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.