit‑risk ratio. Clinical and/or radiological progression or
regrowth in subtotally resected tumors that were initially kept
on observation following surgery is another clear indication
for RT either after repeat surgery or directly if reexcision has
been ruled out. Finally, recurrent disease, i.e., reoccurrence
of tumor after documented gross total resection with no
discernible residue on postoperative MRI (that may be seen
in nearly 25% of cases at 10 years) is also a valid indication
for RT. [5,7,10] The current indications of RT in NFPA are
residual, recurrent, and/or progressive tumor with the aim of
causing growth arrest and preventing further progression. In
comparison, the aim of RT in functional pituitary adenomas
is two‑fold to cause growth arrest to provide local tumor
control as well as result in normalization of hormonal
hypersecretion to achieve biochemical control which can vary
according to the involved hormonal axis and prior medical
management. Presently, RT is an integral component in the
multimodality management of uncured Cushing’s disease
due to adrenocorticotrophic hormone (ACTH)‑secreting
corticotrope adenoma; acromegaly/gigantism due to growth
hormone (GH)‑secreting somatotroph adenoma; and rarely
if ever, in amenorrhoea‑galactorrhoea syndrome due to
prolactin (PRL)‑secreting lactotroph adenoma after failure
of medical therapy. Similar principles of management apply
to gonadotroph and thyrotrope adenomas which are rarely
encountered in clinical practice. Upfront adjuvant RT should
also be considered in patients with adverse features such as
high proliferative index, atypical histology, or invasion, that
may be associated with a higher risk of local recurrence after
surgery alone. Finally, definitive RT may be the only curative
treatment option for elderly patients who refuse surgery or
deemed as medically inoperable due to comorbidities.
Principles of radiation therapy
Biological basis of radiation therapy: The most widely used
form of RT in oncology are photons or high‑energy X‑rays
which belong to the spectrum of electromagnetic radiation.
Photons are indirectly ionizing form of radiation that ionize
the molecules by release of free electrons (predominantly
by Compton effect in the therapeutic range). The ultimate
biological effect is double‑strand DNA damage which is lethal
to the cell. The damaging effects of irradiation are seen both in
cancer cells as well as normal cells. The better ability of normal
cells and tissues to undergo repair in between the fractions as
opposed to cancer cells (due to defective and dysregulated
repair mechanisms in cancer cells) forms the biological basis
of fractionation in RT. Conventionally fractionated RT refers
to the delivery of 1.8–2Gy per fraction, one fraction per day,
five fractions per week over a continuous course of 5–6 weeks
to an appropriate and desired dose. The term stereotactic
radiosurgery (SRS) is reserved for the delivery of a highly
precise and focused dose of irradiation (typically >12–20Gy) to
a well‑defined intracranial target volume, commonly as single
large fraction (but increasingly in 2–5 fractions) with high
spatial accuracy under stereotactic guidance. The radiobiology
of high doses per fraction (>10Gy) is quite different from
conventional fractionation with endothelial cell damage and
direct activation of apoptotic pathway playing additional roles
in cell kill. Particle beam radiation such as protons and heavy
ions are directly ionizing radiation modalities that have gained
Neurology India | Volume 68 | Supplement 1 | May-June 2020
 Gupta and Chatterjee: RT in pituitary adenoma
popularity due to their inherently superior physical depth‑dose
characteristics as well as radiobiological advantages. Heavy
ions (carbon, helium) produce dense ionizations in DNA
leading to more effective cell kill with resultant higher relative
biological effectiveness.
Workflow, process, and treatment planning: The workflow
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of RT planning, delivery, and verification in contemporary
neurooncologic practice is represented graphically in Figure 1.
The process of treatment planning begins with patient
positioning and immobilization. For cranial irradiation, every
single patient is positioned in the supine position on a suitable
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neck rest with the head immobilized using a customized
thermoplastic mask. The use of invasive stereotactic frames or
relocatable stereotactic masks further improves spatial accuracy
allowing the use of conservative set‑up margins. The primary
imaging of choice for RT planning is the planning CT scan
since it provides information regarding electron density of
different tissues and forms basis of dosimetry calculations. For
precise anatomical delineation of various target volumes and
organs‑at‑risk (OARs), the planning CT dataset should be fused
with a volumetric MRI sequence, typically T1‑post‑contrast
three‑dimensional (3D)‑fast‑spoiled gradient echo (FSPGR)
or equivalent. For NFPA, any grossly visible tumor is
delineated as gross tumor volume (GTV). There is no specific
need for defining a clinical target volume (CTV) in NFPA to
encompass microscopic extension of disease given its benign
nature, well‑defined margins, and lack of infiltration/invasion.
However, in view of potential uncertainties in GTV delineation,
errors in multimodality fusion, and particularly in the presence
of cavernous sinus invasion, it is recommended to use an
isotropic margin of 3–5 mm around the GTV, which should be
edited away from natural anatomic barriers to create the CTV.
In patients with functional/secretory pituitary adenoma, gross
tumor may or may not be visible on imaging, with microscopic
Figure 1: Contemporary radiation therapy workflow and process of treatment
planning
Neurology India | Volume 68 | Supplement 1 | May-June 2020
tumor cell rests being responsible for persistently elevated
hormonal levels in the absence of visible tumor. Consequently,
the entire sella should be included in the CTV to encompass
any residual cell rests. An isometric expansion of the CTV
by 3–5 mm [11] defines the planning target volume (PTV)
to account for geometric uncertainties and set‑up errors
expected during a course of fractionated RT. However, robust
immobilization using stereotactic frames/masks and daily
volumetric image‑guidance with online correction protocol
can help reduce CTV to PTV margins without compromising
tumor control.
Treatment techniques and recommended doses: Given that
pituitary adenomas are located deep in the midline, it brings
in the challenge of delivering the desired dose of RT to
the delineated target volume in the sella/supra‑sellar and
para‑sellar regions while minimizing dose deposited in the
pathway of irradiation and areas beyond (photons undergo
attenuation as function of distance). This can sometimes get
further complicated by the complex, irregular shapes and
large treatment volumes. Historically, pituitary adenoma
was treated on simple bony landmarks with relatively
simple field arrangement typically parallel‑opposed portals
or three‑field technique (bilateral and anterior) with no
major emphasis on shielding of normal brain tissues. The
advent of linear accelerators with high‑energy photons have
resulted in the replacement of the older generation telecobalt
machines (with fixed lower energy photons) across the world.
The integration of multileaf collimators (MLCs) on modern
linear accelerators has paved the way for beam‑shaping to treat
irregular‑shaped tumors and prompted a paradigm shift from
two‑dimensional (2D) techniques to the era of 3D‑conformal
RT (3D‑CRT). Computerized treatment planning allows the
use of multiple MLC‑shaped beams with more complex field
arrangement including noncoplanar beams from various
directions with dosimetric advantage of reducing the volume of
normal brain tissue irradiated to medium to high (50%–100%)
doses of RT.[12] Further improvements in treatment planning
have been made possible by the use of intensity‑modulated
radiation therapy (IMRT), wherein beam intensities are varied
using computerized algorithms to achieve a sharp dose fall‑off
resulting in the desired dose‑distribution delivering high doses
to the target volumes while maximally sparing the surrounding
OARs. IMRT allows for exquisite sculpting of dose away from
important regions of the brain such as hippocampus and
surrounding neural stem‑cell niche, which can potentially
alleviate long‑term neurocognitive dysfunction. Figure 2 is an
illustrative case example of the comparative dose distributions
of 2D‑RT, simple 3D‑CRT, complex 3D‑CRT, and IMRT in
a patient with GH‑secreting pituitary adenoma. Indeed,
preliminary data from the authors’ institution suggests that
hippocampal‑sparing IMRT preserves neurocognitive function
at least in the short term in patients of pituitary adenomas.[13]
The recommended dose of fractionated RT in pituitary adenoma
is typically between 45 and 50.4Gy in 25–28 fractions delivered
over 5–5.5 weeks, with lower doses (45Gy) representing an
optimal balance of growth‑restraint and tolerance of the optic
apparatus. In addition, there is no demonstrable dose‑response
curve beyond 45Gy.[14] Advancements in RT delivery, such as
on‑board imaging within the treatment room also referred to
as image‑guided radiation therapy (IGRT) allows volumetric
verification on a daily basis immediately prior to every fraction
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 Gupta and Chatterjee: RT in pituitary adenoma
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a b c d

e f g h
Figure 2: Dose wash (ranging from 50%–100%) through the axial section (upper panel) and sagittal section (lower panel) of a patient with growth hormone (GH)‑secreting
pituitary adenoma comparing two‑dimensional radiation therapy (2D‑RT) using bilateral open fields (a and e); simple three‑dimensional conformal radiation therapy (3D‑CRT)
using MLC‑shaped three‑field technique (b and f); advanced 3D‑CRT using multiple noncoplanar fields in a complex geometry (c and g); and intensity modulated radiation
therapy (IMRT) using rotational techniques (d and h). Note the progressive conformation of the medium to high‑doses (50‑95%) from 2D‑RT to 3D‑CRT and IMRT in axial and
sagittal sections

with ability to correct translational and rotational positioning
errors with submillimetric accuracy further improving the
spatial accuracy of treatment delivery.
SRS is usually reserved for small adenomas (typically <2–3 cm)
which are well defined and are located away from the optic
chiasm (≥3 mm). The Leksell GammaKnife (Elekta AB,
Stockholm, Sweden) is a dedicated SRS system comprising
180–201 miniaturized radio‑active cobalt ( 60Co) sources
arranged in a hemispherical array wherein the emitted ionizing
radiation is focused via means of primary and secondary
collimation to achieve extreme degree of conformality
for small intracranial targets with excellent sparing of
surrounding normal critical structures. A more recent and
exciting development is the creation of a robotic radiosurgery
system by mounting a linear accelerator on a robotic arm
called CyberKnife (Accuray Inc, Sunnyvale, CA, USA) which
allows for an extreme degree of conformality due to the
potential of few hundred noncoplanar beam trajectories in
conjunction with a robotic couch (integrating all six degrees
of freedom) and stereoscopic image‑guidance during delivery.
An alternative approach more suitable for centers catering to
a diverse population for a variety of benign and malignant
diseases is the use of linear accelerator‑based SRS wherein
the incident beam is conformally shaped by either fixed or
removable variable apertures (microMLCs, collimators, or
cones) to allow a high degree of conformality for efficient
delivery of radiosurgical treatments. The recommended dose
of SRS in pituitary adenoma ranges from 12–20Gy[15‑17] given in
a single fraction, with higher doses (16–20Gy) being preferred
in functioning/secretory adenomas, while keeping the dose
to optic chiasma constrained to a maximum dose (Dmax)
of <8–10Gy. In recent times, hypofractionated SRS delivering
5–8Gy per fraction in 3–5 fractions over 1–2 weeks has emerged
as an alternative radiosurgery schedule in pituitary adenoma.
The use of with particles (protons and heavy ions) is a
particularly attractive option for pituitary adenomas due to
the inherent physical characteristics of such beams whereby
dose deposition in normal tissues both proximal and distal
to the target is negligible on account of the Bragg peak,
hence reducing RT‑induced late effects, particularly second
malignancies. Proton therapy has been used to treat patients
in single institutional series with high rates of local control.[18,19]
However, limited availability, accessibility, and affordability
preclude its usage in the vast majority of patients across
the world. Longer and mature follow‑up on the available
proton literature with regards to the incremental benefit of
neurocognitive preservation and mitigation of long‑term
toxicities is likely to clarify its role in the future.
Evidence for efficacy of radiation therapy
The quality of evidence for efficacy of RT in pituitary adenoma
is modest, being generally based on large single‑institutional
retrospective analyses and unmatched comparisons with
surgical series with no prospective multiinstitutional
cooperative group studies or randomized controlled trials to
guide therapeutic decision‑making. In a study comparing two
neurosurgical institutions with very similar RT set‑up, Gittoes
et al. reported actuarial progression‑free survival (PFS) of 93%
at 5, 10, and 15 years for patients treated with RT (n = 63) and
68%, 47%, and 33% for those not receiving upfront RT (n = 63)

S116 Neurology India | Volume 68 | Supplement 1 | May-June 2020

 Gupta and Chatterjee: RT in pituitary adenoma

based on physician discretion and institutional bias.[20] Park
et al. reported 10‑year recurrence rates of 2.3% in 44 patients
receiving immediate postoperative RT, compared to 50.5% in
132 patients treated with surgery alone indicating excellent
efficacy of adjuvant RT for reducing the risk of local recurrence
and improving local control.[21]
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effective in causing growth arrest of tumor, providing long‑term
local control in >90% of patients with functional/secretory
pituitary adenoma. However, it is somewhat less efficacious
in controlling hormonal hypersecretion with resultant
normalization of serum levels (50%–80%), which varies
according to the affected hormonal axis, RT technique, definition
of biochemical remission, and continued use of suppressive

Nonfunctioning pituitary adenoma: Much of the data on
efficacy of irradiation in NFPA comes from fractionated RT
doses of 45–55Gy delivered at 1.8–2.0Gy per fraction using
conventional 2D/3D techniques of the 1960‑80s with reported
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medications. In general, biochemical remission is achieved in
50%–70% of ACTH‑secreting tumors, 60%–75% of GH‑secreting
tumors, and 40%–60% of PRL‑secreting tumors. Urinary free
cortisol levels typically normalize by 6–12 months, whereas

local tumor control rates ranging from 80%–90% at 10 years and
75%–90% at 20 years. The largest study of conventional RT in
pituitary adenoma (n = 411) comes from the Royal Marsden
Hospital, which reported a 10‑year and 20‑year PFS of 97%
and 92%, respectively.[22] The advent of modern high‑precision
techniques such as FSRT in 1990s and IMRT since the turn
of the century has completely changed contemporary
neurooncologic practice. The use of FSRT/IMRT to a dose of
45–50.4Gy in 25–28 fractions is associated with local control
rate of >90% at 5–10 years. SRS in appropriately selected cases
of NFPA provides very high rates of local control (>90%–95%
at 3–5 years), though longer‑term data (beyond 5 years) is
presently lacking. Selected large series reporting outcomes
of RT (conventional, FSRT/IMRT, and SRS) in NPFA are
summarized in Table 1.
Functional/secretory pituitary adenoma: Similar to NFPA,
fractionated RT (conventional, conformal, FSRT/IMRT) is very
plasma cortisol levels normalize somewhat later, with a median
time to normalization of about 24 months.[35] Normalization
of GH levels typically takes up to 2 years, while insulin‑like
growth factor‑1 (IGF‑1) takes longer to normalize.[35,36] PRL
levels typically take much longer times to normalize and
may benefit from addition of dopamine agonists. [37] At
the author’s institution, conventionally fractionated RT to
a dose of 45Gy/25 fractions over 5 weeks using modern
high‑precision techniques (3D‑CRT/FSRT/IMRT) have been
used in uncured secretory pituitary adenoma for the last two
decades with 100% local control at 5 years and encouraging
rates (55%–75%) of endocrine control. Biochemical remission
in Cushing’s disease (defined as low‑dose dexamethasone
suppressed cortisol level of < 50 nmol/L) was achieved in 15
of 20 patients with ACTH‑secreting tumors with new‑onset
hypopituitarism in 40% of patients.[38] Updated analysis of a
larger cohort of patients with persistent or recurrent Cushing’s
disease demonstrated biochemical remission in 29 of 42 (69%)

Table 1: Selected series reporting outcomes of radiation therapy (RT) in non-functioning pituitary adenoma
Author[ref] Number of patients MedianRT Median follow- Local tumor control Hypopituitarism(%) Visual deficits
(N) dose up (%) (%)
Conventional/conformal RT techniques
Brada*[22] 411 45Gy 10.5 years 10-years: 94% 30% at 10-years 1.5%
20-years: 88%
Tsang[23] 160 45Gy 8.3 years 10-years: 87% 23% 0%
Zierhut*[24] 138 45.5Gy 6.5 years 95% (time NR) 27% 1.5%
Gittoes[20] 126 45Gy 7.5 years 10-year: 93% Not reported (NR) NR
15-year: 93%
Breen [25] 120 46Gy 9 years 10 year: 87.5% NR 1%
Scheick*[26] 116 45Gy 9 years 10 year: 96% 25% 2%
Fractionated stereotactic radiation therapy (FSRT)/intensity modulated radiation therapy (IMRT)
Minnitti[27] 68 45Gy 75 months 5-year: 97% 40% at 5-years 3%
10-year: 91%
Wilson[28] 67 50Gy 60 months 5 year: 93% 7% 1.5%
Colin[29] 63 50Gy 6.8 years 100% at 6.8 years 35% at 8-years 0%
GammaKnife (GK)-based stereotactic radiosurgery (SRS)
Sheehan[30] 512 16Gy 36 months 5-year: 95% 21% 7.9%
Starke[31] 140 18Gy 50 months 5-year: 97% 30.3% 0%
Liscak[15] 140 20Gy 60 months 5-year: 100% 2% 0%
Park[32] 125 13Gy 62 months 5-year: 94% 24% 0.8%
Mingione[33] 100 18.5Gy 45 months 92.2% (time NR) 19.7% 0%
Linear accelerator (linac)-based SRS
Wilson[28] 51 14Gy 50 months 100% (time NR) 0% 0%
Voges[34] 37 13.4Gy 56 months 100% (time NR) 12.3% 1.4%
Runge[35] 61 13Gy 83 months 98% (time NR) 9.8% 0%
*Series includes some patients with secretory adenomas

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 Gupta and Chatterjee: RT in pituitary adenoma

patients. However, 6 (20.7%) of these 29 patients developed
biochemical recurrence after documented initial remission
following fractionated RT, exclusively seen in patients receiving
cabergoline around the time of RT.[39] Biochemical remission in
GH‑secreting adenomas defined as normalization of both GH
and IGF‑1 levels was achieved in 20 of 36 (55%) patients at a
median of 63 months, with new‑onset hypopituitarism seen
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and anorexia may be experienced by a small proportion
of patient undergoing fractionated RT that rarely if
ever, warrants prophylaxis. However, patient receiving
single fraction SRS are typically premedicated with
steroids and antiemetics to reduce any such event. The
main concern with delivery of RT in benign tumors like
pituitary adenoma is the fear of late irreversible side‑effects

in 33% of patients.[40] including but not limited to hypopituitarism, neurocognitive

Local control (>90%) and biochemical remission
rates (50%–80%) with SRS are also similar to fractionated RT in
Cushing’s disease, acromegaly, and prolactinoma. It has been
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and neuropsychological dysfunction, optic neuropathy,
cerebrovascular accidents (CVA), and second malignant
neoplasms (SMN) with attendant risks of increased morbidity
and even mortality.[54] However, most of the data on long‑term

demonstrated by some reports that reduction of hormonal
hypersecretion, particularly cortisol and less commonly for
GH/IGF‑1 starts earlier leading to faster biochemical remission
with SRS compared to fractionated RT. However, most of this
data comes from retrospective and unmatched comparisons
with inherent selection bias toward radiosurgical series
representing smaller tumor volumes and resultant lower
baseline hormonal levels compared to fractionated RT. It
has also been observed that the hormonal response to SRS is
diminished in patients on medical management of hormonal
hypersecretion, leading to the recommendation of temporary
discontinuation of suppressive medications 6–8 weeks prior
to planned SRS. More recently, biochemical recurrence after
initial remission have been reported in patients receiving
and continued on cabergoline for ACTH‑secreting pituitary
adenoma during fractionated high‑precision RT.[39] It is
therefore recommended that medical management be withheld
temporarily prior to SRS/RT in functioning/secretory
adenomas. Selected large series reporting outcomes of
fractionated RT and SRS in patients with secretory adenomas
by hormonal axis (ACTH, GH, and PRL) are summarized in
Tables 2‑4 respectively.
Toxicity of radiation therapy
Clinically apparent acute toxicity is extremely uncommon
during RT for pituitary adenomas due to lesser overall dose
delivered in conventional fractionation (45Gy–50.4Gy in
25–28 fractions) and very small volume being irradiated
in SRS. Nonetheless, mild self‑limiting nausea, vomiting,
mortality pertains to older RT techniques irradiating large
volumes of normal brain tissues, which is no longer practiced
and of historical importance alone. The following section
summarizes the significant late toxicities encountered after
pituitary irradiation in the context of available evidence.
Hypopituitarism: New‑onset hypopituitarism or worsening
of preexisting hormonal deficits is the most common toxicity
of pituitary RT, that affects the GH, cortisol, thyroxine,
and/or gonadal hormones in 20%–30% of patients by 5 years
and 30%–60% of patients by 10 years after fractionated
RT,[22,23,45,51,55] necessitating long‑term endocrine surveillance.
The decline follows a typical pattern, with GH being the
earliest axis to be affected, followed by gonadal, steroidal,
and thyroidal axes. For SRS, large series have reported the
development of hormonal deficiencies in 24% of patients
at 2–4 years post therapy,[17,56] which increases to as high
as 80% at 10 years. [10,35] Possible measures to reduce the
incidence may include sparing of uninvolved pituitary gland
in well‑defined and lateralized adenomas and reducing the
volume of pituitary stalk/hypothalamus being irradiated,
though this needs careful clinical consideration and must
never be done at the cost of possibly jeopardizing disease
outcomes.[57] Recent reports suggest that mean dose of ≥ 27Gy
to the hypothalamic‑pituitary axis is associated with a
statistically significant (P = 0.038) increase in risk of endocrine
dysfunction with an odds ratio (OR) of 4.05 and 95% confidence
interval (CI) ranging from 1.07 to 15.62.[58]

Table 2: Selected series reporting on radiation therapy (RT) in ACTH-secreting pituitary adenoma
Author[ref] Number of Median RTdose Median follow-upLocal control and/or Hypopituitarism Visual deficits
patients (N) biochemical control (%) (%) (%)
Fractionated RT (conventional/conformal techniques)
Estrada[42] 30 50Gy 42 months 2-year control: 73% 48% 0%
Minniti[36] 40 45Gy 9 years 5-year control: 78% 62% 0%
10-year control: 84%
GammaKnife (GK)-based stereotactic radiosurgery (SRS)
Sheehan[43] 96 22Gy mean 48 months Local control: 98% 36% 5%
margin dose Biochemical control: 70%
Jagannathan[44] 90 25Gy tumor 45 months Tumor control: 96% 22% 5.5%
margin dose Biochemical control: 54%
Linear accelerator (linac)-based SRS
Voges[34] 17 15Gy 82 months Local control: 96.5% 12.3% 1.4%
Hormonal control: 51.5%
Devin[45] 35 15Gy 5.3 years Local control: 91% 40% 0%
Hormonal control: 49%
ACTH=adreno-cortico-trophic hormone

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 Gupta and Chatterjee: RT in pituitary adenoma

Table 3: Selected series reporting on radiation therapy (RT) in GH-secreting pituitary adenoma
Author[ref] Number of Median RTdose Median follow-upLocal control and/or Hypopituitarism Visual deficits
patients (N) biochemical control (%) (%) (%)
Fractionated RT (conventional/conformal techniques)
Jenkins[46] 656 45Gy 7years Biochemical control 58% at 10 years 0%
10-year: 60%
20-year: 77%
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Barrande[47] 128 52Gy 11.5 years Biochemical control 80% at 10 years Not reported
10-year: 53%
15 year: 66%
Jallad[48] 99 50Gy 5.9 years Biochemical control: 54% 47% 4%
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GammaKnife (GK)-based stereotactic radiosurgery (SRS)

Lee[49] 136 25Gy tumor 61 months Local control: 98.5% 31.6% 3.7%
margin Biochemicalcontrol: 73.3%
Franzin[50] 103 22.5Gy mean 71 months Local control: 97.3% 7.8% 0%
margin dose Biochemical control: 58.3%
Jezkova[51] 96 35Gy tumor 54 months Local control: 100% 27.1% 0%
periphery Biochemical control: 44%
Linear accelerator (linac)-based SRS
Voges[34] 64 15.3Gy (mean 54 months Local control: 97% 18% at 5 years 1.4%
dose) Biochemical control: 33%
GH=growth hormone

Table 4: Selected series reporting on radiation therapy (RT) inPRL-secreting pituitary adenoma
Author[ref] Number of Median RT doseMedian follow upLocal control and/or Hypopituitarism(%) Visual Deficits
patients (N) biochemical control (%) (%)
Fractionated RT (conventional/conformal techniques)
Tsang[52] 64 50Gy 7.3 years Local control: 96% at 10-yr 35% at 10 years Not reported
Biochemical control
RT alone: 39%
RT+ medical treatment: 56%
Erridge[53] 58 45Gy 9.1 years Local control: 97% at 10-yr 26% 0.8% at 10 yrs
Local control: 96% at 20-yr
GammaKnife (GK)-based stereotactic radiosurgery (SRS)
Wan[54] 176 >12Gy to the 67 months Local control: 90.3% 1.8 0
margin Biochemical control: 23.3%
Pan[55] 128 31.2Gy (mean) 41 months Local control: 99% Not reported 0
Biochemical control: 41%
PRL=prolactin

Neurocognitive dysfunction: Patients with pituitary adenoma
can develop neurocognitive and neuropsychological
dysfunction with impaired quality of life (QOL) both due to
the disease itself as well as late effects of therapy (surgical,
irradiation, and pharmacological). The prevalence of such
neurocognitive dysfunction is reportedly variable (15%–60%)
depending on population, setting, subtype, pharmacotherapy,
and exposure to RT, with the most commonly affected domains
being memory, attention, logic reasoning, and visuo‑spatial
abilities.[59] The consequent QOL impairment seen in nearly
25%–40% of patients leads to substantial work disability, with
the largest impact on social functioning in patients treated for
pituitary adenoma.[60]
Cerebrovascular accidents: Irradiation of pituitary adenomas is
associated with high doses to the cavernous segment of internal
carotid artery, either on one side or generally bilaterally due to
extension of disease or delineation of entire sell as target volume.
Irradiation of larger volume disease with supra‑sellar extension
may also result in irradiation of the circle of Willis. Irradiation
of these arteries predisposes them to accelerated atherosclerosis
which increases the risk of CVA and stroke. Large series of
historical cohorts have reported an increased risk of mortality
due to CVA with a relative risk (RR) of 4.11 (95%CI: 2.84–5.75;
P = 0.04).[61] However, more recent studies show that there
are no increased brain abnormalities in patients receiving RT
compared to patients treated without RT, including cumulative
incidence of cerebral atrophy, CVA, or cerebral infarction.[62]
Indeed, another study showed that RT was not associated with
an increased incidence of stroke or differences in causative
mechanism or anatomic localization of stroke as compared
to surgery alone in pituitary adenoma (RR = 0.62, 95%CI:
0.28–1.35; P = 0.23). The primary risk factors were preexisting
coronary or peripheral artery disease (RR = 10.4, 95%CI:
4.7–22.8; P < .001) and hypertension (RR = 3.9, 95%CI: 1.6–9.8;
P = 0.002).[63] The data on the incidence of CVA in patients of

Neurology India | Volume 68 | Supplement 1 | May-June 2020 S119

 Gupta and Chatterjee: RT in pituitary adenoma
pituitary adenoma treated with SRS is lacking; however, one
must always exercise caution while delivering high doses of
irradiation in the region of sensitive vascular structures.
Second malignant neoplasms: The prolonged survival of
patients with pituitary adenoma treated with RT predisposes
them to RT‑induced carcinogenesis and development
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of SMN. Long‑term follow‑up of patients has suggested
that cumulative risk of developing RT‑induced SMN is
1.3%–2% (95% CI: 0.9%–4.4%) at 10 years and 2.4% (95%CI:
1.2%–5%) at 20 years.[64,65] The average time‑latency before
the development of a SMN is 15.2 ± 8.7 years, emphasizing
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the need and importance of long‑term follow‑up.[66] The most
common RT‑induced SMNs are meningeal tumors (RR = 24.3)
and gliomas (RR = 7.0).[65] Gliomas and sarcomas have most
commonly developed in patients treated with large bilateral
open fields or simple three‑field arrangements without
shielding or beam‑shaping. [66] The widespread usage of
conformal techniques including IMRT may reduce the volumes
of normal tissue irradiated to higher doses, at the expense
of an increased “low‑dose bath” which has been postulated
to increase the incidence of second cancers.[67] Therefore, a
careful assessment of risk versus benefit with careful planning
to minimize low‑dose spillage is required in addition to the
long‑term surveillance. The risk of RT‑induced SMN, though
somewhat lesser, persists even with proton beam therapy,
especially in older facilities using passive scattering techniques
that lead to neutron contamination. Newer generation proton
facilities using modern pencil beam scanning technology may
help reduce this small, yet, significant risk of RT‑induced SMN
in patients with pituitary adenoma.
Optic neuropathy and injury to neural structures: The
risk of RT‑induced optic neuropathy injury is negligible in
fractionated RT with a reported incidence of 1% at 10 years
to 1.5% at 20 years [22,51] with current dose‑fractionation
recommendations (45–50.4Gy in 25–28 fractions). Even for SRS,
optic neuropathy occurs rarely, if Dmax to the optic chiasma is
restricted to <8–10Gy; the risk increases with increasing dose
to the chiasma reaching around 5% for Dmax of 12Gy.[68,69] The
risk of RT‑induced cranial neuropathy or symptomatic brain
necrosis with fractionated RT in pituitary adenoma is virtually
unknown, though incidents as low as 0.2% have been reported
in literature.[70]
Conclusions
Radiation therapy should not be considered as a first‑line
alternative to surgery or medical management in pituitary
adenomas, but should be offered to patients with residual,
recurrent, progressive, or high‑risk tumors with careful
assessment of the benefit‑risk ratio by an experienced
multidisciplinary neurooncology team. RT is an effective
treatment modality providing excellent (>90%) local control, but,
somewhat lower and variable (50%–80%) rates of biochemical
remission in functional/secretory tumors. Modern RT planning
and delivery allows a significant reduction of high‑doses of
doses to adjacent normal uninvolved neurovascular structures
compared to the older conventional techniques, which should
potentially reduce the risk of RT‑induced late toxicity. Both
fractionated RT and SRS achieve similar outcomes in terms
of long‑term local control and biochemical remission, with
S120
no evidence of superiority of one particular technique over
the other. The choice of RT technique should be based on
size (volume), site (anatomic location and extensions), and
availability of infrastructure and expertise. Finally, further
research in pituitary RT should focus on deriving robust
dose‑volume constraints of the hypothalamic‑pituitary axis
by correlating the dose to pituitary gland and stalk with
development of pituitary deficits, determining the optimal
dose‑fractionation schedules for different subtypes of pituitary
adenoma, and identifying imaging and molecular biomarkers
of tumor control and/or biochemical remission.[73]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Neurology India | Volume 68 | Supplement 1 | May-June 2020