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REVIEW ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 7  |  Page : 113-122

Modern Radiation Therapy for Pituitary Adenoma: Review of Techniques and Outcomes


Department of Radiation Oncology; Department of Neuro-Oncology Disease Management Group, TMH/ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Tejpal Gupta
Radiation Oncology, ACTREC, Tata Memorial Centre, HBNI, Kharghar - 410 210, Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.287678

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 » Abstract 


Pituitary adenomas are benign tumors arising in the adenohypophysis and comprise 8%–20% of all reported primary brain tumors in the west. Transsphenoidal surgery with an aim to achieve complete tumor resection 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.


Keywords: Pituitary adenoma, radiotherapy, secretory, stereotactic radiosurgery, toxicity
Key Message: 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.


How to cite this article:
Gupta T, Chatterjee A. Modern Radiation Therapy for Pituitary Adenoma: Review of Techniques and Outcomes. Neurol India 2020;68, Suppl S1:113-22

How to cite this URL:
Gupta T, Chatterjee A. Modern Radiation Therapy for Pituitary Adenoma: Review of Techniques and Outcomes. Neurol India [serial online] 2020 [cited 2020 Sep 28];68, Suppl S1:113-22. Available from: http://www.neurologyindia.com/text.asp?2020/68/7/113/287678




Pituitary 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 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 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 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 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],[6],[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 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 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 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 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 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.
Figure 1: Contemporary radiation therapy workflow and process of treatment planning

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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 with ability to correct translational and rotational positioning errors with submillimetric accuracy further improving the spatial accuracy of treatment delivery.
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

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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 (60 Co) 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],[16],[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) 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]

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 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].
Table 1: Selected series reporting outcomes of radiation therapy (RT) in non-functioning pituitary adenoma

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Functional/secretory pituitary adenoma: Similar to NFPA, fractionated RT (conventional, conformal, FSRT/IMRT) is very 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 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 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%) 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 in 33% of patients.[40]

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 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 [Table 2], [Table 3], [Table 4] respectively.
Table 2: Selected series reporting on radiation therapy (RT) in ACTH-secreting pituitary adenoma

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Table 3: Selected series reporting on radiation therapy (RT) in GH-secreting pituitary adenoma

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Table 4: Selected series reporting on radiation therapy (RT) in PRL-secreting pituitary adenoma

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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, 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 including but not limited to hypopituitarism, neurocognitive 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 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]

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 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 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 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 Top


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 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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