Reasons for uncontrolled orbital tumors after Gamma Knife surgery

Abstract

Background

To analyze the reasons for uncontrolled Gamma Knife surgery (GKS) of orbital tumors. If we can avoid selecting tumors that are easy to recur, the application of Gamma Knife in ophthalmology will be safer and more popular.

Methods

Retrospective clinical analysis of 72 patients with orbital tumors treated with GKS over a 10-year period from January 2010 to December 2020.The study included 29 males and 43 females with mean age of 42.3years (range 11–75 years).Collect the tumor type, tumor volume, clinical symptoms, GKS dose of all patients before GKS.25 cases were treated with surgery before GKS and had a clear pathological diagnosis; 47 cases were treated without surgery before GKS and a clinical diagnosis was made based on clinical features and imaging manifestations.

Results

After GKS, the volume increased in 39 cases, stabilized in 17 cases, and decreased in 16 cases.In the 16 cases with reduced volume, the average volume of was 3.35 (0.31–8.26) cm³; The median margin dose is 11Gy (7-14Gy), and the median isodose curve is 50% (45%-50%).Of the 39 cases with volume growth, the mean volume was 17.37 (3.19–50.91) cm³, the median margin dose was 12 Gy (7–16 Gy), and the median isodose curve was 50% (45%-65%).Of the 39 patients who grew in size, 20 were reoperated, 10 underwent GKS again, and the remaining 9 were under clinical observation.Of the 20 cases of surgery after GKS,7 cases in which the postoperative pathological diagnosis was inconsistent with the clinical diagnosis at the time of GKS.The average Ki67 index of the patients at the time of surgery after GKS was 7.7%.No serious acute side effects were observed after GKS.

Conclusions

The following factors affect the efficacy of GKS: 1. orbital tumor volume; 2. orbital tumor type and Ki67 index; 3. GKS dose and parameters.

Introduction

Since 1968, GKS was used for the treatment of intracranial tumors, it has accumulated rich experience as a more precise and less toxic treatment than radiotherapy^[1].Tumors with orbital-cranial communication or encircling the optic nerve are relatively difficult to remove due to their special location.GKS is an alternative method with small trauma and accurate localization.Through literature review, we found that,GKS of orbital vascular tumors^[2–5], optic nerve gliomas^[6–8], small and medium-sized orbital schwannomas^{[9, 10]}, metastatic solid tumors^[11], small meningiomas or fractionated treatment of cranio-orbital communicating meningiomas^{[12, 13]} has proven effective.However, we observed that some orbital tumors still recurred after GKS.At present, there is little research on the causes of recurrence of orbital tumors after GKS.This paper retrospectively analyzes the efficacy of orbital tumors treated with gamma knife in the ophthalmology department of West China Hospital during 10 years from January 2010 to December 2020, and analyzes the reasons for uncontrolled disease after GKS.

Patients And Methods

Ethical approval

This study was approved by Biomedical Ethics Board of Sichuan University West China Hospital. Owing to the retrospective nature of the study, The Biomedical Ethics Board of Sichuan University West China Hospital approval to waive informed consent.

Participants

Retrospective analysis of 72 patients(29 males and 43 females with a mean age of 42.3years[range 11–75 years])with orbital tumors treated by GKS in neurosurgery in our hospital from January 2010 to December 2020.Inclusion criteria: (1) GKS in our neurosurgery department with a complete treatment plan.(2)The tumor is located in the orbit or cranio-orbital communication and invades the orbit.Among the patients accord with the inclusion criteria, the diagnoses were determined based on pathological analyses in 25 patients and presumed based on characteristic clinical and imaging findings in 47 patients.

Clinical characteristics of patients pre-GKS

Symptoms pre-GKS include progressive protrusion of the eye with tearing, visual deterioration, conjunctival congestion and edema, visual field defects, orbit pain, limited eye rotation, diplopia, ptosis, loss of light reflex, facial numbness and chronic headache(Table 1).Protrusion of the eye is the most common symptom, followed by visual deterioration and diplopia. At the time of reoperative treatment, most patients have worsened clinical symptoms, the presence of signs correlate with the location of tumors. Symptoms include further protrusion of the eyeball, loss of vision or even blindness, increased visual field defects, progressive worsening of ptosis, hard to open the eyes, increased restriction of eye movements, increased headache, etc.

Table 1 Clinical characteristics of patients pre-GKS

GKS method

The type C Leksell Gamma Knife was used in radiosurgery, and the Leksell stereotaxic frame was fixed to the patient's head under conscious sedation and local anesthesia. The fiducial system was attached to the orbit, and all patients underwent high-definition computed tomography or volumetric MRI. Obtain thin-slice axial and/or coronal images after intravenous contrast when the patient is MRI-eligible; when MRI studies are not available due to medical contraindications (eg, metallic materials on which surgical implants are installed), Thin-layer stereotaxic computed tomography is available. All patients were discharged within 24 hours.

Results

Effective cases treated with GKS

After GKS, the volume grew in 39 cases, stabilized in 17 cases and shrunk in 16 cases. Volume reduction and stability after GKS were considered as effective, and GKS was effective in a total of 33 cases.In the 16 cases with reduced volume, the average volume was 3.35 (0.31-8.26) cm³; The median margin dose is 11Gy (7-14Gy), and the median isodose curve is 50% (45% - 50%) (Table 2).From our results, we found that GKS is effective in treating tumors less than 3.35 cm³ .A case of cranio-orbital communicating meningioma was re-examination one year after GKS, the tumor volume was significantly reduced (Fig. 1).

Table 2 Clinical characteristics of 16 patients with reduced tumor volume

Uncontrolled cases after GKS

Of the 39 cases that grew in size after GKS, the mean tumor volume at the time of GKS was 17.37 (3.19-50.91) cm³, and 6 cases were malignant tumors.The median margin dose is 12Gy (7-16Gy), and the median isodose curve is 50% (45% - 65%) (Table 3). A tumor with volume of 16.68 cm³ was clinically diagnosed as a right-sided cranio-orbital communicating meningioma pre-GKS. At 114 months of follow-up, the tumor was found to have grown and was treated surgically. The tumor volume pre-surgery was 38.23cm³, and post-surgery pathology diagnosis was cranio-orbital communicating solitary fibroma (Fig.2).

Table 3 Clinical characteristics of 39 patients with volume grew

Of the 39 patients who grew in size, 20 were operated, 10 underwent GKS again, and the remaining 9 were under clinical observation. Among the patients who underwent operation after GKS, the mean time between GKS and operation was 41.5 (2-114) months. Among patients who underwent GKS again after GKS, the average interval between two Gamma Knife surgeries was 7 (2-24) months. Among the 20 cases of operation after GKS, 11 cases had a pathological diagnosis before GKS, 9 cases had only a clinical diagnosis before GKS, and there were 7 cases in which the pathological diagnosis after surgery was inconsistent with the clinical diagnosis at the time of GKS, and only 2 patients with glioma had the same clinical diagnosis and pathological diagnosis (Table 4).Tumors with high Ki67 expression are more malignant and prone to recurrence and metastasis. We counted the Ki67 index of patients at the time of operation after GKS, and the Ki67 index ranged from 2%-30% with a mean of 7.7%. tumors with Ki67 index ≥10% were: 1 case of poorly differentiated carcinoma infiltration, 1 case of adenoid cystic carcinoma of lacrimal gland, 3 cases of orbital solitary fibroma, and 1 case of orbital schwannoma.

Table 4 Diagnostic changes in patients undergoing surgery after GKS

Complications of GKS

No serious acute side effects were observed post-GKS.One case of nausea and vomiting, two cases of headache and orbital pain occurred within 24 hours after GKS, both of which resolved on their own.Two cases presented with bulbar conjunctival edema on the affected side, which resolved 3-7 days after treatment with topical dexamethasone eye drops.

Discussion

The orbital tumor located in the retrobulbar muscle cone is deep, and mostly adhered to the optic nerve and extraocular muscles. The previous approach was to remove the major part of the lesion surgically or microsurgically with minimal serious ocular complications. The residual and recurrence of tumor is inevitable. GKS has unique advantages in treating tumors that are deeply located or scattered in the posterior bulbar muscle cone. It can effectively make up for the shortcomings of microsurgery and not only controls the growth of tumor, but also avoids the direct injury of surgery. We observed that some orbital tumors still recur after GKS. If we can avoid selecting tumors that are easy to recur, the application of Gamma Knife in ophthalmology will be safer and more popular. From our retrospective study, the following factors were found to influence the efficacy of GKS.

Orbital tumors size

The results in Tables 2 and 3 show that the mean volume of tumors with better outcome after GKS was 3.35 (0.31-8.26) cm³; the mean volume of tumors with uncontrolled disease after GKS was 17.37 (3.19-50.91) cm3.GKS control rates are significantly lower for large tumors than for small tumors of the same tumor type. International Stereotactic Radiosurgery Society(ISRS) showed significantly poorer local control with a single GKS for large tumors greater than 2.5 cm in diameter preoperatively^[14].

Tumor type and Ki67 index

From the types of tumors that increased in size after GKS, we found that GKS of orbital malignancies or metastatic tumors(Adenoid cystic carcinoma of lacrimal gland, invasion of poorly differentiated carcinoma of orbit, orbital mesenchymal chondrosarcoma, nasopharyngeal carcinoma invading orbit, non-Hodgkin lymphoma invading orbit, pleomorphic sarcoma invading orbit) can reduce the patient's symptoms, but cannot stop the progression of the malignancy. A comparative analysis of meningioma cases that had shrunk in size and those that had grown after GKS revealed that GKS was less effective for large meningiomas. It has been reported that most meningiomas are WHO grade I lesions, with a few classified as WHO grade II or III lesions based on local infiltrative and cellular heterogeneity features^[15].Grade II and III meningiomas are more likely to recur^[16].Incomplete resection of meningiomas poses a significant risk of tumor recurrence^[17].The principle of GKS for vascular tumors is that radiation causes thrombosis and secondary fibrosis in the lesion, leading to closure of vascular space and contraction of the lesion^[18].In our study, one case of hemangioma was operated after GKS. Postoperative pathology confirmed that this case had formed thrombus and thrombus organization. The reason why GKS failed to control the disease may be related to the closure or partial closure of vascular space. In 2 cases of optic nerve glioma operated after GKS and postoperative pathological analysis were WHO grade I. Sadik ZHA concluded^[6] that patients with recurrent low-grade gliomas are suitable for surgery because these tumors have a low response to radiation; in the case of high-grade tumors, patients have limited survival and are suitable for GKS. Unclear diagnosis at the time of GKS and inability to determine the type of tumor may be one of the reasons for uncontrolled disease after GKS. One case of pleomorphic sarcoma and one case of poorly differentiated carcinoma were diagnosed as cranio-orbital communicating meningioma and inflammatory pseudotumor respectively during GKS. Recurrence surgery was performed 2 and 4 months after GKS.GKS should be followed up closely and if the outcome is not good, surgical pathology should be performed to clarify the diagnosis. Goh et al.^[19] suggested that in the case of uncertain diagnosis, tissue biopsy should be performed before starting GKS.Young SM found^[18] that GKS responded poorly to meningiomas and nerve sheath tumors compared to venous cavernous malformations, indicating the importance of tumor type selection when treating with gamma knife.

Orbital tumors with high Ki67 expression have a high probability of operation after GKS. Ki67 expression is closely related to cell proliferation and can be used as an important reference indicator for clinical prognosis and further treatment after surgery. It has been shown^[20] that Ki67 levels higher than 10-14% are defined as high prognostic risk. Mirian C^[21] found by multivariate analysis of meningiomas that each 1 percentage point increase in Ki67 proliferation index was associated with a 12% increase in the risk of recurrence. Four cases of orbital solitary fibroma that grew in size after GKS showed high Ki67 index on postoperative pathology, which may be the cause of uncontrolled disease. However, the long time from GKS to operation (mean 63.7 months) is related to the inhibition of blood vessels by GKS, which slows down tumor growth. The 2016 edition of the WHO classification of central nervous system tumors combines solitary fibroma and hemangioepithelial cell tumors into one^[15], confirming that orbital solitary fibroma have abundant blood supplying arteries.Ki67 is somewhat variable, and it is not possible to determine the proliferation cut-off time for highly proliferative tumors, and it is becoming increasingly challenging to rely on Ki67 for daily decision making^[22].

Gamma knife dose and parameters

In our study, the median margin dose was 12 Gy(7-16Gy) and the median isodose curve was 50% (45%-65%) in 39 cases with uncontrolled disease after GKS; In 16 cases with reduced volume, the median margin dose was 11Gy (7-14Gy), and the median isodose curve was 50% (45%-50%).It has been shown^[23-27] that stereotactic radiosurgery (SRS) is more effective in treating small volume meningiomas with a single applied marginal dose of 14-16Gy. The application of prescription doses greater than 13.4Gy resulted in a significant reduction in the recurrence rate of treated meningiomas^[28].Shaw E^[29] described the maximum tolerated dose of SRS, suggesting a maximum tolerated dose of 24 Gy for tumors≤20 mm in diameter, 18 Gy for tumors 21-30mm in diameter, and 15 Gy for tumors 31-40mm in diameter. However, due to the proximity of orbital tumors to the optic nerve, the dose of GKS is limited. The maximum single dose to the optic nerve is 10 Gy, and a "spot" dose of 12 Gy in a very small volume is safe; if this threshold is exceeded, there is a risk of visual damage^[19,30,31].

Among the 10 patients who underwent GKS again after GKS, the average interval between two Gamma Knife surgeries was 7 (2-24) months. 9 of them were treated with stereotactic fractionated radiotherapy (SFRT), which was chosen to avoid damage to the optic nerve because of the indistinct demarcation between the tumor and the optic nerve and its large size. Based on the results of this study and several references, we believe that single-dose stereotactic radiosurgery is more effective for small volume (volume＜3.35cm³) orbital tumors, and SFRT is more effective for large orbital tumors^[32-35].The European Association of Neuro-Oncology(EANO) recommends^[11] for patients with metastatic tumor with maximum diameter greater than 3cm and irradiation volume greater than 10cm³,SFRT should be considered because the toxicity of SRS increases, resulting in radiation necrosis of normal brain tissue. The ISRS suggests that SFRT may provide better local control in patients with large tumors of 2.5-3cm in diameter^[14].Squires JE^[36] suggested increasing the use of SFRT.

Generalizability and limitations

This study is the first to discuss reasons for uncontrolled orbital tumors after GKS. If we can avoid selecting tumors that are easy to recur, the application of GKS in ophthalmology will be safer and more popular. However, due to the large number of tumor types and the small number of patients with each type of tumor, the research results have some limitations. In the future, a larger sample size study is needed to further confirm the indications of GKS for orbital tumors.

Conclusions

Through retrospective analysis of orbital tumor cases treated with GKS in our hospital, we found that the factors affecting the efficacy of GKS for orbital tumors are: 1. orbital tumor volume; 2. orbital tumor type and Ki67 index; 3. gamma knife dose and parameters. If we can avoid selecting tumors that are easy to recur, the application of Gamma Knife in ophthalmology will be safer and more popular.

ABBREVIATIONS

GKS, Gamma Knife surgery; SRS, stereotactic radiosurgery; SFRT, stereotactic fractionated radiotherapy; MRI: Magnetic Resonance Imaging; ISRS, International Stereotactic Radiosurgery Society; EANO, The European Association of Neuro-Oncology; WHO, World Health Organization.

Declarations

Ethics approval and consent to participate

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Biomedical Ethics Board of Sichuan University West China Hospital. Owing to the retrospective nature of the study, The Biomedical Ethics Board of Sichuan University West China Hospital approval to waive informed consent.

Consent for publication

Not applicable.

Availability of data and materials

The data and materials are available from the corresponding author on reasonable request.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Funding

None.

Acknowledgement

None.

Author contribution

Dongfang Wu participated in data collection, data analysis, data interpretation and manuscript writing.Hao Deng participated in data collection. Weimin He was responsible for conceptualization and supervision. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring the accuracy or integrity of the work. All the authors have read and approved the study.

References

1. Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, Greenspoon J, Parney IF, Laack NNI, Ashman JB, Bahary JP, Hadjipanayis CG, Urbanic JJ, Barker FG 2nd, Farace E, Khuntia D, Giannini C, Buckner JC, Galanis E, Roberge D. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2. Epub 2017 Jul 4. PMID: 28687377; PMCID: PMC5568757.
2. Yamamoto M, Kida Y, Fukuoka S, Iwai Y, Jokura H, Akabane A, Serizawa T. Gamma Knife radiosurgery for hemangiomas of the cavernous sinus: a seven-institute study in Japan. J Neurosurg. 2010 Apr;112(4):772-9. doi: 10.3171/2009.6.JNS08271. PMID: 19612972.
3. Xu D, Liu D, Zhang Z, Zhang Y, Song G. Gamma knife radiosurgery for primary orbital varices: a preliminary report. Br J Ophthalmol. 2011 Sep;95(9):1264-7. doi: 10.1136/bjo.2009.170001. Epub 2010 Oct 22. PMID: 20971792.
4. Liu X, Xu D, Zhang Y, Liu D, Song G. Gamma Knife surgery in patients harboring orbital cavernous hemangiomas that were diagnosed on the basis of imaging findings. J Neurosurg. 2010 Dec;113 Suppl:39-43. PMID: 21218532.
5. Kim YT, Kang SW, Lee JI. Gamma knife radiosurgery for choroidal hemangioma. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1399-404. doi: 10.1016/j.ijrobp.2010.08.016. Epub 2010 Oct 13. PMID: 20950946.
6. Sadik ZHA, Hanssens PEJ, Verheul JB, Beute GN, Te Lie S, Leenstra S, Ardon H. Gamma knife radiosurgery for recurrent gliomas. J Neurooncol. 2018 Dec;140(3):615-622. doi: 10.1007/s11060-018-2988-0. Epub 2018 Sep 6. PMID: 30191361; PMCID: PMC6267255.
7. El-Shehaby AM, Reda WA, Abdel Karim KM, Emad Eldin RM, Nabeel AM. Single-session Gamma Knife radiosurgery for optic pathway/hypothalamic gliomas. J Neurosurg. 2016 Dec;125(Suppl 1):50-57. doi: 10.3171/2016.8.GKS161432. PMID: 27903182.
8. Tsang DS, Murphy ES, Merchant TE. Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children. Int J Radiat Oncol Biol Phys. 2017 Nov 1;99(3):642-651. doi: 10.1016/j.ijrobp.2017.07.023. Epub 2017 Jul 23. PMID: 29280458.
9. Fu VX, Verheul JB, Beute GN, Leenstra S, Kunst HPM, Mulder JJS, Hanssens PEJ. Retreatment of vestibular schwannoma with Gamma Knife radiosurgery: clinical outcome, tumor control, and review of literature. J Neurosurg. 2018 Jul;129(1):137-145. doi: 10.3171/2017.3.JNS162033. Epub 2017 Oct 6. PMID: 28984523.
10. Hasegawa T, Kida Y, Kato T, Iizuka H, Kuramitsu S, Yamamoto T. Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with Gamma Knife surgery. J Neurosurg. 2013 Mar;118(3):557-65. doi: 10.3171/2012.10.JNS12523. Epub 2012 Nov 9. PMID: 23140152.
11. Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, Marosi C, Metellus P, Radbruch A, Villa Freixa SS, Brada M, Carapella CM, Preusser M, Le Rhun E, Rudà R, Tonn JC, Weber DC, Weller M. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 2017 Feb 1;19(2):162-174. doi: 10.1093/neuonc/now241. PMID: 28391295; PMCID: PMC5620494.
12. Minniti G, Esposito V, Clarke E, Scaringi C, Lanzetta G, Salvati M, Raco A, Bozzao A, Maurizi Enrici R. Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):623-9. doi: 10.1016/j.ijrobp.2013.03.037. Epub 2013 May 15. PMID: 23683828.
13. Rogers L, Barani I, Chamberlain M, Kaley TJ, McDermott M, Raizer J, Schiff D, Weber DC, Wen PY, Vogelbaum MA. Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg. 2015 Jan;122(1):4-23. doi: 10.3171/2014.7.JNS131644. PMID: 25343186; PMCID: PMC5062955.
14. Redmond KJ, De Salles AAF, Fariselli L, Levivier M, Ma L, Paddick I, Pollock BE, Regis J, Sheehan J, Suh J, Yomo S, Sahgal A. Stereotactic Radiosurgery for Postoperative Metastatic Surgical Cavities: A Critical Review and International Stereotactic Radiosurgery Society (ISRS) Practice Guidelines. Int J Radiat Oncol Biol Phys. 2021 Sep 1;111(1):68-80. doi: 10.1016/j.ijrobp.2021.04.016. Epub 2021 Apr 20. PMID: 33891979.
15. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20. doi: 10.1007/s00401-016-1545-1. Epub 2016 May 9. PMID: 27157931.
16. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, Okonechnikov K, Koelsche C, Reuss DE, Capper D, Sturm D, Wirsching HG, Berghoff AS, Baumgarten P, Kratz A, Huang K, Wefers AK, Hovestadt V, Sill M, Ellis HP, Kurian KM, Okuducu AF, Jungk C, Drueschler K, Schick M, Bewerunge-Hudler M, Mawrin C, Seiz-Rosenhagen M, Ketter R, Simon M, Westphal M, Lamszus K, Becker A, Koch A, Schittenhelm J, Rushing EJ, Collins VP, Brehmer S, Chavez L, Platten M, Hänggi D, Unterberg A, Paulus W, Wick W, Pfister SM, Mittelbronn M, Preusser M, Herold-Mende C, Weller M, von Deimling A. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017 May;18(5):682-694. doi: 10.1016/S1470-2045(17)30155-9. Epub 2017 Mar 15. PMID: 28314689.
17. Jung HW, Yoo H, Paek SH, Choi KS. Long-term outcome and growth rate of subtotally resected petroclival meningiomas: experience with 38 cases. Neurosurgery. 2000 Mar;46(3):567-74; discussion 574-5. doi: 10.1097/00006123-200003000-00008. PMID: 10719852.
18. Young SM, Kim KH, Kim YD, Lang SS, Park JW, Woo KI, Lee JI. Orbital apex venous cavernous malformation with optic neuropathy: treatment with multisession gamma knife radiosurgery. Br J Ophthalmol. 2019 Oct;103(10):1453-1459. doi: 10.1136/bjophthalmol-2018-312893. Epub 2019 Jan 5. PMID: 30612095.
19. Goh ASC, Kim YD, Woo KI, Lee JI. Benign orbital apex tumors treated with multisession gamma knife radiosurgery. Ophthalmology. 2013 Mar;120(3):635-641. doi: 10.1016/j.ophtha.2012.08.015. Epub 2012 Nov 11. PMID: 23149128.
20. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010 Feb;11(2):174-83. doi: 10.1016/S1470-2045(09)70262-1. PMID: 20152769.
21. Mirian C, Skyrman S, Bartek J Jr, Jensen LR, Kihlström L, Förander P, Orrego A, Mathiesen T. The Ki-67 Proliferation Index as a Marker of Time to Recurrence in Intracranial Meningioma. Neurosurgery. 2020 Nov 16;87(6):1289-1298. doi: 10.1093/neuros/nyaa226. PMID: 32614441.
22. Ignatiadis M, Azim HA Jr, Desmedt C, Veys I, Larsimont D, Salgado R, Lyng MB, Viale G, Leyland-Jones B, Giobbie-Hurder A, Kammler R, Dell'Orto P, Rothé F, Laïos I, Ditzel HJ, Regan MM, Piccart M, Michiels S, Sotiriou C. The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence.JAMA Oncol. 2016 Feb;2(2):217-24. doi: 10.1001/jamaoncol.2015.4377. PMID: 26633571.
23. dos Santos MA, de Salcedo JB, Gutiérrez Diaz JA, Calvo FA, Samblás J, Marsiglia H, Sallabanda K. Long-term outcomes of stereotactic radiosurgery for treatment of cavernous sinus meningiomas. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1436-41. doi: 10.1016/j.ijrobp.2010.07.2002. Epub 2010 Oct 23. PMID: 20971572.
24. Goldsmith B, McDermott MW. Meningioma. Neurosurg Clin N Am. 2006 Apr;17(2):111-20, vi. doi: 10.1016/j.nec.2006.03.002. PMID: 16793503.
25. Colombo F, Casentini L, Cavedon C, Scalchi P, Cora S, Francescon P. Cyberknife radiosurgery for benign meningiomas: short-term results in 199 patients. Neurosurgery. 2009 Feb;64(2 Suppl):A7-13. doi: 10.1227/01.NEU.0000338947.84636.A6. PMID: 19165077.
26. Tuniz F, Soltys SG, Choi CY, Chang SD, Gibbs IC, Fischbein NJ, Adler JR Jr. Multisession cyberknife stereotactic radiosurgery of large, benign cranial base tumors: preliminary study. Neurosurgery. 2009 Nov;65(5):898-907; discussion 907. doi: 10.1227/01.NEU.0000359316.34041.A8. PMID: 19834402.
27. Jung HW, Yoo H, Paek SH, Choi KS. Long-term outcome and growth rate of subtotally resected petroclival meningiomas: experience with 38 cases. Neurosurgery. 2000 Mar;46(3):567-74; discussion 574-5. doi: 10.1097/00006123-200003000-00008. PMID: 10719852.
28. Lippitz BE, Bartek J Jr, Mathiesen T, Förander P. Ten-year follow-up after Gamma Knife radiosurgery of meningioma and review of the literature. Acta Neurochir (Wien). 2020 Sep;162(9):2183-2196. doi: 10.1007/s00701-020-04350-5. Epub 2020 Jun 26. PMID: 32591948; PMCID: PMC7415024.
29. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):291-8. doi: 10.1016/s0360-3016(99)00507-6. PMID: 10802351.
30. Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, Gorman DA, Schomberg PJ. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1177-81. doi: 10.1016/s0360-3016(02)04380-8. PMID: 12654424.
31. Milano MT, Usuki KY, Walter KA, Clark D, Schell MC. Stereotactic radiosurgery and hypofractionated stereotactic radiotherapy: normal tissue dose constraints of the central nervous system. Cancer Treat Rev. 2011 Nov;37(7):567-78. doi: 10.1016/j.ctrv.2011.04.004. Epub 2011 May 14. PMID: 21571440.
32. Ahn YC, Lee KC, Kim DY, Huh SJ, Yeo IH, Lim DH, Kim MK, Shin KH, Park S, Chang SH. Fractionated stereotactic radiation therapy for extracranial head and neck tumors. Int J Radiat Oncol Biol Phys. 2000 Sep 1;48(2):501-5. doi: 10.1016/s0360-3016(00)00612-x. PMID: 10974468.
33. Soliman H, Myrehaug S, Tseng CL, Ruschin M, Hashmi A, Mainprize T, Spears J, Das S, Yang V, da Costa L, Maralani P, Heyn C, Atenafu EG, Sahgal A. Image-Guided, Linac-Based, Surgical Cavity-Hypofractionated Stereotactic Radiotherapy in 5 Daily Fractions for Brain Metastases. Neurosurgery. 2019 Nov 1;85(5):E860-E869. doi: 10.1093/neuros/nyz162. PMID: 31173150.
34. Minniti G, Esposito V, Clarke E, Scaringi C, Lanzetta G, Salvati M, Raco A, Bozzao A, Maurizi Enrici R. Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):623-9. doi: 10.1016/j.ijrobp.2013.03.037. Epub 2013 May 15. PMID: 23683828.
35. Angelov L, Mohammadi AM, Bennett EE, Abbassy M, Elson P, Chao ST, Montgomery JS, Habboub G, Vogelbaum MA, Suh JH, Murphy ES, Ahluwalia MS, Nagel SJ, Barnett GH. Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases ≥ 2 cm. J Neurosurg. 2018 Aug;129(2):366-382. doi: 10.3171/2017.3.JNS162532. Epub 2017 Sep 22. PMID: 28937324.
36. Squires JE, Asad S, Varin MD, Dorrance K, Chow E, Fairchild A, Wong R, Graham ID, Grimshaw JM, Dennis K. Behavioral Determinants of Canadian Radiation Oncologists' Use of Single Fraction Palliative Radiation Therapy for Uncomplicated Bone Metastases. Int J Radiat Oncol Biol Phys. 2021 Feb 1;109(2):374-386. doi: 10.1016/j.ijrobp.2020.09.030. Epub 2020 Sep 20. PMID: 32966890.