Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

BACKGROUND AND OBJECTIVES: Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway. METHODS: Two cohorts of patients with residual or recurrent NFPAs in contact to the optic pathway were retrospectively included in this study: (1) a group of patients who underwent a 3-day course of F-GKRS in Europe and (2) a group of patients treated with S-GKRS in the United States. A propensity score matching (ratio 1:1) was carried out to obtain and compare 2 homogeneous groups of patients with NFPA. RESULTS: A total of 84 patients were included for analysis (42 in the S-GKRS cohort and 42 in the F-GKRS group). The 2 cohorts did not differ for age, sex, number of previous surgical procedure, tumor volume, and follow-up. The mean follow-up was 60.2 ± 37.0 months and 62.4 ± 37.4 months for F-GKRS and S-GKRS cohort, respectively ( P = .38). The overall tumor control at last follow-up was achieved in 95.2% and 92.9% of patients in F-GKRS and S-GKRS, respectively ( P = .64). The 1-year, 3-year, 5-year, and 7-year progression-free survival rate after F-GKRS was 100%, 97.1%, 97.1%, and 91%, respectively. In the S-GKRS sample, progression-free survival rates were 100%, 100%, 92.5%, and 92.5% at 1, 3, 5, and 7 years after treatment, respectively. Two patients (4.7%) from the F-GKRS cohort and 2 (4.7%) from the S-GKRS cohort sustained visual worsening after radiosurgery ( P = 1.0). CONCLUSION: In the management of NFPAs adjacent to the optic pathway both F-GKRS and S-GKRS had comparable outcomes and risks at 7 years. Future prospective studies including larger cohorts with longer follow-up are needed to confirm our results.

Radiotherapy and Mortality in Pituitary Adenomas.

BACKGROUND: Pituitary adenomas (PA), comprising 10-20% of intracranial tumors, are classified as functioning and non-functioning and are further divided by size. Non-functioning tumors cause mechanical symptoms while functioning ones result in hormonal hypersecretion syndromes. Initial treatment involves surgery, with medical treatment for prolactinomas. Radiotherapy (RT) is employed as an adjuvant treatment, with various modalities including conventional, stereotactic radiosurgery (SRS), and fractionated stereotactic RT (FSRT). Although effective, RT is associated with complications and toxicities such as hypopituitarism, optic neuritis, secondary CNS tumors, and neurocognitive deficits. AIM: Describe the information on mortality from radiotherapy as treatment of functioning PA. METHODS: A PubMed search spanning 2000-2017 was conducted for articles on pituitary RT. RESULTS: Conventional RT entails high-energy radiation over multiple sessions, while SRS delivers precise high doses in a single session. FSRT offers enhanced precision using a linear accelerator, delivering multiple doses. Optic structure proximity and tumor volume dictate RT modality. Studies have shown SRS and FSRT's efficacy in tumor and endocrine control, with variable risks and complications. Mortality rates in pituitary adenomas treated with RT have been evaluated, revealing complexities. Acromegaly, associated with increased mortality due to cerebrovascular disease, may result from RT. Irradiation of non-functioning pituitary macroadenomas also elevates cerebrovascular risk, while radiotherapy-induced hypopituitarism is associated with increased cardiovascular mortality. RT-induced damage is attributed to microvascular lesions and arteriolar changes. CONCLUSION: Modern techniques mitigate complications, and although safer, long-term studies are needed. Multidisciplinary evaluation guides the treatment decision, optimizing efficacy and minimizing risk, ultimately improving the patient's quality of life.

Early Versus Delayed Fractionated Stereotactic Radiotherapy for Nonfunctioning Pituitary Adenoma.

BACKGROUND: Fractionated stereotactic radiotherapy (FSRT) is a common modality used to treat pituitary adenomas with good control rates. It is not known whether FSRT should be performed early or delayed until progression occurs. We compared FSRT in treating nonfunctional pituitary adenomas (NFPA) as an adjuvant (ADJ) or on-progression (PRG) therapy. METHODS: A retrospective review of patients who underwent FSRT for an NFPA between January 2004 and December 2022 at a single institution was performed. We compared endocrinologic, ophthalmologic, and radiographic outcomes in FSRT delivered as ADJ and PRG treatment. RESULTS: Seventy-five patients were analyzed, with a median follow-up of 53 months. FSRT was administered to 35 and 40 patients as ADJ and PRG, with a median time to treatment of 5.5 and 40 months, respectively. The tumor control rate was 94.3% for ADJ and 95.0% for PRG. Treatment resulted in 4 (11.4%) versus 7 (17.5%) new endocrinopathies and 2 (5.7%) versus 1 (2.5%) new visual deficits for ADJ versus PRG. A survival analysis of time to new endocrinopathy showed no difference between the 2 cohorts. The median time from surgery to new endocrinopathy was significantly different between ADJ and PRG, at 15.5 and 102.0 months, respectively. CONCLUSIONS: FSRT is effective in treating NFPA for residual and progressive tumors, with excellent tumor control rates and a low risk of developing new endocrinopathies and visual deficits. Delaying treatment delayed the development of new endocrinopathies, suggesting that observation with FSRT on tumor progression may delay the onset of hypopituitarism and maintain similar effectiveness in tumor control.

Volumetric Assessment of Nonfunctional Pituitary Adenoma Treated With Stereotactic Radiosurgery: An Assessment of Long-Term Response.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is widely used to manage recurrent or residual nonfunctioning pituitary adenomas (NFPAs). Studies on the long-term volumetric response of NFPAs to SRS are lacking. Such a post-SRS volumetric study will allow us to set up appropriate radiographic follow-up protocols and predict tumor volumetric response. METHODS: Two providers independently performed volumetric analyses on 54 patients who underwent single-session SRS for a recurrent/residual NFPA. In the case of discrepancy between their results, the final volume was confirmed by an independent third provider. Volumetry was performed on the 1-, 3-, 5-, 7-, and 10-year follow-up neuroimaging studies. RESULTS: Most patients showed a favorable volumetric response, with 87% (47/54) showing tumor regression and 13% (7/54) showing tumor stability at 10 years. Year 3 post-SRS volumetric results correlated (R 2 = 0.82, 0.63, 0.56) with 5-, 7-, and 10-year outcomes. The mean interval volumetric reduction was 17% on year 1; further interval volumetric reduction was 17%, 9%, 4%, and 9% on years 3, 5, 7, and 10, respectively. CONCLUSION: Year 3 post-SRS volumetric response of patients with residual or recurrent NFPAs is predictive of their 7-10-year follow-up response. For patients demonstrating NFPA regression in the first 1-3 years, interval follow-up MRI's can likely be performed at 2-year periods unless otherwise clinically indicated. Further studies are needed to better define the volumetric response to adenomas more than a decade after SRS.

The Role of Stereotactic Radiosurgery for Functioning and Nonfunctioning Pituitary Adenomas.

Pituitary adenomas are benign brain tumors that comprise 10%-20% of all central nervous system neoplasms. In recent years, stereotactic radiosurgery (SRS) has emerged as a highly effective treatment option in the management of functioning and nonfunctioning adenomas. It is associated with tumor control rates frequently ranging from 80% to 90% in published reports. While permanent morbidity is uncommon, potential side effects include endocrine dysfunction, visual field deficits, and cranial nerve neuropathies. In patients where single fraction SRS would pose an unacceptable risk (e.g. large lesion size or close proximity to the optic apparatus), hypofractionated SRS delivered in 1-5 fractions is a potential treatment option; however, available data are limited. A comprehensive literature search of PubMed/MEDLINE, CINAHL, Embase, and the Cochrane Library was conducted to identify articles reporting on the use of SRS in functioning and nonfunctioning pituitary adenomas.

Contemporary radiotherapy and radiosurgery techniques for refractory pituitary adenomas.

The pituitary gland is a potential site for a range of pathologies, for which treatment can involve resection and/or ionizing radiation. Modern stereotactic radiosurgery (SRS) involves highly conformal radiation, allowing for the delivery of high doses to the tumor while simultaneously sparing nearby healthy structures. SRS has become a standard treatment option for residual or recurrent pituitary adenomas. It has been used for both functioning and nonfunctioning pituitary adenomas, with reported local tumor control over 90% and moderate rates of endocrine remission in functioning adenomas. We aim to briefly review the existing indictions and supporting literature for the use of SRS for refractory adenomas.

Effects of Neuroanatomic Structural Distances on Pituitary Function After Stereotactic Radiosurgery: A Multicenter Study.

BACKGROUND: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. OBJECTIVE: To investigate the relationship between neuroanatomic structure distances from the radiation target and anterior pituitary function preservation after SRS through multicenter study. METHODS: We retrospectively reviewed the International Radiosurgery Research Foundation database from January 2002 to December 2021 for adult patients undergoing SRS for pituitary adenomas with >6 months of follow-up. Distances between centers or edges of hypothalamic-pituitary axis structures and SRS target volumes were measured using MRI. The primary outcome was anterior pituitary function preservation. Predictors were analyzed using multivariable logistic regression and area under the receiver operating curve (AUROC) curve analyses. RESULTS: Four hundred eighty-seven patients were categorized by preservation (n = 384) and no preservation (n = 103) of anterior pituitary function. The mean margin dose was 19.1(6.2) Gy. Larger distance from the center of the stalk to the tumor margin isodose was a positive predictor (adjusted odds ratio [aOR] = 1.162 [1.046-1.291], P = .005), while pre-SRS hypopituitarism (aOR = 0.646 [0.405-1.031], P = .067) and larger treatment volume (aOR = 0.965 [0.929-1.002], P = .061) were near negative predictors of the primary outcome. An interaction between the treatment volume and center stalk to margin isodose distance was found (aOR = 0.980 [0.961-0.999], P = .045). Center stalk to margin isodose distance had an AUROC of 0.620 (0.557-0.693), at 3.95-mm distance. For patients with treatment volumes of <2.34 mL, center stalk to margin isodose distance had an AUROC of 0.719 (0.614-0.823), at 2.95-mm distance. CONCLUSION: Achieving a distance between the center of the pituitary stalk and the tumor margin isodose ≥3.95 mm predicted anterior pituitary function preservation. For smaller treatment volumes <2.34 mL, the optimal distance was ≥2.95 mm. This may be modifiable during trans-sphenoidal resection to preserve pituitary function.

Role of biological effective dose for prediction of endocrine remission in acromegaly patients treated with stereotactic radiosurgery.

PURPOSE: Stereotactic radiosurgery (SRS) can be used in acromegaly patients to achieve endocrine remission. In this study we evaluate the biological effective dose (BED) as a predictor of SRS outcomes for acromegaly. METHOD: This retrospective, single-center study included patients treated with single-fraction SRS with growth hormone secreting pituitary adenomas and available endocrine follow-up. Kaplan-Meier analysis was used to study endocrine remission, new pituitary deficit, and tumor control. Cox analyses were performed using two models [margin dose (model 2) versus BED (model 1)]. RESULTS: Sixty-seven patients (53.7% male) with a median age of 46.8 years (IQR 21.2) were treated using a median dose of 25 Gy (IQR 5), and a median BED of 171.9Gy2.47 (IQR 66.0). Five (7.5%) were treated without stopping antisecretory medication. The cumulative probability of maintained endocrine remission off suppressive medications was 62.5% [47.9-73.0] at 3 years and 76.5% [61.0-85.9] at 5 years. IGF1i > 1.5 was a predictor of treatment failure [Hazard ratio (HR) 0.40 (0.21-0.79) in model 1, p = 0.00783]. Margin dose > 22 Gy [HR 2.33 (1.06-5.13), p = 0.03593] or a BED > 170Gy2.47 [HR 2.02 (1.06-3.86), p = 0.03370] were associated with endocrine remission. The cumulative probability of new hypopituitarism after SRS was 36.8% (CI 95% 22.4-45.9) at 3 years and 53.2% (CI 95% 35.6-66) at 5 years. BED or margin dose were not associated with new hypopituitarism. CONCLUSION: BED is a strong predictor of endocrine remission in patients treated with SRS. Dose planning and optimization of the BED to > 170Gy2.47 give a greater probability of endocrine remission in acromegalic patients.

Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas.

Pituitary adenomas (PAs) are neoplasms derived from the endocrine cells of the anterior pituitary gland. Most frequently, they are benign tumors, but may sometimes display an aggressive course, and in some cases metastasize. Their biology, including their wide range of behavior, is only partly understood. In terms of therapeutic targeting, most PAs are easily treated with available medical treatments, surgery, and sometimes radiotherapy. Nevertheless, gonadotroph adenomas lack medical therapeutic options, and treatment of aggressive PAs and pituitary carcinomas remains challenging. Here, we present an overview of the implications of the tumor microenvironment in PAs, reviewing its composition and function, as well as published cases that have been treated thus far using tumor microenvironment-targeting therapies. Additionally, we discuss emerging views, such as the concept of nonangiogenic tumors, and present perspectives regarding treatments that may represent future potential therapeutic options. Tumor-infiltrating lymphocytes, tumor-associated macrophages, folliculostellate cells, tumor-associated fibroblasts, angiogenesis, as well as the extracellular matrix and its remodeling, all have complex roles in the biology of PAs. They have been linked to hormone production/secretion, size, invasion, proliferation, progression/recurrence, and treatment response in PAs. From a therapeutic perspective, immune-checkpoint inhibitors and bevacizumab have already shown a degree of efficacy in aggressive PAs and pituitary carcinomas, and the use of numerous other tumor microenvironment-targeting therapies can be foreseen. In conclusion, similar to other cancers, understanding the tumor microenvironment improves our understanding of PA biology beyond genetics and epigenetics, and constitutes an important tool for developing future therapies.

Management after initial surgery of nonfunctioning pituitary adenoma: surveillance, radiotherapy or surgery?

INTRODUCTION: The first line of treatment for nonfunctioning pituitary adenoma (NFPA) is surgery. Adjuvant radiotherapy or surveillance and new treatment (second surgical operation or salvage radiotherapy) in case of recurrence are options discussed at the multidisciplinary tumor board. The purpose of this study was to evaluate the therapeutic outcome for each option. METHODS: The records of 256 patients followed with NFPA between 2007 and 2018 were retrospectively reviewed. Mean age at initial surgery was 55 years [18-86]. Post-operative MRI found a residual tumor in 87% of patients. Mean follow-up was 12.1 years [0.8-42.7]. RESULTS: After initial surgery, 40 patients had adjuvant radiotherapy. At 5, 10 and 15 years progression-free survival (PFS) was significantly different after surgery alone (77%, 58% and 40%) compared to surgery and adjuvant radiotherapy (84%, 78% and 78%) (HR = 0.24 [0-0.53] p < 0.0005). Overall, after first, second or third surgical operation, 69 patients had adjuvant radiotherapy and 41 salvage radiotherapy. Five-year PFS was similar for adjuvant (90%) and salvage radiotherapy (97%) (p = 0.62). After a second surgical operation, 62% and 71% of patients were irradiated after 2 and 5 years respectively. The risk of corticotropic and thyrotropic deficiency rates were 38% and 59% after second or third surgical operation and 40% and 73% after radiotherapy. Brain tumors occurred in 4 patients: 1 meningioma present at initial surgery, and after radiotherapy, 1 neurinoma which appeared at 5 years, 1 glioblastoma at 13 years and 1 meningioma at 20 years. CONCLUSION: Among patients treated by surgery for NFPA, a "wait-and-see" attitude should be an option since adjuvant radiotherapy is not superior to salvage radiotherapy. However, in case of recurrence or progression, the authors recommended delivery of salvage radiotherapy to avoid a second surgical operation.

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance.

BACKGROUND: Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls. METHODS: In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls. FINDINGS: Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years. INTERPRETATION: Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. FUNDING: Pfizer.

Predictors of Hypothyroidism Following Empirical Dose Radioiodine in Toxic Thyroid Nodules: Real-Life Experience.

OBJECTIVE: We aimed to determine the factors predicting hypothyroidism after radioactive iodine (RAI) treatment in patients with toxic adenoma and toxic multinodular goiter. METHODS: We retrospectively collected the data of 237 patients with toxic multinodular goiter or toxic adenoma who had consecutively received RAI treatment between 2014 and 2020 at 2 medical centers. Patients who received the second RAI treatment and whose medical records could not be accessed were excluded from the study. Finally, 133 patients were included in the study. RAI was administered at an empirical dose of 15 or 20 mCi. RESULTS: The median age of the 133 participants was 69 years (interquartile range, 62-75 years), and 64.7% of the participants were women. A total of 42.1% of the patients had toxic adenoma, whereas 57.9% of patients had toxic multinodular goiter. The median follow-up was 24 months (interquartile range, 11-38 months). During the follow-up, 61.7% of patients became euthyroid, 30.8% developed hypothyroidism, and 7.5% remained hyperthyroid. The median month of hypothyroidism onset was 4 months (interquartile range, 2-9 months). Regression analysis revealed 2 factors that could predict hypothyroidism: thyroid-stimulating hormone (odds ratio, 2.548; 95% CI, 1.042-6.231; P = .04) and thyroid volume (odds ratio, 0.930; 95% CI, 0.885-0.978; P = .005). CONCLUSION: Overall, 30.8% of the cases developed hypothyroidism after the RAI treatment. Approximately 78% of hypothyroidism developed within the first 10 months. The risk of hypothyroidism was higher in patients with higher thyroid-stimulating hormone and smaller thyroid volume.

Long-term hormonal and imaging outcomes of adjunctive gamma knife radiosurgery in non-functioning pituitary adenomas: a single center experience.

PURPOSE: Gamma Knife Radiosurgery(GKRS) is an established modality for treatment of non-functioning pituitary adenomas(NFPA). The objective of the study was to assess long-term hormonal and imaging outcomes after adjunctive GKRS in patients with NFPA. METHODS: A retrospective review of records of 109 patients with NFPA, from 1996 to 2020, who received adjunctive GKRS, was performed. Patients who had received GKRS as the primary modality of treatment for NFPA were not included. RESULTS: Sixty-three (57.8%) patients were available for follow up at our institute. The median follow-up period was 47 months (range, 6-260). At a median time of 38 months (range, 8-97), 25 (39.7%) patients developed ≥ 1 new pituitary hormone deficiency. Median time to cortisol deficiency was 38 months (range, 8-55), thyroid hormone deficiency was 45.5 months (range, 12-97) and gonadotropin deficiency was 45 months (range, 21-75). The actuarial risk of developing a new pituitary hormone deficit at 1, 3, 5, 7, and 10 years was 2.5%, 11%, 26.3%, 28% and 29.7%, respectively. Adenoma size decreased in 36 (57.1%) patients, remained unchanged in 19 (30.2%) patients, and increased in 8 (12.7%) patients. Overall tumor control rate was 87.3%. Endocrinopathy-Free Survival was 47.1%, and tumor Progression-Free Survival was 93.3%, at 5 years. Five (4.6%) patients required additional treatment after GKRS. One (1.6%) patient each had worsening of headache, optic atrophy and cerebellar infarct after GKRS therapy. CONCLUSION: GKRS offers a safe adjunctive treatment modality, with satisfactory long-term preservation of hormone functions and a high rate of tumor control, in patients with NFPA.

Effect of distance from target on hypopituitarism after stereotactic radiosurgery for pituitary adenomas.

INTRODUCTION: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. The aim of this study was to investigate the relationship between the distance from the hypothalamic-pituitary axis to the treatment target and anterior pituitary function preservation after SRS. METHODS: Between 2007 and 2020, consecutive adult patients who underwent single-session SRS for non-functioning or hormone-secreting pituitary adenomas with ≥ 6 months of follow-up were included. Distance measurements between hypothalamic-pituitary axis structures and the SRS target volume were quantified on MRI. The primary outcome was anterior pituitary function preservation. Outcomes were compared using multivariable regression and area under the receiver operator characteristic curve (AUROC) analyses. RESULTS: The study cohort comprised 224 patients, who were categorized by preservation (n = 168) and no preservation (n = 56) of anterior pituitary function after SRS. The mean and median clinical follow-up durations were 53.7 (38.0) and 46.0 (17.0-75.0) months, respectively. Independent predictors of anterior pituitary function preservation were a greater distance between the center of the pituitary gland and center of the SRS target [OR 1.101 (1.000-1.213), p = 0.050], and a shorter clinical follow-up duration [OR 0.985 (0.977-0.993), p < 0.0001]. The adjusted AUROC for the distance from the center of the pituitary gland and center of the SRS target in predicting anterior pituitary function preservation was 0.595. The sensitivity, specificity, positive predictive value and negative predictive value in predicting anterior pituitary function preservation at the optimal cut-off distance of 15 mm were 30.0, 88.0, 89.9 and 26.2%, respectively. CONCLUSIONS: Greater distance between the normal pituitary gland and the SRS target is associated with anterior pituitary function preservation and increasing this distance should be a goal of adenoma resection. Larger prospective, multi-center studies are necessary to corroborate this finding and establish the effects of distance on hypopituitarism after SRS for pituitary adenomas.

Endocrine disorders after primary gamma knife radiosurgery for pituitary adenomas: A systematic review and meta-analysis.

PURPOSE: Gamma Knife radiosurgery (GKRS) is feasible for pituitary adenomas, but post-surgery GKRS may cause severe hormone deficits. We reviewed the literature on primary GKRS for pituitary adenoma focusing on radiation-induced hormone deficiencies. METHODS: PubMed, Web-of-Science, Scopus, and Cochrane were searched upon the PRISMA guidelines to include studies describing primary GKRS for pituitary adenomas. Pooled-rates of GKRS-induced hormone deficiencies and clinical-radiological responses were analyzed with a random-effect model meta-analysis. RESULTS: We included 24 studies comprising 1381 patients. Prolactinomas were the most common (34.2%), and 289 patients had non-functioning adenomas (20.9%). Median tumor volume was 1.6cm3 (range, 0.01-31.3), with suprasellar extension and cavernous sinus invasion detected in 26% and 31.1% cases. GKRS was delivered with median marginal dose 22.6 Gy (range, 6-49), maximum dose 50 Gy (range, 25-90), and isodose line 50% (range, 9-100%). Median maximum point doses were 9 Gy (range, 0.5-25) to the pituitary stalk, 7 Gy (range, 1-38) to the optic apparatus, and 5 Gy (range, 0.4-12.3) to the optic chiasm. Pooled 5 year rates of endocrine normalization and local tumor control were 48% (95%CI 45-51%) and 97% (95%CI 95-98%). 158 patients (11.4%) experienced endocrinopathies at a median of 45 months (range, 4-187.3) after GKRS, with pooled 5-year rates of 8% (95%CI 6-9%). GKRS-induced hormone deficiencies comprised secondary hypothyroidism (42.4%) and hypogonadotropic hypogonadism (33.5%), with panhypopituitarism reported in 31 cases (19.6%). CONCLUSION: Primary GKRS for pituitary adenoma may correlate with lower rates of radiation-induced hypopituitarism (11.4%) than post-surgery GKRS (18-32%). Minimal doses to normal pituitary structures and long-term endocrine follow-up are of primary importance.

Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS: This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS: The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17-2.68, p = 0.006). CONCLUSIONS: SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas: An alternative escalating protocol of hypofractionated stereotactic radiotherapy delivering 35Gy in 5 fractions.

PURPOSE: Evaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for patients treated for pituitary adenoma (PA) with an alternative HSRT escalating protocol delivering 35Gy in 5 fractions. MATERIAL AND METHODS: From June 2007 to March 2017, 29 patients with pituitary adenoma were treated in Antoine Lacassagne Cancer Centre with an alternative HSRT protocol. Prescribed dose was 35Gy in 5 fractions of 7Gy. Radiographic responses were assessed by annual MRI. Hormone blood samples were evaluated each year after HSRT. RESULTS: A total of 29 patients aged between 23 and 86 years (median 54 years) were included. Twelve patients received HSRT for recurrent cases and 12 received postoperative adjuvant HSRT, 5 patients did not have surgery. After a median follow-up period of 47 months local control rate was 96%. One patient presented an out-field tumor regrowth 73 months after HSRT. The majority of PA were endocrine-active (18 patients, 62%). After HSRT, 8 patients (44%) presented complete response on initial secretion, 4 patients (23%) presented partial response on initial secretion. Four patients (14%) presented grade 2 or more acute radiation toxicities. One grade 4 visual disorder was observed for one patient. CONCLUSIONS: HSRT delivering 35Gy in 5 fractions represents a feasible treatment and shows promising results to reduce hormonal overproduction and to improve local control in PA.