Pituitary neuroendocrine tumors (PiNETs), according to the new WHO 2022 classification and previously referred to as pituitary adenomas, represent a proliferation of pituitary cells that is considered benign but has the potential for local invasion and aggressiveness (1). The prevalence of these tumors has increased due to the widespread utilization of magnetic resonance imaging (MRI) for various indications as headaches, seizures, and visual deficits. Unlike computed tomography (CT), MRI has the capability to detect small PiNETs that would otherwise remain invisible (2). According to the largest brain tumor registry in the United States, the incidence rate stands at 4.07 cases per 100,000 individuals per year, with no significant gender-based disparities. The prevalence of different subtypes of PiNETs is as follows: clinically functioning lactotroph tumors (66.2%), clinically non-functioning pituitary tumor (NFPT) (14.7%), clinically functioning somatotroph tumors causing acromegaly (13.2%), clinically functioning corticotroph tumors causing Cushing’s disease (5.9%), and the remaining 1% comprises other types such as thyrotroph tumors (TSH), gonadotroph tumors, and more (3).

Despite their benign nature, PiNETs have the potential to compress or invade surrounding tissues and organs, including the optic pathway, brainstem, and cavernous sinus. Furthermore, these tumors can secrete hormones, leading to disturbances in the hormonal system and consequential diseases with significant prognostic implications (4).

The primary treatment options commonly recommended for patients with these pathologies include surgical intervention and medical treatments (5). Radiotherapy has been recognized as an effective treatment since the 1960s (6, 7). However, its use is generally limited to the second or third line of treatment, potentially due to the side effects that were associated with older techniques. Additionally, concerns about radiation-induced cancers persist, particularly among younger patients who have several decades of life ahead of them (8). Over the past two decades, advancements in stereotactic irradiation and intensity-modulated radiotherapy (IMRT) have significantly improved the protection of critical organs surrounding the pituitary gland (9, 10). The aim of this review is to analyze the results of the most recent publications using the IMRT or stereotactic irradiation on local and hormonal control and its side-effects.

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) method was employed in this study (11). A comprehensive search of articles was conducted in the Medline database using specific keywords related to PiNETs, including “pituitary adenoma,” “Cushing,” “Acromegaly,” “prolactinoma,” “TSH-secreting,” “Nelson syndrome,” combined with “radiation therapy” or “radiotherapy.” The search was limited to articles published from 2011 onwards. Approximately 1500 publications were initially identified.

The selection process for the final articles involved two stages: title screening and abstract review. Inclusion criteria were applied, which included articles written in either French or English, studies involving more than 20 patients, reports describing the technique of radiotherapy, classification of PiNETs subtypes, and providing details on local control or hormonal control outcomes, as well as side effects.

From 2011 to 2021, 52 articles were selected for analysis ( Figure 1 ). All the included studies were retrospective ( Tables 1 - 6 ). Among them, thirteen studies provided data on patients from multiple centers. The number of patients enrolled in the studies varied, ranging from 21 to 1023. Treatment periods spanned from 1964 to 2019. Median follow-up ranged from 33 to 198 months ( Tables 1 – 6 ).

In term of specific tumor subtypes, 25 articles focused on patients with NFPT, 39 on acromegaly patients, 24 on Cushing’s disease, 18 on prolactinoma, 5 clinically functioning gonadotroph PiNETs, 5 on Nelson syndrome and 3 on TSH secretion.

This review analyzed a substantial pool of retrospective studies, collectively demonstrating the efficacy of radiation therapy in treating PiNETs (local control range: 79%-100%; hormonal control range: 10-94,7%). These studies had considerable median follow-up periods ranging from 33 to 198 months. The lack of prospective studies can be attributed to the low incidence of these tumor and the necessity of long-term follow-up to validate the treatment outcomes.

MRI is widely regarded as the gold standard for evaluating the pituitary region and devising the planning treatment. Contrast-enhanced fat-suppressed T1-weighted (Fat sat) sequences appear to be beneficial after surgical treatment as they reduce the obscuring effects caused by post-surgical modifications and augment the contrast between the tumor and adjacent structures (54). The slices should be as thin as possible considering that microtumors can be smaller than 5 mm. Additionally, a coronal acquisition could aid in delineating tumors that have a superior-inferior extension (55).

Delineation guidelines for PiNETs are often lacking in detail. The process is not precisely described and can vary depending on individual practices, which introduces a significant bias when comparing treatment results without a clear understanding of what is being clearly treated.

However, there are recent recommendations provided by the ESTRO (European Society for Radiotherapy and Oncology) (56). According to these guidelines, the gross tumor volume (GTV) is defined as the visible tumor on thin-slice MRI (specifically, on T1-weighted enhanced images using gadolinium). The clinical target volume (CTV) is not mandatory, but if there are criteria indicating invasiveness or aggressiveness, a margin of 2-3 mm can be applied. In stereotactic conditions, the planning target volume (PTV) margins range from 1-3 mm, while in conventional radiotherapy, a margin of 5 mm is used. These guidelines aim to provide more standardized and consistent approaches to delineating the pituitary tumors, taking into account the tumor visibility on MRI and various treatment conditions (56). The volume required to be irradiated is currently questioned depending on the type of PiNET. For NFPTs only the lesion could be targeted, while for FPT, the entire sella could be treated to minimize the risk of missing active secreting cells spread throughout the sella. Three series of studies have described irradiating the entire sellar region, suggesting that this approach may be appropriate in certain cases (18, 41, 43). Lee et al. conducted a study involving 64 patients with FPTs who experienced biological relapse post-surgery, with no visible tumor or infiltrative tumor prior to surgery. The patients were administered a median single dose of 25 Gy to the whole sellar. The achieved control rates were not different to the other published series, with 68.8% for acromegaly, 71.4% for Cushing’s disease, and 50% for prolactinoma. The authors did not report a dramatic rate of possibly radiation-induced onset of hypothyroidism with a rate of 43.5%. Notably, predictive factors for hypothyroidism and control rates were dose margin and maximum dose (43).

Shepard et al. conducted a study comparing whole sellar irradiation versus tumor-targeted irradiation in patients with Cushing’s disease, using stereotactic radiosurgery (SRS) with a mean margin dose of 22.4 Gy at a median isodose of 50% (30-60%). The study found no significant difference in terms of efficacy between the two approaches, as well as no significant difference in the development of induced endocrine deficits (18). Taylor et al. conducted a similar comparison study involving 128 patients with Cushing’s disease with comparable results in terms of disease control rates. However, they observed a potentially higher incidence of mortality and visual deficits in the whole sellar group, although this difference did not reach statistical significance (41).

Radiotherapy is generally considered a second- or third-line treatment option for PiNETs after surgery or medical therapy (4). While the side-effects of surgery and medication cannot be directly compared to radiation-induced effects, each treatment option has shown acceptable results and similar rates of complications or side effects. In a 2018 review, Alzhrani et al. studied the complications of transsphenoidal surgery for PiNETs. He described few pituitary deficits ranging from 3% to 6.1%, and a rate of 3-19% of central hyponatremia, 0.3%-3.5% epistaxis, 1.1% carotid pseudoaneurysm, 5.8% of hydrocephalus and 29.6% sino-nasal disorders (57).

Indeed, two sets of studies have investigated the use of radiotherapy as a first-line treatment. Wu et al. conducted a comparing study of 75 patients with acromegaly retrospectively recorded. Among them, half received stereotactic radiosurgery (SRS) as the first-line treatment, while the other half underwent radiation postoperatively. The indication of primary SRS was for patients unable to tolerate surgical risks or unwilling to undergo surgery. The indication for post operative SRS was for those who suffered recurrent or residual lesion after surgical removal. The postoperative group exhibited a statistically younger mean age (p = 0.028), a higher proportion of female patients (p = 0.010), larger tumor volume (p = 0.042), and a greater number of cases with Knosp grade ≧ 3 (p > 0.001). The hormone levels before SRS did not significantly differs between the two groups. In the postoperative SRS group, the median duration from surgery to SRS was 7 months (range: 3− 97 months). The median maximum dose and margin dose of the postoperative GKS group was significantly lower than that in the primary group (p = 0.014, p = 0.008). Biochemical recurrence rate was 2.63% in the primary group and 5.41% in the postoperative group (p = 0.981). Durable endocrine remission rate was 21% in the primary group and 21.6% in the postoperative group (p = 0.831). Only the base nadir GH level after treatment was identified as a predictor of durable biochemical remission (HR = 0.829,95% CI:0.704− 0.976; p = 0.025). So the study found no significant difference in endocrine remission, biochemical recurrence, imaging outcomes, or complications between the two groups (42). This study demonstrates the effectiveness of radiation therapy as a first-line treatment compared to a group considered to have experienced surgical failure due to incomplete removal of the lesion or relapse on it. However, these findings do not preclude the need for a direct comparison between up-front irradiation and complete removal of the lesion.

Yu et al. studied the outcomes of 81 patients with NFPT treated with a single session of GK as their first-line treatment. Forty-eight patients (59.3%) presented a lesion with suprasellar extension. The results found that the complete response (CR) rate was 88.9%, and tumor treatment failures were confirmed in nine patients (11.1%), indicating a high rate of tumor control. Fourteen patients (17.3%) developed hypopituitarism, including hypogonadism (n = 7), hypothyroidism (n = 8), and hypercortisolism (n = 7). This rates remained moderate compared to other studies (32).

These findings suggest that radiation therapy can be considered as a viable first-line treatment option for PiNETs, with outcomes comparable to those of surgery or medical therapy. However, individual patient factors and tumor characteristics should be considered when making treatment decisions, and a multidisciplinary approach is often necessary to determine the most appropriate treatment strategy. However, these factors still need to be clearly defined.

Regarding irradiation techniques, monofractionated irradiation is overrepresented in the published article. Several reasons can explain this observation: i/tumors mostly remain as small tumors confined to the sellar region, allowing for high doses per fraction; ii/The limited ability of PiNET cells to spread out permits the use of smaller or no margins around the GTV, which is favorable for high doses per fraction; iii/patients were often initially referred to neurosurgeons for surgery, but they frequently have access to Gamma Knife (GK) treatment, providing an opportunity for both treatments; iv/In terms of quality of life, monofractionated treatment is less restrictive for patients; v/finally, in terms of cost, monofractionated irradiation is often less expensive than fractionated irradiation. FSRT was less commonly used in NFPTs, possibly because the lesions tend to be smaller, and the need for fractionation to protect organs at risk is less frequent. NFRT appears to be less likely to be associated with visual deficits, but the conclusions are limited due to a lower number of studies and smaller patient populations, particularly in the case of stereotactic and FPTs. In Table 8 , the local control rates ranged from 85% to 100%. based on radiation technique. No technique appears to be superior, and all PiNETs subtypes exhibit excellent response rates.

In terms of hormonal control rates, results remained good but with wide and overlapping intervals ( Table 9 ), whatever the technique used. However, when examining specific subtypes such as prolactinomas, the intervals for hormonal control rates tend to be lower (ranging from 10% to 66%), compared to acromegaly (26% to 88%) and Cushing’s disease (40% to 99%).

However, comparison between techniques is not possible in this review. There isn’t much data comparing the different radiotherapy techniques, but IMRT/VMAT irradiation seems to provide better coverage and protection of adjacent structures, although it exposes them to more low doses (58). This could be theoretically improved by proton therapy, but no high-quality data currently favors one technique over another (10, 59).

Consequently, the choice of technique should not solely depend on the tumors subtype but also on the need to protect sensitive structures near the treated area. In studies where the tumor is in close to the optic nerves or optic chiasm, fractionation is often employed to minimize the risk to these at risk structures (16, 60). Tumor size is also a factor, as larger tumors tend to necessitate fractionation in treatment planning (15, 27, 50). NFPTs were considered to be more radioresistant, so higher doses were often administered. However, no radiobiological studies investigating radiosensitivity in vitro could be found in the literature to confirm this hypothesis.

The dose and treatment planning of radiotherapy for PiNETs should take into consideration various predictive factors. Factors such as tumor size, invasiveness, hormonal levels, and patient age can guide the decision-making process for selecting the appropriate margin and maximum dose. The aim is to balance tumor control with minimizing the risk of radiotherapy-induced side effects (10).

Since PiNETs are often considered as benign tumors, it is crucial to choose a treatment option with the least side effects and good tolerability. One of the major concerns of radiation treatment is the potential development of hypopituitarism, which refers to a deficiency in pituitary hormone production (61). Table 10A demonstrates the variability in hypopituitarism rates, with overlapping intervals and rates ranging from 1.9% to 58%. Interestingly, even proton therapy, which is often considered to have better sparing of surrounding tissues, exhibits a relatively high rate of pituitary deficits at 54% (62).

And Table 10B describes the evolution of hypopituitarism rates before and after radiotherapy. This shows that before radiotherapy, pituitary function is often impaired in 15.4-65% of treated patients, especially in cases of NFPT (in cause the compressive nature of non-secreting macrotumors). The rate of new cases of hypopituitarism related to radiotherapy is moderate, with a wide range from +17.3% to +58.3%, and affects equally the corticotropic and thyrotropic gonadotropic axes.

The predictive factors for radiotherapy-induced side effects in PiNETs treatment include a larger tumor volume and a shorter distance between the tumor and the pituitary stalk. However, the article by Deng et al. comparing radiotherapy versus no radiotherapy after surgery found no significant differences between the groups in terms of hormone deficiency at presentation, at 3 months postoperatively, or at the last follow-up. This suggests that the addition of radiotherapy did not significantly impact hormone deficiency rates in this study (27).

In the study by Wilson et al., which treated 176 patients with NFPTs using different radiotherapy techniques (SRS, FSRT, CRT), the risk of new pituitary deficits was assessed by comparing pre- and post-treatment hormonal replacement. The results showed that for SRS and FSRT, there was an improvement in preexisting hypopituitarism in 5 patients (10%), but a new deficit was observed in 4 (7%) new patients and requiring hormonal replacement after treatment, while for CRT 17 patients (32%) experienced a correction of their hypopituitarism. This suggests that conventional radiotherapy (CRT) had a higher rate of sparing pituitary function compared to SRS and FSRT (50).

Indeed, visual side effects are less frequent in pituitary tumors radiotherapy, and the intervals in Table 11A overlap, indicating similar rates among different techniques. However, if we look at the upper intervals, SRS seems induce higher rates of visual deficits (ranging from 5.5% to 9.4%) compared to FSRT (2.85%) and CRT (1% to 3.8%). Although the lower intervals are all at 0%, these findings suggest that SRS may have a slightly higher risk of visual deficits, emphasizing the importance of fractionating the dose when the planning target volume (PTV) is near the optic pathways. In Table 11B , we can see that there are higher rates of improvement in visual function (5.5%-34.5%) than deterioration (0-7.7%) after radiotherapy, so the risk-benefit ratio is in favor of radiotherapy from this point of view.

Other side effects, such as neurocognitive effects, stroke, seizure, radionecroses, or radio-induced brain tumors are occasionally described in some studies. For example, Sattler et al. compared the incidence of stroke in patients treated with surgery alone versus surgery plus radiotherapy (mostly NFRT with a dose of 45 Gy) with a median follow-up of 14 years. The study found that postoperative radiotherapy in PiNET was not associated with an increased incidence or causative mechanism of stroke compared to patients treated with surgery alone (63). A large size retrospective cohort involving 4292 patients treated with radiotherapy for pituitary adenomas or craniopharyngiomas found an association between radiotherapy and an increased risk of second brain tumors. The rate ratio for irradiated patients was 2.18 (95% CI 1.31–3.62, p < 0.05) (8).

The results of local and hormonal controls must be correlated with their real impact on patients’ lives, particularly in terms of improving clinical symptoms and quality of life.

In the case of a large tumor, whether secretory or not, the aim is to control the size of the tumor in order to avoid visual symptoms, damage to the cranial nerves, headaches or intracranial hypertension syndrome. In this context, controlling or even reducing the size of the tumor may alone lead to an improvement in symptoms. However, there is also a risk of radiotherapy induced neuropathy of cranial nerves, although radiation doses generally remain below the usual constraints (optic tracts: NFRT: <54Gy, SRS: <8 Gy, SFRT: 13,7Gy/3Fractions to 29,6Gy/8fractions) (64). As the Table 11B shows, the benefit-risk balance favors radiotherapy, which appears to result in a better improvement in visual function compared with post-radiotherapy visual disorders.

For clinically functioning pituitary tumors, particularly small recurrent tumors or the ones that are difficult to localize, the therapeutic approach differs. There are several lines of medication available to control hormone secretion, and radiotherapy is indicated later if medical treatments fail, are poorly tolerated or are contraindicated. In the case of Cushing’s disease in particular, drug treatments are more complex to manage, and tolerance is uncertain. In addition, the hypercortisolism induced by ACTH hypersecretion carries a significant risk of morbidity, particularly cardiovascular morbidity, hence the importance of hormonal control. Radiotherapy appears to be a wise choice after failure of drug or surgical treatment. On the other hand, in the case of hyperprolactinemia, hypersecretion is generally not very symptomatic and can be easily controlled by medication. In this case, radiotherapy is aimed more at reducing the volume of the tumor (65–67).

With regard to the assessment of radio-induced pituitary deficits, not all articles specify which specific hormonal axes are affected, as not all deficits have the same impact on the patient. A corticotropic or thyrotropic deficiency has a real daily impact, requiring strict supplementation and presenting vital risks, particularly in the case of acute adrenal deficiency. Prolactin deficiency, on the other hand, has no major impact on the patient, and the effects of growth hormone (GH) deficiency remain debated in adulthood. For FSH/LH deficiency, supplementation is generally straightforward (67, 68).

In Table 10B , when focusing only on hormonal axes that have an impact on patients, we observe an incidence ranging from 5.8% to 28.8% for LH/FSH, 10.7% to 32.5% for ACTH, and 11.5% to 29% for TSH. This could potentially affect up to one-third of patients, and thus, this data should always be weighed against the anticipated benefits for the patient. In fact, if the objective is to reduce the treatment burden for a patient with hypersecretion, radiotherapy might potentially lead to a reduction in hypersecretion. However, it comes with the risk of inducing a new deficiency that would require medication, which could be more or less demanding.

Overall, these findings indicate that the choice of radiotherapy technique may influence the risk of new pituitary deficits. However, it’s important to note that individual patient factors and tumor characteristics can also play a role in determining the impact of radiotherapy on hormone deficiency. Therefore, treatment decisions should be made on a case-by-case basis, considering the specific characteristics and needs of each patient.

Radiation therapy is an effective treatment option for both NFPT and FPT, with high rates of local control and good hormonal control. However, it is important to note that the review is skewed towards SRS, and there is a lack of studies directly comparing SRS, FSRT, and CRT. The major side effect of radiotherapy is hypopituitarism, which can affect up to half of the patients. Prospective studies with larger sample sizes and direct comparisons between different techniques are needed to obtain a higher level of evidence and further elucidate the optimal approach for PiNETs radiotherapy.