Results of Stereotactic Radiotherapy Using The CyberKnife-M6 For Patients With Pituitary Tumors Running Head: Radiotherapy For Pituitary Tumors

Results of Stereotactic Radiotherapy Using The CyberKnife-M6 For Patients With Pituitary Tumors Running Head: Radiotherapy For Pituitary Tumors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Results of Stereotactic Radiotherapy Using The CyberKnife-M6 For Patients With Pituitary Tumors Running Head: Radiotherapy For Pituitary Tumors Sureyya Sarihan, Aybuke Tugce Metin, Javad Teimouri, Elmas Nur Ece Uygur, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8422217/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 22 You are reading this latest preprint version Abstract Background This study aimed to evaluate the efficacy of hypofractionated stereotactic radiotherapy (hSRT) using the CyberKnife-M6 (CK-M6) system in patients with pituitary tumors. Methods Between 2020 and 2024, 27 patients were treated. Follow-up evaluations were conducted at 3 months, 9 months, and annually after treatment. Results The median follow-up duration was 22 months (10–58), and the median age was 51 years (32–78). The median interval between surgery and hSRT was 45 months (3- 214). The median planning target volume was 5.23 cc (0.15–30.42). Patients received a median dose of 23 Gy (18–25) over 3 to 5 fractions. The median biologically effective dose (BED 2 ) value was 81.6 (60- 94.5). The median beam-on time was 16 minutes (12–22). Visual function was preserved in 96% of the cases, while new-onset hypopituitarism was observed in 11%. At the last follow-up, radiologically objective response, stable disease, and progression rates were 30%, 63%, and 7%, respectively. Hormonal response was achieved in 67% (4 out of 6) of functioning adenomas, with a median time of 22 months (3–39). The two-year rates for local control, overall survival, and progression-free survival were 96,3%, 91,2%, and 90,8%, respectively. Conclusions CK-M6-based hSRT offers a precise treatment option for patients with pituitary adenoma, with 96% local control, and the added benefit of a shorter treatment duration. pituitary adenoma stereotactic radiotherapy CyberKnife-M6 local control Figures Figure 1 Figure 2 BACKGROUND The prevalence of pituitary tumors in autopsy series is approximately 10.7%, occurring clinically in 1 in 1100 people, and accounting for 10–15% of all intracranial tumors [ 1 , 2 , 3 ]. Tumors smaller than 10 mm are classified as microadenomas, which make up 52% of all cases, while those measuring 10 mm or larger are termed macroadenomas, comprising 48%. Pituitary tumors can also be categorized as functioning or non-functioning adenomas (NFAs) [ 1 , 2 ]. Hormonally active tumors secrete various hormones: prolactin (53%), growth hormone (GH, 12%), adrenocorticotropic hormone (4%), and thyroid-stimulating hormone (1–2%) [ 3 ]. Most pituitary tumors are asymptomatic but may present with symptoms due to mass effect, such as headaches, visual disturbances, and cranial nerve deficits, or hormone secretion, leading to conditions like prolactinoma, acromegaly, and Cushing's disease [ 3 ]. The majority of NFAs are macroadenomas, and 37–85% of them have partial hypopituitarism at diagnosis [ 1 , 2 ]. According to the WHO 2022 classification, pituitary adenomas are labeled as pituitary neuroendocrine tumors (PitNETs) based on their cell type and hormone production; NFAs constitute 15–40% of these cases [ 4 ]. This classification identified three cell lineages: pituitary-specific transcription factor 1, steroidogenic transcription factor 1, and T-box transcription factor, which exhibit variations in terms of invasion, extrasellar growth patterns, and Ki-67 index. It was also reported that progression-free survival (PFS) was different for these. Standard treatment for pituitary adenomas typically involves surgery and/or pharmacological therapy. In many situations, complete resection is not feasible due to its proximity to neurovascular structures, invasion of the cavernous sinus, or extension beyond the pituitary fossa. Current meta-analyses indicate that recurrence rates after surgery range from 32% to 68% [ 5 ]. Radiotherapy (RT) is a suitable option for recurrent or inoperable pituitary adenomas [ 6 ]. Depending on the tumor’s proximity to the optic structures, RT can be administered as conventional or stereotactic RT (SRT). SRT offers local control (LC) rates up to 90% and endocrine control rates between 59% and 96% [ 7 ]. CyberKnife (CK), a form of robotic RT, delivers high-dose radiation to the tumor while minimizing exposure to surrounding critical structures through real-time imaging guidance [ 6 , 8 , 9 ]. The next-generation CyberKnife Model 6 (CK-M6) improved plan quality and reduced treatment time, providing a more precise and comfortable treatment experience [ 10 ]. This study aimed to evaluate the efficacy of hypofractionated SRT (hSRT) using the CK-M6 in patients with pituitary tumors. METHODS Study design This retrospective cohort study included 27 patients with histologically confirmed pituitary tumors treated between June 2020 and July 2024. hSRT was initiated after previous treatments, including surgery and/or pharmacological therapy, had failed. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethics Committee (2025/12–18). Written informed consent was obtained from all participants. Study population Patients were immobilized with a non-invasive cranial mask and underwent simulation computed tomography (CT) and magnetic resonance imaging (MRI) scans, both performed in the supine position with a slice thickness of 1 mm. Then, CT and MRI images were fused. The gross target volume (GTV) was defined as the visible tumor volume, while the planning target volume (PTV) was created by adding a median margin of 1 mm (0–1) to the GTV, based on its proximity to critical structures. Dose constraints for organs at risk (OARs) were established following the American Association of Physicists in Medicine Task Group Report 101 [ 11 ]. Treatment plans were generated using the VOLO optimizer, which employed a high-resolution calculation method, inverse optimization, and a non-isocentric algorithm. All plans were created with a multileaf collimator using a finite-size pencil-beam algorithm, except for two patients treated with a fixed collimator. The treatment plan aimed to have at least 95% of the PTV receive the prescribed dose. Treatment was administered consecutively or every other day on the CK-M6 device, with kilovoltage imaging taken at intervals of 20 to 60 seconds, depending on the stability of patient positioning. Patients were followed through MRI and hormone panels at 3 months, 9 months, and annually after treatment. The primary endpoints of the study included LC and hormonal response, and preservation of visual function. Secondary endpoints included overall survival (OS), PFS, and adverse events. Radiographic response was evaluated according to the Response Evaluation Criteria in Solid Tumours, 1.1 criteria. Hormonal responses were evaluated according to the International Radiosurgery Society guidelines (12). Acute and late side effects were assessed using the Common Terminology Criteria for Adverse Events, v5.0. Statistical analysis Data were analyzed using SPSS version 21 software. Local control was defined as the time from the beginning of hSRT to local recurrence, death, or the last follow-up. OS was calculated from the beginning of hSRT to death, or the last follow-up. PFS was measured from the beginning of hSRT to any recurrence, death, or the last follow-up. Clinical and dosimetric parameters were reported as medians. LC, OS, and PFS were estimated using the Kaplan-Meier method, and univariate analysis was conducted using the log-rank test. A multivariate analysis was not performed because statistically significant prognostic factors could not be determined in the univariate analysis. A p-value of < 0.05 was considered statistically significant. RESULTS Clinical characteristics Clinical characteristics of patients are presented in Table 1. The median age of the patients was 51 years (32- 78), with 59% being male. The median duration of symptoms was 1 month (1- 72) before diagnosis. The most common symptom reported by the patients was visual disturbances (n: 20, 74%), but visual field deficits were observed in 13 cases (48%) on ophthalmologic examination. Other symptoms included headache (n: 9, 33%), menstrual irregularities (n: 4, 15%), acral enlargement (n: 3, 11%), and galactorrhea (n: 2, 7%). Among the cases, 74% were diagnosed with NFAs, while 26% had functioning adenomas. The median tumor size at diagnosis was 31 mm (10- 70), and all were macroadenomas. Cavernous sinus invasion was detected in 70% of patients, and suprasellar extension was present in all but one case. Before hSRT, patients had a median of one surgery (1- 3). The median interval between diagnosis and surgery was 1.5 months (1- 120). Postoperatively, 6 patients (85%, 6/7) with functioning adenomas continued medical treatment. Fourteen patients (70%, 14/20) with NFA were receiving hormone replacement therapy after surgery due to hypopituitarism. Visual field deficits improved in 7 patients (54%, 7/13), regressed in 2 (15%, 2/13), and remained stable in 4 (31%, 4/13), while 2 patients (7%, 2/27) developed new visual field deficits after surgery. Treatment outcomes Patients were evaluated as of May 1, 2025, with a median follow-up of 22 months (10- 58). Dosimetric data are shown in Table 2. Before hSRT, the median tumor diameter was 20 mm (5- 40). The median interval between the last surgery and hSRT was 24 months (3- 214). One patient with acromegaly had a history of previous hSRT (20 Gy in 4 fractions) and received a second series of CK-based hSRT (18 Gy in 3 fractions) 135 months later. Fractionated regimens were selected based on tumor size, proximity to optical structures, and patient factors such as comorbidities and performance status. A median of 23 Gy was administered in 3 fractions (18- 25 Gy in 3- 5 fractions) over a median of 8 days (4- 10). The median biologically effective dose (BED) was 81.6 (60- 94.5) and 61.75 (46.67- 70) when the α/β ratio was 2 and 3, respectively. The median GTV and PTV were 4 cc (0.15- 30.42) and 5.23 cc (0.15- 30.42), respectively. The median coverage of PTV was 95.02% (94.82- 98.11). The median beam-on time was 16 minutes (12- 22). Treatment was well tolerated with no cases exceeding dose constraints for OARs (Table 3). Of the 8 patients with visual field deficit before hSRT, none except one showed any deterioration or new deficits after hSRT. Among these, one patient, diagnosed with non-functioning neuroendocrine carcinoma (NEC), experienced visual deterioration 10 months after hSRT, despite receiving 22.5 Gy in 5 fractions within the tolerance limit. Overall, visual function was preserved in 96% of patients. At first evaluation, with a median of 3 months (2.5- 9) after hSRT, partial response (PR), stable disease (SD), and progression were observed in 11% (n= 3), 81% (n= 22), and 4% (n=1) of patients, respectively (Figure 1). Pseudoprogression was noted at 3 months in one NFA patient, with regression at the next control and SD at 24 months follow-up. One patient with an NFA who showed progression underwent two surgeries and was alive with LC at the last follow-up. Among patients with SD at 3 months, at a median follow-up of 12 months (10- 21), one achieved a complete response (CR) and five achieved PR (Figure 2). One of the acromegaly patients with initial PR progressed 40 months after hSRT and underwent a second surgery. At the last follow-up, CR, PR, SD, and progression rates were 4% (1/27), 26% (7/27), 63% (17/27), and 7% (2/27), respectively. At diagnosis, 6 patients (22%) were on thyroid replacement therapy; three due to prior thyroid surgery (two papillary carcinoma, one hyperthyroidism) and three for hypothyroidism. Among 14 patients receiving medication for postoperative hypopituitarism, nine also required thyroid replacement. New treatment-related hypopituitarism occurred in a total of 3 patients (11%) at a median of 27 months (6- 54). At the last follow-up, 17 patients (63%) were on thyroid replacement therapy. Adrenal insufficiency developed in two patients at 6 and 27 months after hSRT. Three patients with acromegaly had normal postoperative GH levels, but elevated insulin-like growth factor 1 (IGF-1) levels, and two patients also had residual mass progression. Following hSRT, IGF-1 levels returned to normal in two patients at 34 and 39 months. The third patient experienced a regression in hormone levels at 3 months after hSRT, with stability maintained thereafter. One of the prolactinoma patients received hSRT due to residual mass and extrasellar growth pattern despite achieving hormonal normalization after surgery. Of the other two cases, one achieved biochemical control at 22 months after hSRT, and the other has a stable hormonal status at 31 months of follow-up. These 6 patients were on medication until the last follow-up. Hormonal response was observed in 67% of them (4 out of 6) at a median of 22 months (3- 39). At the last follow-up, 24 patients were alive. One patient with Cushing's disease who showed PR after hSRT died of an unknown cause with 18 months of follow-up. The patient diagnosed with NEC developed widespread bone metastases at 28 months and local recurrence at 30 months after hSRT; despite systemic therapy, palliative RT, and Lutetium-177 treatment, the patient died of progression at 53 months. One of the NFA patients developed a second primary lung cancer five months after hSRT, unrelated to treatment, and died of distant metastases ten months later. The mean and 2-year LC rates were 49 months (± 3.07) and 96.3%. The mean and 2-year OS and PFS rates were 53 months (± 2.65) and 91.2%, and 49 months (± 3.17) and 90.8%, respectively. DISCUSSION The treatment of pituitary adenomas includes surgery, pharmacological therapy, and RT. Recurrence after surgery can occur in 24–80% of cases, and the goal of RT is to reduce recurrence rates while improving local and hormonal control [ 5 , 6 ]. The choice of RT modality is influenced by the tumor’s proximity to optic structures, and it may involve either conventional or stereotactic RT. In studies using conventional RT (45- 50.4 Gy over 25–28 fractions), LC rates range from 83% to 100%, and hormonal remission was achieved in 20–42% of cases. However, it is important to note that pituitary function worsened in 18–40% of patients [ 6 , 13 , 14 ]. Modern RT techniques include single-fraction stereotactic radiosurgery (SRS) or hSRT, typically consisting of up to 5 treatments. These can be delivered using various systems, such as linear accelerators (LINAC), GammaKnife (GK), or CyberKnife. SRS provides several benefits, including a shorter overall treatment duration, increased patient comfort, and earlier endocrine remission [ 7 ]. Studies on GK-based or LINAC-based SRS have reported LC rates of 83–100%, similar to conventional RT, with rates of new hypopituitarism ranging from 0% to 40% [ 15 ]. One notable advantage of SRS is its higher hormonal remission rates, which range from 5–63% compared to 20–42% for conventional RT [ 15 ]. However, in cases involving larger tumors (GTV > 5 cc), SRS has been associated with visual deterioration in 3–9% of patients [ 16 ]. Due to the need for rigid immobilization and the limitations of GK-based SRS in delivering multiple fractions, CK-based hSRT is a reliable, non-invasive, and alternative treatment option. In a study of 100 patients treated with CK-based hSRT (17–25 Gy in 3–5 fractions), both 3-year LC and OS rates were reported at 98% [ 17 ]. Visual complications occurred in only 2% of patients, and hypopituitarism was observed in 4%, demonstrating that hSRT is effective and safe, even for large tumors near optical structures. Puataweepong et al. administered CK-based hSRT at a median dose of 25 Gy (20–28 Gy in 3–5 fractions) to 40 patients with perioptic tumors [ 15 ]. With a median follow-up period of 38.5 months, they reported a 20% PR and 77.5% SD. Importantly, no new cases of hypopituitarism were observed, and hormonal normalization was achieved in 54% of the patients. Visual deficits were present in 28% of patients before hSRT, with 18% showing improvement post-treatment, and no new deterioration in vision was reported. In a more recent study involving 178 patients with perioptic NFAs, CK-based SRT was administered at a median dose of 18 Gy (12–33) over 1 to 5 fractions [ 8 ]. This resulted in a 5-year PFS rate of 95%. Hypopituitarism was associated with a BED exceeding 140 Gy (α/β = 2.1) and a single-fraction equivalent dose greater than 16 Gy. At a median follow-up of 42 months, 5.1% of patients developed new visual deficits, with a tumor volume greater than 2.5 cc identified as a significant factor. In our study, before hSRT, 52% of patients had hypopituitarism, and new cases developed in 11% at a median of 27 months (6–54). The median PTV was 5,23 cc, and the median BED 2,1 was 54.85 (38.09- 70), with no significant complications. Overall, vision was preserved in 96% of the patients. SRT is more effective in controlling hypersecretion within a shorter timeframe than conventional RT and requires higher doses compared to NFAs [ 9 , 13 , 18 , 19 , 20 ]. In a study involving 57 patients with acromegaly, postoperative CK-M6-based SRS yielded the following outcomes after 4 years of follow-up: biochemical remission in 46% of patients (without medical treatment), biochemical control in 33% (with medical treatment), and a biochemical cure in 12% at the last follow-up [ 9 ]. Notably, high levels of IGF-1 (greater than 1.2 times the upper limit of normal) before SRS and the presence of cavernous sinus invasion were identified as unfavorable prognostic factors. Additionally, new hypopituitarism was observed in 24.5% of patients, and secondary brain malignancies occurred in 3.5%. Importantly, no cases of stroke or optic neuritis were reported. Abdali et al. evaluated 41 patients with postoperative recurrent or persistent hypercortisolism due to Cushing’s disease [ 19 ]. They treated the patients with CK-based SRS (83%) or hSRT (17%). Hormonal remission was achieved in 61% of patients after a median period of 14 months (5–62), with tumor control reached in 95% of cases. However, new hypopituitarism developed in 34% of patients, predominantly presenting as hypothyroidism and hypogonadism. For patients with prolactinomas who do not respond to medical or surgical treatments, the effectiveness of SRS has been assessed in a meta-analysis [ 20 ]. Although the LC rate was 90%, only 33% of patients achieved endocrine remission, often for a long time, at a median of 54 months. Furthermore, 26% of patients developed new hypopituitarism. In one study using CK-based hSRT, hormonal remission was noted at a median of 28 months (24–71), with success rates of 57% for acromegaly, 100% for Cushing's disease, and 40% for prolactinoma [ 21 ]. NECs of the pituitary gland are rare, accounting for only 1–3% of such tumors, and most of them are non-functioning [ 4 ]. These tumors typically present at a young age, are often large, and frequently invade the cavernous sinus. Unfortunately, their prognosis is poor due to the likelihood of distant metastasis. Factors such as age over 50, larger tumor diameter, tumor volume greater than 5 cc, cavernous sinus invasion, suprasellar extension, and postoperative residual tumor serve as significant predictors of poor outcomes in pituitary adenomas [ 5 , 9 , 18 , 22 , 23 ]. For endocrine remission, relevant prognostic factors include age, cavernous sinus invasion, diagnosis of acromegaly, and radiation dose [ 12 , 19 ]. In our study, biochemical control was achieved in 67% (4 out of 6) of functioning adenomas at a median of 22 months (3–39). Biochemical control was 100% for acromegaly and 50% (1 in 2) for prolactinoma. No statistically significant factors were identified for LC, hormonal control, or survival, likely due to the small sample size and the fact that all cases were macroadenomas. In SRT applications, radiobiological effectiveness is related to treatment duration and BED [ 24 ]. CK-based hSRT provides excellent target coverage and conformity due to a steep dose fall-off behind the target [ 10 , 25 ]. Additionally, new optimization techniques (such as VOLO) offer advantages including reduced body dose with fewer monitor units, a lower risk of secondary malignancies, and shorter treatment durations [ 26 ]. Different cutoff values ​​for the α/β ratio ​​have been reported in the calculation of BED in pituitary tumors [ 8 , 15 , 17 , 21 ]. In a study involving 100 cases of perioptic tumors treated with CK-based hSRT using a total dose of 25 Gy over 5 fractions, a high median BED 2 of 87.5 was observed [ 21 ]. This result indicates a radiobiological advantage, alongside low optical toxicity and high treatment compliance due to completion within one week. Furthermore, there was a 54% hormonal normalization at a median follow-up of 28 months. In the study by Iwata et al., a 15% higher BED 3 value, as well as better conformity and homogeneity index, were seen with CK-based hSRT compared with GK-based SRS [ 17 ]. Puataweepong et al. also reported a LC rate of 97.5% with a median BED 3 of 66.7 Gy in a study involving 40 patients treated with CK-based hSRT [ 15 ]. Current guidelines indicate that there is no difference between hSRT and SRS; however, fractionated treatments tend to reduce toxicity [ 12 , 27 ]. It is also emphasized that upfront hSRT within 6 months after surgery increases the LC and hormonal response. In our study, the median coverage rate of 95.02%, indicating good conformity and homogeneous dose distribution. Although the median gradient index was 4.02 (2.86–10.79), no OARs dose thresholds were exceeded in any case. The median treatment duration was 16 minutes, demonstrating high patient compliance. BED 2 and BED 3 values were recorded at 81.6 and 61.75, respectively, and consistent with the literature, a 2-year LC rate of 96.3% was achieved. The median interval from surgery to hSRT was 24 months (5- 144) for acromegaly patients, 15 months (3-197) for prolactinomas, and 6 months for one patient with Cushing's disease. Due to the small number of patients, we were unable to evaluate the relationship between interval and response rates, and no correlation was found between dosimetric factors and LC or survival. The study presents a significant advantage in that it provides a safe and comfortable therapy by selecting a treatment regimen tailored to each patient’s characteristics. However, a notable disadvantage is the small patient population and the need for longer follow-up periods to adequately assess side effects and the potential for secondary malignancies. CONCLUSIONS The results indicate that CK-M6-based hSRT is an effective and non-invasive treatment option for patients with pituitary tumors. Our patients exhibited a high 2-year LC rate of 96.3%, which is consistent with previous studies. Visual function was preserved in 96% of patients. Hormonal control was achieved in 67% of cases, although new-onset hypopituitarism occurred in 11% of patients. With a median beam-on time of 16 minutes, CK-M6-based hSRT offers a precise, safe, and well-tolerated treatment option. Abbreviations NFAs non-functioning adenomas GH growth hormone PitNETS pituitary neuroendocrine tumors (PitNETs) PFS progression-free survival RT radiotherapy SRT stereotactic RT LC local control CK CyberKnife CK-M6 CyberKnife Model 6 hSRT hypofractionated SRT CT computed tomography MRI magnetic resonance imaging GTV gross target volume PTV planning target volume OARs organs at risk OS overall survival BED biologically effective dose NEC non-functioning neuroendocrine carcinoma PR partial response SD stable disease CR complete response IGF-1 insulin-like growth factor 1 SRS single-fraction stereotactic radiosurgery LINAC linear accelerator GK GammaKnife. Declarations ETHICS APPROVAL and CONSENT TO PARTICIPATE This study was conducted in accordance with the principles of the Declaration of Helsinki Approval was granted by the Ethics Committee of Bursa Uludag University (2025/12–18). CONSENT FOR PUBLICATION Informed consent was obtained from all patients included in the study. COMPETING INTEREST The authors declare that they have no relevant financial or non-financial interests to disclose. FUNDING None declared. Author Contribution SS, ATM, JT, ENEU, SGT all met the ICMJE criteria for authorship. SS performed the design and conceptualization of the study. SS, ATM, JT, ENEU, and SGT performed data collection and analysis. Statistical analysis was conducted by SS. The first draft of the manuscript was written by SS. All authors read and approved the final manuscript. ACKNOWLEDGEMENTS The authors declare that no funds, grants, or other forms of support were received during the preparation of this manuscript. Data Availability The datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request. References Chin SO. Epidemiology of functioning pituitary adenomas. Endocrinol Metab (Seoul). 2020;35(2):237–42. https://doi:10.3803/EnM.2020.35.2.237 . 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Stereotactic radiosurgery for residual and recurrent nonfunctioning pituitary adenomas: A contemporary case series of GammaKnife and CyberKnife radiosurgery. World Neurosurg. 2020;143:e60–9. https://doi:10.1016/j.wneu.2020.06.191 . Kotecha R, Sahgal A, Rubens M, et al. Stereotactic radiosurgery for non-functioning pituitary adenomas: meta-analysis and International Stereotactic Radiosurgery Society practice opinion. Neuro Oncol. 2020;22(3):318–32. https://doi:10.1093/neuonc/noz225 . Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table13.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 22 Apr, 2026 Reviews received at journal 05 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviews received at journal 03 Feb, 2026 Reviews received at journal 03 Feb, 2026 Reviews received at journal 02 Feb, 2026 Reviews received at journal 01 Feb, 2026 Reviewers agreed at journal 01 Feb, 2026 Reviews received at journal 31 Jan, 2026 Reviewers agreed at journal 31 Jan, 2026 Reviews received at journal 31 Jan, 2026 Reviews received at journal 30 Jan, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers agreed at journal 30 Jan, 2026 Reviewers invited by journal 30 Jan, 2026 Editor invited by journal 09 Jan, 2026 Editor assigned by journal 26 Dec, 2025 Submission checks completed at journal 26 Dec, 2025 First submitted to journal 22 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8422217","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":564910319,"identity":"c35dfca3-55ce-473c-8789-c3a6df606d3e","order_by":0,"name":"Sureyya 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08:49:09","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98338,"visible":true,"origin":"","legend":"","description":"","filename":"28689aaf3ba34858b6507b460076d95c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/32ee023a6da330a1a6053726.xml"},{"id":99214437,"identity":"740dc246-90c9-4274-b737-2eaff46dc9f9","added_by":"auto","created_at":"2025-12-30 08:49:09","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109491,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/1bd4f56e48c3ffad6ce1e054.html"},{"id":99214427,"identity":"f711110c-08ce-40ea-86f0-f20da0eeec48","added_by":"auto","created_at":"2025-12-30 08:49:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":347130,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e1a.\u003c/strong\u003e A 40-year-old male patient with recurrent prolactinoma received 25 Gy in 5 fractions of hSRT. \u003cstrong\u003eDmax/Volume dose:\u003c/strong\u003e Chiasm 1433/ 665, Right optic nerve 1985/ 414, Left optic nerve 236/ 101, Brainstem 324/ 239 cGy. \u003cstrong\u003e1b\u003c/strong\u003e. MRI imaging 3 months after hSRT. Local control (stable response) and hormonal control were achieved at 3 months and remained stable through 31 months of follow-up.\u003c/p\u003e","description":"","filename":"figure1tiff300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/fbcde1ff768f8b0edf521e1f.png"},{"id":99317874,"identity":"375c8899-1a23-44f7-8614-379a3b8196bb","added_by":"auto","created_at":"2025-12-31 16:30:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":379035,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e2a.\u003c/strong\u003e A 53-year-old male patient with an NFA received 23 Gy in 5 fractions of hSRT. \u003cstrong\u003eDmax/Volume dose:\u003c/strong\u003e Chiasm 2340/ 2265, Right optic nerve 1152/ 137, Left optic nerve 1229/ 106, Brainstem 872/ 682 cGy. \u003cstrong\u003e2b.\u003c/strong\u003e MR imaging before hSRT. \u003cstrong\u003e2c.\u003c/strong\u003eMRI imaging 19 months after hSRT. The patient with a stable response at 3 months after hSRT achieved a partial response after 19 months and was stable at the last control with 40 months of follow-up.\u003c/p\u003e","description":"","filename":"figure2tiff300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/131b8779e4655cdc469da4b9.png"},{"id":99788216,"identity":"718aee04-6bea-4e82-a112-2a2bfaed9d05","added_by":"auto","created_at":"2026-01-08 12:45:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1583430,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/20e5fd3d-1d07-4eb5-bc23-358e41296a8b.pdf"},{"id":99214425,"identity":"72957dd9-c99b-44a4-8c43-2675cf1e9315","added_by":"auto","created_at":"2025-12-30 08:49:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18646,"visible":true,"origin":"","legend":"","description":"","filename":"Table13.docx","url":"https://assets-eu.researchsquare.com/files/rs-8422217/v1/3ee06f7ace5e06ca021484e0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Results of Stereotactic Radiotherapy Using The CyberKnife-M6 For Patients With Pituitary Tumors Running Head: Radiotherapy For Pituitary Tumors","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eThe prevalence of pituitary tumors in autopsy series is approximately 10.7%, occurring clinically in 1 in 1100 people, and accounting for 10\u0026ndash;15% of all intracranial tumors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Tumors smaller than 10 mm are classified as microadenomas, which make up 52% of all cases, while those measuring 10 mm or larger are termed macroadenomas, comprising 48%. Pituitary tumors can also be categorized as functioning or non-functioning adenomas (NFAs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hormonally active tumors secrete various hormones: prolactin (53%), growth hormone (GH, 12%), adrenocorticotropic hormone (4%), and thyroid-stimulating hormone (1\u0026ndash;2%) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Most pituitary tumors are asymptomatic but may present with symptoms due to mass effect, such as headaches, visual disturbances, and cranial nerve deficits, or hormone secretion, leading to conditions like prolactinoma, acromegaly, and Cushing's disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The majority of NFAs are macroadenomas, and 37\u0026ndash;85% of them have partial hypopituitarism at diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to the WHO 2022 classification, pituitary adenomas are labeled as pituitary neuroendocrine tumors (PitNETs) based on their cell type and hormone production; NFAs constitute 15\u0026ndash;40% of these cases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This classification identified three cell lineages: pituitary-specific transcription factor 1, steroidogenic transcription factor 1, and T-box transcription factor, which exhibit variations in terms of invasion, extrasellar growth patterns, and Ki-67 index. It was also reported that progression-free survival (PFS) was different for these.\u003c/p\u003e \u003cp\u003eStandard treatment for pituitary adenomas typically involves surgery and/or pharmacological therapy. In many situations, complete resection is not feasible due to its proximity to neurovascular structures, invasion of the cavernous sinus, or extension beyond the pituitary fossa. Current meta-analyses indicate that recurrence rates after surgery range from 32% to 68% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Radiotherapy (RT) is a suitable option for recurrent or inoperable pituitary adenomas [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Depending on the tumor\u0026rsquo;s proximity to the optic structures, RT can be administered as conventional or stereotactic RT (SRT). SRT offers local control (LC) rates up to 90% and endocrine control rates between 59% and 96% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCyberKnife (CK), a form of robotic RT, delivers high-dose radiation to the tumor while minimizing exposure to surrounding critical structures through real-time imaging guidance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The next-generation CyberKnife Model 6 (CK-M6) improved plan quality and reduced treatment time, providing a more precise and comfortable treatment experience [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate the efficacy of hypofractionated SRT (hSRT) using the CK-M6 in patients with pituitary tumors.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included 27 patients with histologically confirmed pituitary tumors treated between June 2020 and July 2024. hSRT was initiated after previous treatments, including surgery and/or pharmacological therapy, had failed. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethics Committee (2025/12\u0026ndash;18). Written informed consent was obtained from all participants.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003ePatients were immobilized with a non-invasive cranial mask and underwent simulation computed tomography (CT) and magnetic resonance imaging (MRI) scans, both performed in the supine position with a slice thickness of 1 mm. Then, CT and MRI images were fused. The gross target volume (GTV) was defined as the visible tumor volume, while the planning target volume (PTV) was created by adding a median margin of 1 mm (0\u0026ndash;1) to the GTV, based on its proximity to critical structures. Dose constraints for organs at risk (OARs) were established following the American Association of Physicists in Medicine Task Group Report 101 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Treatment plans were generated using the VOLO optimizer, which employed a high-resolution calculation method, inverse optimization, and a non-isocentric algorithm. All plans were created with a multileaf collimator using a finite-size pencil-beam algorithm, except for two patients treated with a fixed collimator. The treatment plan aimed to have at least 95% of the PTV receive the prescribed dose. Treatment was administered consecutively or every other day on the CK-M6 device, with kilovoltage imaging taken at intervals of 20 to 60 seconds, depending on the stability of patient positioning.\u003c/p\u003e \u003cp\u003ePatients were followed through MRI and hormone panels at 3 months, 9 months, and annually after treatment. The primary endpoints of the study included LC and hormonal response, and preservation of visual function. Secondary endpoints included overall survival (OS), PFS, and adverse events. Radiographic response was evaluated according to the Response Evaluation Criteria in Solid Tumours, 1.1 criteria. Hormonal responses were evaluated according to the International Radiosurgery Society guidelines (12). Acute and late side effects were assessed using the Common Terminology Criteria for Adverse Events, v5.0.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using SPSS version 21 software. Local control was defined as the time from the beginning of hSRT to local recurrence, death, or the last follow-up. OS was calculated from the beginning of hSRT to death, or the last follow-up. PFS was measured from the beginning of hSRT to any recurrence, death, or the last follow-up. Clinical and dosimetric parameters were reported as medians. LC, OS, and PFS were estimated using the Kaplan-Meier method, and univariate analysis was conducted using the log-rank test. A multivariate analysis was not performed because statistically significant prognostic factors could not be determined in the univariate analysis. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eClinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical characteristics of patients are presented in Table 1. The median age of the patients was 51 years (32- 78), with 59% being male. The median duration of symptoms was 1 month (1- 72) before diagnosis. The most common symptom reported by the patients was visual disturbances (n: 20, 74%), but visual field deficits were observed in 13 cases (48%) on ophthalmologic examination. Other symptoms included headache (n: 9, 33%), menstrual irregularities (n: 4, 15%), acral enlargement (n: 3, 11%), and galactorrhea (n: 2, 7%). Among the cases, 74% were diagnosed with NFAs, while 26% had functioning adenomas. The median tumor size at diagnosis was 31 mm (10- 70), and all were macroadenomas. Cavernous sinus invasion was detected in 70% of patients, and suprasellar extension was present in all but one case. Before hSRT, patients had a median of one surgery (1- 3). The median interval between diagnosis and surgery was 1.5 months (1- 120). Postoperatively, 6 patients (85%, 6/7) with functioning adenomas continued medical treatment. Fourteen patients (70%, 14/20) with NFA were receiving hormone replacement therapy after surgery due to hypopituitarism. Visual field deficits improved in 7 patients (54%, 7/13), regressed in 2 (15%, 2/13), and remained stable in 4 (31%, 4/13), while 2 patients (7%, 2/27) developed new visual field deficits after surgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were evaluated as of May 1, 2025, with a median follow-up of 22 months (10- 58). Dosimetric data are shown in Table 2. Before hSRT, the median tumor diameter was 20 mm (5- 40). The median interval between the last surgery and hSRT was 24 months (3- 214). One patient with acromegaly had a history of previous hSRT (20 Gy in 4 fractions) and received a second series of CK-based hSRT (18 Gy in 3 fractions) 135 months later. Fractionated regimens were selected based on tumor size, proximity to optical structures, and patient factors such as comorbidities and performance status. A median of 23 Gy was administered in 3 fractions (18- 25 Gy in 3- 5 fractions) over a median of 8 days (4- 10). The median biologically effective dose (BED) was 81.6 (60- 94.5) and 61.75 (46.67- 70) when the \u0026alpha;/\u0026beta; ratio was 2 and 3, respectively. The median GTV and PTV were 4 cc (0.15- 30.42) and 5.23 cc (0.15- 30.42), respectively. The median coverage of PTV was 95.02% (94.82- 98.11). The median beam-on time was 16 minutes (12- 22).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTreatment was well tolerated with no cases exceeding dose constraints for OARs (Table 3). Of the 8 patients with visual field deficit before hSRT, none except one showed any deterioration or new deficits after hSRT. Among these, one patient, diagnosed with non-functioning neuroendocrine carcinoma (NEC), experienced visual deterioration 10 months after hSRT, despite receiving 22.5 Gy in 5 fractions within the tolerance limit. Overall, visual function was preserved in 96% of patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt first evaluation, with a median of 3 months (2.5- 9) after hSRT, partial response (PR), stable disease (SD), and progression were observed in 11% (n= 3), 81% (n= 22), and 4% (n=1) of patients, respectively (Figure 1). Pseudoprogression was noted at 3 months in one NFA patient, with regression at the next control and SD at 24 months follow-up. One patient with an NFA who showed progression underwent two surgeries and was alive with LC at the last follow-up. Among patients with SD at 3 months, at a median follow-up of 12 months (10- 21), one achieved a complete response (CR) and five achieved PR (Figure 2). One of the acromegaly patients with initial PR progressed 40 months after hSRT and underwent a second surgery. At the last follow-up, CR, PR, SD, and progression rates were 4% (1/27), 26% (7/27), 63% (17/27), and 7% (2/27), respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt diagnosis, 6 patients (22%) were on thyroid replacement therapy; three due to prior thyroid surgery (two papillary carcinoma, one hyperthyroidism) and three for hypothyroidism. Among 14 patients receiving medication for postoperative hypopituitarism, nine also required thyroid replacement. New treatment-related hypopituitarism occurred in a total of 3 patients (11%) at a median of 27 months (6- 54). At the last follow-up, 17 patients (63%) were on thyroid replacement therapy. Adrenal insufficiency developed in two patients at 6 and 27 months after hSRT.\u003c/p\u003e\n\u003cp\u003eThree patients with acromegaly had normal postoperative GH levels, but elevated insulin-like growth factor 1 (IGF-1) levels, and two patients also had residual mass progression. Following hSRT, IGF-1 levels returned to normal in two patients at 34 and 39 months. The third patient experienced a regression in hormone levels at 3 months after hSRT, with stability maintained thereafter. One of the prolactinoma patients received hSRT due to residual mass and extrasellar growth pattern despite achieving hormonal normalization after surgery. Of the other two cases, one achieved biochemical control at 22 months after hSRT, and the other has a stable hormonal status at 31 months of follow-up. These 6 patients were on medication until the last follow-up. Hormonal response was observed in 67% of them (4 out of 6) at a median of 22 months (3- 39).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the last follow-up, 24 patients were alive. One patient with Cushing\u0026apos;s disease who showed PR after hSRT died of an unknown cause with 18 months of follow-up. The patient diagnosed with NEC developed widespread bone metastases at 28 months and local recurrence at 30 months after hSRT; despite systemic therapy, palliative RT, and Lutetium-177 treatment, the patient died of progression at 53 months. One of the NFA patients developed a second primary lung cancer five months after hSRT, unrelated to treatment, and died of distant metastases ten months later. The mean and 2-year LC rates were 49 months (\u0026plusmn; 3.07) and 96.3%. The mean and 2-year OS and PFS rates were 53 months (\u0026plusmn; 2.65) and 91.2%, and 49 months (\u0026plusmn; 3.17) and 90.8%, respectively.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe treatment of pituitary adenomas includes surgery, pharmacological therapy, and RT. Recurrence after surgery can occur in 24\u0026ndash;80% of cases, and the goal of RT is to reduce recurrence rates while improving local and hormonal control [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The choice of RT modality is influenced by the tumor\u0026rsquo;s proximity to optic structures, and it may involve either conventional or stereotactic RT. In studies using conventional RT (45- 50.4 Gy over 25\u0026ndash;28 fractions), LC rates range from 83% to 100%, and hormonal remission was achieved in 20\u0026ndash;42% of cases. However, it is important to note that pituitary function worsened in 18\u0026ndash;40% of patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eModern RT techniques include single-fraction stereotactic radiosurgery (SRS) or hSRT, typically consisting of up to 5 treatments. These can be delivered using various systems, such as linear accelerators (LINAC), GammaKnife (GK), or CyberKnife. SRS provides several benefits, including a shorter overall treatment duration, increased patient comfort, and earlier endocrine remission [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Studies on GK-based or LINAC-based SRS have reported LC rates of 83\u0026ndash;100%, similar to conventional RT, with rates of new hypopituitarism ranging from 0% to 40% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. One notable advantage of SRS is its higher hormonal remission rates, which range from 5\u0026ndash;63% compared to 20\u0026ndash;42% for conventional RT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, in cases involving larger tumors (GTV\u0026thinsp;\u0026gt;\u0026thinsp;5 cc), SRS has been associated with visual deterioration in 3\u0026ndash;9% of patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to the need for rigid immobilization and the limitations of GK-based SRS in delivering multiple fractions, CK-based hSRT is a reliable, non-invasive, and alternative treatment option. In a study of 100 patients treated with CK-based hSRT (17\u0026ndash;25 Gy in 3\u0026ndash;5 fractions), both 3-year LC and OS rates were reported at 98% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Visual complications occurred in only 2% of patients, and hypopituitarism was observed in 4%, demonstrating that hSRT is effective and safe, even for large tumors near optical structures. Puataweepong et al. administered CK-based hSRT at a median dose of 25 Gy (20\u0026ndash;28 Gy in 3\u0026ndash;5 fractions) to 40 patients with perioptic tumors [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. With a median follow-up period of 38.5 months, they reported a 20% PR and 77.5% SD. Importantly, no new cases of hypopituitarism were observed, and hormonal normalization was achieved in 54% of the patients. Visual deficits were present in 28% of patients before hSRT, with 18% showing improvement post-treatment, and no new deterioration in vision was reported. In a more recent study involving 178 patients with perioptic NFAs, CK-based SRT was administered at a median dose of 18 Gy (12\u0026ndash;33) over 1 to 5 fractions [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This resulted in a 5-year PFS rate of 95%. Hypopituitarism was associated with a BED exceeding 140 Gy (α/β\u0026thinsp;=\u0026thinsp;2.1) and a single-fraction equivalent dose greater than 16 Gy. At a median follow-up of 42 months, 5.1% of patients developed new visual deficits, with a tumor volume greater than 2.5 cc identified as a significant factor. In our study, before hSRT, 52% of patients had hypopituitarism, and new cases developed in 11% at a median of 27 months (6\u0026ndash;54). The median PTV was 5,23 cc, and the median BED\u003csub\u003e2,1\u003c/sub\u003e was 54.85 (38.09- 70), with no significant complications. Overall, vision was preserved in 96% of the patients.\u003c/p\u003e \u003cp\u003eSRT is more effective in controlling hypersecretion within a shorter timeframe than conventional RT and requires higher doses compared to NFAs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In a study involving 57 patients with acromegaly, postoperative CK-M6-based SRS yielded the following outcomes after 4 years of follow-up: biochemical remission in 46% of patients (without medical treatment), biochemical control in 33% (with medical treatment), and a biochemical cure in 12% at the last follow-up [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Notably, high levels of IGF-1 (greater than 1.2 times the upper limit of normal) before SRS and the presence of cavernous sinus invasion were identified as unfavorable prognostic factors. Additionally, new hypopituitarism was observed in 24.5% of patients, and secondary brain malignancies occurred in 3.5%. Importantly, no cases of stroke or optic neuritis were reported. Abdali et al. evaluated 41 patients with postoperative recurrent or persistent hypercortisolism due to Cushing\u0026rsquo;s disease [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. They treated the patients with CK-based SRS (83%) or hSRT (17%). Hormonal remission was achieved in 61% of patients after a median period of 14 months (5\u0026ndash;62), with tumor control reached in 95% of cases. However, new hypopituitarism developed in 34% of patients, predominantly presenting as hypothyroidism and hypogonadism.\u003c/p\u003e \u003cp\u003eFor patients with prolactinomas who do not respond to medical or surgical treatments, the effectiveness of SRS has been assessed in a meta-analysis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although the LC rate was 90%, only 33% of patients achieved endocrine remission, often for a long time, at a median of 54 months. Furthermore, 26% of patients developed new hypopituitarism. In one study using CK-based hSRT, hormonal remission was noted at a median of 28 months (24\u0026ndash;71), with success rates of 57% for acromegaly, 100% for Cushing's disease, and 40% for prolactinoma [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. NECs of the pituitary gland are rare, accounting for only 1\u0026ndash;3% of such tumors, and most of them are non-functioning [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These tumors typically present at a young age, are often large, and frequently invade the cavernous sinus. Unfortunately, their prognosis is poor due to the likelihood of distant metastasis. Factors such as age over 50, larger tumor diameter, tumor volume greater than 5 cc, cavernous sinus invasion, suprasellar extension, and postoperative residual tumor serve as significant predictors of poor outcomes in pituitary adenomas [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For endocrine remission, relevant prognostic factors include age, cavernous sinus invasion, diagnosis of acromegaly, and radiation dose [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study, biochemical control was achieved in 67% (4 out of 6) of functioning adenomas at a median of 22 months (3\u0026ndash;39). Biochemical control was 100% for acromegaly and 50% (1 in 2) for prolactinoma. No statistically significant factors were identified for LC, hormonal control, or survival, likely due to the small sample size and the fact that all cases were macroadenomas.\u003c/p\u003e \u003cp\u003eIn SRT applications, radiobiological effectiveness is related to treatment duration and BED [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CK-based hSRT provides excellent target coverage and conformity due to a steep dose fall-off behind the target [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Additionally, new optimization techniques (such as VOLO) offer advantages including reduced body dose with fewer monitor units, a lower risk of secondary malignancies, and shorter treatment durations [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Different cutoff values ​​for the α/β ratio ​​have been reported in the calculation of BED in pituitary tumors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a study involving 100 cases of perioptic tumors treated with CK-based hSRT using a total dose of 25 Gy over 5 fractions, a high median BED\u003csub\u003e2\u003c/sub\u003e of 87.5 was observed [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This result indicates a radiobiological advantage, alongside low optical toxicity and high treatment compliance due to completion within one week. Furthermore, there was a 54% hormonal normalization at a median follow-up of 28 months. In the study by Iwata et al., a 15% higher BED\u003csub\u003e3\u003c/sub\u003e value, as well as better conformity and homogeneity index, were seen with CK-based hSRT compared with GK-based SRS [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Puataweepong et al. also reported a LC rate of 97.5% with a median BED\u003csub\u003e3\u003c/sub\u003e of 66.7 Gy in a study involving 40 patients treated with CK-based hSRT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Current guidelines indicate that there is no difference between hSRT and SRS; however, fractionated treatments tend to reduce toxicity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. It is also emphasized that upfront hSRT within 6 months after surgery increases the LC and hormonal response. In our study, the median coverage rate of 95.02%, indicating good conformity and homogeneous dose distribution. Although the median gradient index was 4.02 (2.86\u0026ndash;10.79), no OARs dose thresholds were exceeded in any case. The median treatment duration was 16 minutes, demonstrating high patient compliance. BED\u003csub\u003e2\u003c/sub\u003e and BED\u003csub\u003e3\u003c/sub\u003e values were recorded at 81.6 and 61.75, respectively, and consistent with the literature, a 2-year LC rate of 96.3% was achieved. The median interval from surgery to hSRT was 24 months (5- 144) for acromegaly patients, 15 months (3-197) for prolactinomas, and 6 months for one patient with Cushing's disease. Due to the small number of patients, we were unable to evaluate the relationship between interval and response rates, and no correlation was found between dosimetric factors and LC or survival.\u003c/p\u003e \u003cp\u003eThe study presents a significant advantage in that it provides a safe and comfortable therapy by selecting a treatment regimen tailored to each patient\u0026rsquo;s characteristics. However, a notable disadvantage is the small patient population and the need for longer follow-up periods to adequately assess side effects and the potential for secondary malignancies.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe results indicate that CK-M6-based hSRT is an effective and non-invasive treatment option for patients with pituitary tumors. Our patients exhibited a high 2-year LC rate of 96.3%, which is consistent with previous studies. Visual function was preserved in 96% of patients. Hormonal control was achieved in 67% of cases, although new-onset hypopituitarism occurred in 11% of patients. With a median beam-on time of 16 minutes, CK-M6-based hSRT offers a precise, safe, and well-tolerated treatment option.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNFAs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-functioning adenomas\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egrowth hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePitNETS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epituitary neuroendocrine tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e(PitNETs)\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estereotactic RT\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elocal control\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCyberKnife\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCK-M6\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCyberKnife Model 6\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ehSRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehypofractionated SRT\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egross target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplanning target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOARs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eorgans at risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBED\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebiologically effective dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-functioning neuroendocrine carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIGF-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einsulin-like growth factor 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esingle-fraction stereotactic radiosurgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLINAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elinear accelerator\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGammaKnife.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eETHICS APPROVAL and CONSENT TO PARTICIPATE\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki Approval was granted by the Ethics Committee of Bursa Uludag University (2025/12\u0026ndash;18).\u003c/p\u003e\u003ch2\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e \u003cp\u003eInformed consent was obtained from all patients included in the study.\u003c/p\u003e \u003ch2\u003eCOMPETING INTEREST\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003ch2\u003eFUNDING\u003c/h2\u003e\u003cp\u003eNone declared.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSS, ATM, JT, ENEU, SGT all met the ICMJE criteria for authorship. SS performed the design and conceptualization of the study. SS, ATM, JT, ENEU, and SGT performed data collection and analysis. Statistical analysis was conducted by SS. The first draft of the manuscript was written by SS. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants, or other forms of support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChin SO. Epidemiology of functioning pituitary adenomas. 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Neuro Oncol. 2020;22(3):318\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1093/neuonc/noz225\u003c/span\u003e\u003cspan address=\"https://doi:10.1093/neuonc/noz225\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"pituitary adenoma, stereotactic radiotherapy, CyberKnife-M6, local control","lastPublishedDoi":"10.21203/rs.3.rs-8422217/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8422217/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate the efficacy of hypofractionated stereotactic radiotherapy (hSRT) using the CyberKnife-M6 (CK-M6) system in patients with pituitary tumors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBetween 2020 and 2024, 27 patients were treated. Follow-up evaluations were conducted at 3 months, 9 months, and annually after treatment.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median follow-up duration was 22 months (10\u0026ndash;58), and the median age was 51 years (32\u0026ndash;78). The median interval between surgery and hSRT was 45 months (3- 214). The median planning target volume was 5.23 cc (0.15\u0026ndash;30.42). Patients received a median dose of 23 Gy (18\u0026ndash;25) over 3 to 5 fractions. The median biologically effective dose (BED\u003csub\u003e2\u003c/sub\u003e) value was 81.6 (60- 94.5). The median beam-on time was 16 minutes (12\u0026ndash;22). Visual function was preserved in 96% of the cases, while new-onset hypopituitarism was observed in 11%. At the last follow-up, radiologically objective response, stable disease, and progression rates were 30%, 63%, and 7%, respectively. Hormonal response was achieved in 67% (4 out of 6) of functioning adenomas, with a median time of 22 months (3\u0026ndash;39). The two-year rates for local control, overall survival, and progression-free survival were 96,3%, 91,2%, and 90,8%, respectively.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCK-M6-based hSRT offers a precise treatment option for patients with pituitary adenoma, with 96% local control, and the added benefit of a shorter treatment duration.\u003c/p\u003e","manuscriptTitle":"Results of Stereotactic Radiotherapy Using The CyberKnife-M6 For Patients With Pituitary Tumors Running Head: Radiotherapy For Pituitary Tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 08:48:58","doi":"10.21203/rs.3.rs-8422217/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-22T18:43:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-05T05:23:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"136412117843256698540323860599886662406","date":"2026-02-05T04:26:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T22:08:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T13:15:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-02T07:36:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-01T08:54:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284268411110735783046922031155901458312","date":"2026-02-01T08:09:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-31T18:08:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"289301961972251197168843008556696467648","date":"2026-01-31T17:58:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-31T09:13:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-30T14:38:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228272593575138059815223833450628393893","date":"2026-01-30T14:24:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"283018753078873606936236053536290124963","date":"2026-01-30T11:22:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321560518213310392100839653884328888588","date":"2026-01-30T08:08:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"91000281183890425802207972955552890949","date":"2026-01-30T07:32:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197263504978188040456072041906386599181","date":"2026-01-30T07:26:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-30T07:10:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-09T07:06:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-26T06:29:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-26T06:27:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2025-12-22T07:19:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9bb0010b-fafc-47d8-a864-7806232dae2e","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T16:38:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 08:48:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8422217","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8422217","identity":"rs-8422217","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}