Radiotherapeutic Strategies and Advances in the Management of Pituitary Adenomas.

Background and Rationale for Radiotherapy in Pituitary Adenoma Treatment
Pituitary adenomas (which have recently been proposed to be renamed as “pituitary neuroendocrine tumors”) are benign brain tumors that develop from hormone-producing cells in the anterior pituitary gland and account for 10–20% of all intracranial tumors [1]. Despite their benign nature, they can be locally invasive and hormonally active, presenting with a wide range of clinical symptoms. Pituitary adenomas can be classified as functioning or non-functioning based on their overproduction of pituitary hormones. Following subtotal resection, tumor progression has been found to occur in up to 58% of cases; therefore, adjuvant radiation therapy is frequently utilized following initial surgical management in order to improve long-term patient outcomes and reduce the risk of tumor recurrence [2, 3]. This underscores the importance of collaborative decision-making between neurosurgeons and radiation oncologists on the timing of postoperative radiotherapy.
Conventional radiotherapy (CRT) has been used in the treatment of pituitary adenomas for over 5 decades [4–6]. However, significant advancements have recently been made in the development of newer and radiation delivery techniques, including stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy. While the use of radiation therapy has historically been associated with high tumor control rates for most pituitary adenomas, rates of hormonal normalization following treatment have been variably reported in the literature (ranging from 18 to 88%) [7]. Hypopituitarism is also a well-documented side effect following radiotherapy, with estimates of 30–60% of patients developing hormonal deficiencies 5–10 years following treatment [8]. Visual side effects are rarely reported and neurocognitive deficits following treatment are frequently mild [9, 10]. Despite this, radiation therapy is still considered an important tool in the management of pituitary adenomas as the long-term benefits and superior tumor control rates frequently outweigh the minimal risks of adverse side effects.

Presentation and Diagnosis of Pituitary Adenomas
The prevalence of pituitary adenomas is estimated to be approximately 10% of the population, and these tumors are often categorized into microadenomas (<1 cm in size), macroadenomas (≥1 cm in size), or giant adenomas (≥4 cm in size) [11]. Pituitary microadenomas are often incidentally found during intracranial imaging and asymptomatic (unless they are hormonally active), while pituitary macroadenomas commonly present with symptoms related to mass effect, including headache, visual deficits, and oculomotor nerve palsies, along with possible symptoms related to hormone overproduction or deficiency [12, 13]. While only two-thirds of pituitary adenomas are functional, 50% of these cases are macroadenomas [11]. The most common hormones produced by pituitary adenomas are prolactin (32–66%), growth hormone (8–16%), adrenocorticotropic hormone (ACTH) (2–6%), and thyroid-stimulating hormone (<1%) [11]. Prolactinomas frequently present as microadenomas (in 80% of cases) and are more common in women (with a female-to-male incidence ratio of 10:1) who often report observing changes in menstruation, galactorrhea, and infertility [14–16]. Growth hormone-secreting pituitary adenomas are often associated with symptoms of acromegaly in adults and gigantism in children, traditionally presenting with enlargement of extremities and changes in facial features along with headaches, hyperhidrosis, and joint pains [17, 18]. Patients with ACTH-producing adenomas are also more commonly female (with female-to-male incidence ratio of 3:1) and present with symptoms of Cushing’s disease, including hypertension, diabetes mellitus, osteoporosis, and changes in mood and cognition [14, 17]. The treatment of ACTH-producing microadenomas with unclear tumor visualization on imaging may also include inferior petrosal sinus sampling in order to confirm the diagnosis and localize a potential surgical target [19]. Thyroid-stimulating hormone-secreting tumors are the rarest type of pituitary adenoma and often present with neurological symptoms (such as headache and visual deficits) along with signs of hyperthyroidism, which include weight loss, fatigue, heat intolerance, tachycardia, and anxiety [20, 21]. Cases of pituitary adenoma are often spontaneous and rarely found to be inherited, though certain syndromes including multiple endocrine neoplasia have been associated with an increased risk of developing pituitary tumors [12].
The diagnosis of pituitary adenoma is confirmed with magnetic resonance imaging (MRI), particularly sellar imaging protocols which provide improved soft tissue resolution of the pituitary region [22]. Pituitary adenomas frequently demonstrate isointense signal to gray matter on T1- and T2-weighted sequences, and solid intratumor components are often seen as regions of lower contrast-enhancement compared to surrounding normal tissue [22]. Concerning findings which may also be observed include hyperintensity on T1 without contrast, suggestive of an intratumoral hemorrhage, and sellar or parasellar flow voids on T2 which could indicate the presence of an intracranial aneurysm [22].

Biological Advances regarding Pituitary Adenoma
Recent biological advances in pituitary adenoma research have focused on improving our understanding of tumorigenesis at the molecular level. Targeting the tumor microenvironment has shown promising results, with immune checkpoint inhibitors and bevacizumab demonstrating efficacy in controlling tumor progression [23, 24]. The identification of other molecular pathways has highlighted the roles of epidermal growth factor receptor, mammalian target of rapamycin, vascular endothelial growth factor, fibroblast growth factor (FGF), and signal transduction and activator of transcription 3 pathways in the growth of pituitary adenomas, all of which serve as potential targets for therapy [25, 26].
Toader et al. [27] reported on predictive biomarkers and established the roles of matrix metalloproteinase-9, pituitary tumor-transforming gene (PTTG), and high mobility group A2 protein in the development and recurrence of adrenocorticotropic hormone-secreting tumors. More recent studies utilizing DNA methylation profiling have identified epigenetic markers that are able to differentiate between invasive and noninvasive pituitary adenomas, highlighting a promising direction for the use of noninvasive genomic tools in tumor diagnosis and treatment [28].
In addition, a recent study by Durcan et al. [29] found that elevated expression of fibroblast growth factor-4 receptor (FGFR-4) may correlate with more aggressive behavior in pituitary adenomas, although further studies are required to establish FGFR-4’s role in tumorigenesis.

Surgical Timing and Extent of Resection in Guiding Decisions regarding Postoperative Radiotherapy
Tumor control following surgical treatment alone is estimated to occur in approximately 50–90% of cases depending on functional status and the degree of tumor invasion, and complete surgical resection of nonfunctioning adenomas is thought to only be achievable in around 60% of cases [30, 31]. Tumor recurrence rates have been seen at 10 years to be between 10–20% following gross total resection (GTR) and in up to 50% following subtotal resection [32]. Adjuvant therapy with radiation treatment has therefore been recommended in select cases to improve tumor control rates for both nonfunctioning and functioning adenomas.
A multitude of surgical approaches has been developed for the treatment of pituitary tumors, including endoscopic and microscopic transsphenoidal resection. Through advancements in endoscopic technology, transsphenoidal surgery has become the gold standard in the treatment of skull base tumors due to the wide field of view and relatively safe working corridors offered to the surgeon [33]. In addition, microscopic transsphenoidal surgery utilizes an intraoperative microscope to improve visualization of the sellar region, though one study has shown that endoscopic transsphenoidal surgery is associated with a higher GTR rate of 74% compared to a GTR rate of 66.4% with microscopic transsphenoidal surgery for nonfunctioning pituitary adenomas [33, 34]. Factors which have been found to influence the extent of tumor resection include preoperative tumor volume, tumor consistency, surgical approach, and Knosp classification [35–37].

External Beam Radiotherapy
External beam radiotherapy (EBRT) is often administered in 25–30 fractions of 1.8–2.0 Gy daily for 5–6 weeks [38, 39]. EBRT can be delivered by utilizing both three-dimensional conformal radiation therapy, volumetric modulated arc therapy, and intensity-modulated therapy, which allow for precise targeting of the pituitary tumor while minimizing radiation exposure to surrounding healthy tissue [38, 39]. Reported adverse side effects include stroke (with an incidence of up to 21% at 20 years) and anterograde memory deficits [40, 41]. Long-term visual complications are a less common side effect, occurring in less than 2% of patients [42, 43]. The incidence rate of secondary tumors following radiotherapy for pituitary adenoma was estimated in a multicenter study to be 2.9% [44].
Recent advances in EBRT include hypofractionated stereotactic radiotherapy, which has shown promising short-term outcomes due to its ability to deliver higher doses per fraction in fewer sessions [45, 46]. However, further studies are required to evaluate the long-term outcomes of hypofractionation [46]. Conventional fractionation, or fractionated stereotactic radiotherapy, utilizes 25–30 fractions for pituitary adenomas, while hypofractionated stereotactic radiotherapy consists of 3–5 treatments [46, 47]. In addition, techniques such as intensity-modulated therapy and volumetric modulated arc therapy are increasingly employed to enhance dose conformity while sparing healthy tissue [48]. Collectively, these advancements work toward the goal of improving tumor control while minimizing treatment side effects.

Tumor Control
In patients with nonfunctioning pituitary adenomas, tumor control rates following EBRT have been reported to reach 90% at 10-year follow-up [49]. For functioning pituitary adenomas, tumor control is achieved in 67–89% of patients who were treated with total doses of 45–50.4 Gy over 23–28 fractions delivering 1.8–2.0 Gy per fraction [39]. The 5-year progression-free survival following adjuvant radiation therapy with a median dose of 50.4 Gy delivered over 28–30 fractions has been comparably found to be 95.3% for nonfunctioning pituitary adenomas and 94.8% for functioning pituitary adenomas [50].

Endocrine Control
EBRT has been shown to partially or completely reduce hormone overproduction in a majority of patients with functioning pituitary adenomas, with improvements observed between 3 months and 9 years post-radiation depending on which hormone levels are found to be abnormal [51]. Hypercortisolism is typically controlled in 50–83% of adults with Cushing’s disease within 9 months post-treatment [39]. While EBRT has been associated with improvements in post-treatment hormone levels, it is also associated with radiation-induced hypopituitarism, with an incidence rate ranging from 13 to 56% [39]. Ongoing hormone replacement therapy is frequently required long-term and often expected following surgical resection, such as in the treatment of patients with Cushing’s disease [52].

Stereotactic Radiosurgery
SRS is a form of radiation therapy that utilizes multiple, converging, ionized beams of radiation with steep dose gradients in order to deliver a high-dose of radiation in a single fraction to targeted regions while avoiding damage to nearby anatomic structures [53]. Planning is typically conducted on proprietary radiosurgical software using high-resolution, contrast-enhanced MRI fused with a computed tomography image to maximize anatomic precision, particularly when working near the optic apparatus or pituitary stalk [54]. SRS is used to treat a wide variety of central nervous system pathologies in addition to pituitary adenomas, including metastatic lesions, meningiomas, vestibular schwannomas, arteriovenous malformations, and trigeminal neuralgia [53]. Multiple advancements have been made in treatment techniques to optimize dose delivery and targeting, including linear accelerator based systems, proton beam radiosurgery, CyberKnife, and Zap-X [4, 30]. Linear accelerator-based SRS systems deliver submillimeter-accurate, high-dose radiation using stereotactic localization and cone or multileaf collimators to shape beams delivered through noncoplanar or dynamic arcs and achieve steep dose gradients to spare normal tissue [55]. CyberKnife is a frameless and image-guided SRS platform that employs a robotic arm with six degrees of freedom and advanced collimation (fixed, Iris, or multileaf) to deliver hundreds of noncoplanar beams with real-time motion tracking and highly conformal radiation delivery for the treatment of complex intracranial and extracranial targets [56]. The Zap-X system, a self-shielded and gyroscopic SRS platform, uses circular collimators and multi-axis beam rotation to deliver conformal, noncoplanar radiation and offer precise, bunker-free treatment with comparable submillimeter accuracy [57].
Today, SRS is often utilized as an adjuvant or salvage therapy for patients with pituitary adenomas following initial surgical resection, though it can also be offered as a primary treatment for patients who either refuse or are deemed surgically ineligible [58]. Small retrospective studies of patients who had forgone surgical management and instead received GKRS as definitive treatment have notably shown tumor control to be greater than 85% at 8–10-year follow-up, with comparable rates of hypopituitarism and cranial nerve palsy compared to standard SRS treatment regimens [59, 60]. Nevertheless, treatment with SRS is typically indicated for recurrent or incompletely resected tumors less than 3 cm in size with a contoured margin of greater than 3–5 mm from the optic apparatus [7]. The recommended dose of SRS given in a single fraction is 12–14 Gy for nonfunctioning tumors (comprising approximately 25% of pituitary adenomas) and 16–20 Gy for functioning tumors (comprising approximately 75% of pituitary adenomas) [46, 49, 58, 61]. While the risks of adverse effects following SRS have been well documented (including hypopituitarism, visual deficits, cranial nerve palsies, and development of a secondary neoplasm [at a lower rate than EBRT]), multiple long-term, large-scale studies have continued to demonstrate both the relative safety and overall effectiveness of this treatment modality [30, 32, 62].

Tumor Control
Large-scale studies of patients with nonfunctioning recurrent or residual pituitary adenomas treated with SRS have shown an approximately 92–94% tumor control rate at 5-year follow-up with minimal associated risks for new-onset visual (3.94%) and cranial nerve (<1%) deficits [32, 58]. Treatment factors which have been correlated with improved tumor control have been reported to include radiation doses >15 Gy and an interval of >1 year between surgery and SRS treatment [63]. This time interval may reflect a stabilization period for the tumor bed, though the decision to maintain observation must be balanced with the risk of progression in more aggressive subtypes, highlighting the importance of individualized radiographic and endocrine surveillance protocols. Tumor control rates for nonfunctioning adenomas have not been shown to exhibit significant differences across subgroups based on early, adjuvant, or on-progression treatment timing [63]. However, rates of tumor control were found to decrease significantly with longer term follow-up, with a tumor control rate of 69% at the 15-year mark in a multicenter study [63]. These results suggest that while tumor control is often successful within the short- and medium-term, lifelong observation is often required due to the persistent risk of tumor recurrence (in reported cases even at 120 months posttreatment) [31].

Endocrine Control
While CRT has been associated with higher rates of hypopituitarism and a longer time to hormone normalization (reportedly up to 3 decades in some cases), normalization has been noted to occur rapidly following treatment with SRS, with rates of restoration of endocrine function or improvement seen in more than 80% of patients at 10-year follow-up [7, 31]. In addition, the cessation of IGF-1-lowering medications prior to SRS administration in cases of acromegaly has been correlated with improvements in rates of long-term endocrine remission, which is thought to be due to certain medications such as octreotide providing a radioprotective effect against SRS treatment [64]. Rates of radiation-induced hypopituitarism have also been found to be much lower following SRS (observed in up to 30% of patients at 10 years post-treatment) compared to patients undergoing fractionated radiotherapy, for whom reports of hormonal deficits are reported in 30–60% of patients [7, 32]. Radiation-induced hypopituitarism is predominantly caused by damage to traveling neural fibers (particularly through the highly concentrated pituitary stalk) rather than disruptions in blood flow caused by radiation-induced vasculopathy [7]. Higher risks for developing hypopituitarism have been correlated with elevated radiation doses to the gland and stalk, larger tumor size, prior radiation treatment, previous surgery, and unclear MRI visualization of the pituitary gland [7, 31, 63]. Therefore, limitations in radiation dosing to less than 15 Gy to the gland and less than 17 Gy to the stalk have been proposed to minimize these treatment-related risks. However, the long-term course of endocrine control following SRS treatment is uncertain, with return to hypersecretory states found even after 8 years of hormone normalization, and delayed endocrinopathies have been reported in up to 32% of patients at a median follow-up of 21–79 months [31, 63].

Recent Advances

Proton Therapy
Proton beam therapy is a form of radiotherapy that utilizes proton beams to improve the precision of radiation delivery for targeted tissues. The radiophysical properties of proton beam delivery allow for the deposition of protons directly within the depth of the tumor and minimizes radiation exposure to surrounding healthy tissue. This is in contrast to CRT which uses photon waves to deliver radiation that continue to affect tissue along the entire target radiation path [65, 66]. Proton beam therapy has proven particularly useful in the treatment of diencephalic tumors which are surrounded by multiple critical structures including the optic chiasm and hypothalamus, and pituitary tumor control rates of 98% have been reported at a median follow-up of 3.5 years [66, 67]. In neurosurgical practice, proton therapy is increasingly considered for patients with craniopharyngiomas or complex adenomas extending toward the hypothalamus, cases in which delivery precision and dose-sparing are critical [68]. In addition, the use of proton therapy in patients aged 19 years or younger may also be considered, though consensus guidelines are limited by uncertainty regarding administration timing and the lack of long-term side effect data [69]. Current limitations related to the use of proton beam therapy include high cost, limited number of centers offering this treatment option, and few clinical trials demonstrating its efficacy over more traditional radiotherapy techniques [70].

Peptide Receptor Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT) is a form of radiotherapy which involves the administration of a radioactive isotope (typically lutetium-177) attached to a peptide which binds to somatostatin receptors located on tumor cells, causing internalization of the radionuclide and cellular apoptosis [71]. Somatostatin receptors have been found to be expressed by pituitary adenomas and SSTR2 receptor levels can be determined using routine DOTATATE-positron emission tomography imaging [72]. SSTR receptors are frequently found to be overexpressed in cases of aggressive or, rarely, metastatic pituitary adenomas; therefore, the treatment of this patient subgroup with PRRT can be particularly effective [73]. PRRT outcomes have, however, been reportedly variable, with one study showing only partial tumor shrinkage following eight treatment cycles and no significant effect on tumor size after four treatment cycles [74]. Adverse effects associated with PRRT treatment include cytopenia, facial pain, and pituitary apoplexy [75]. Greater utilization of PRRT is also currently limited by a lack of consensus on optimal treatment dosing and duration for aggressive pituitary adenomas [74].

Conclusion
Pituitary adenomas are a benign entity which often requires a multimodal and multidisciplinary treatment approach involving surgery, hormonal antagonists, radiotherapy, and emerging modalities like proton therapy and PRRT. Over the past few decades, radiotherapy has played a critical role in achieving long-term tumor and endocrine control in the treatment of pituitary adenomas. Advances in SRS have shown to be particularly effective due to its ability to minimize damage to surrounding structures and deliver highly conformal radiation dosing. Ongoing research into the molecular biology of pituitary adenomas and the development of novel therapeutic approaches continue to show promise in further improving patient outcomes.

Conflict of Interest Statement
The authors have no conflicts of interest to declare.

Funding Sources
This study was not supported by any sponsor or funder.

Author Contributions
Conceptualization: N.D.A., J.F.Z., and D.J.P.; writing – original draft preparation: J.F.Z, H.K.C., D.S., and H.A.; writing – review and editing: N.D.A., J.F.Z., H.K.C., and H.A.; supervision: N.D.A., R.S., V.G., V.S.M., D.J.P., T.J.C.W., and D.P.; project administration: N.D.A., R.S., V.G., V.M., D.J.P., T.J.C.W., and D.P. All authors have read and agreed to the published version of the manuscript.