A phase II open label, single arm study of hypofractionated stereotactic radiotherapy with chemoradiotherapy using intensity-modulated radiotherapy for newly diagnosed glioblastoma after surgery: the HSCK-010 trial protocol.

BACKGROUND: The most frequently diagnosed primary brain tumor is glioblastoma (GBM). Nearly all patients experience tumor recurrence and up to 90% of which is local recurrence. Thus, increasing the therapeutic ratio of radiotherapy using hypofractionated stereotactic radiotherapy (HSRT) can reduce treatment time and may increase tumor control and improve survival. To evaluate the efficacy and toxicity of the combination of HSRT and intensity-modulated radiotherapy (IMRT) with temozolomide after surgery in GBM patients and provide evidence for further randomized controlled trials. METHODS/DESIGN: HSCK-010 is an open-label, single-arm phase II trial (NCT04547621) which includes newly diagnosed GBM patients who underwent gross total resection. Patients will receive the combination of 30 Gy/5fx HSRT, and 20 Gy/10fx IMRT adjuvant therapy with concurrent temozolomide and adjuvant chemotherapy. The primary endpoint is overall survival (OS). Secondary outcomes include progression-free survival (PFS) rate, objective-response rate (ORR), quality of life (Qol) before and after the treatment, cognitive function before and after the treatment, and rate of treatment-related adverse events (AE). The combination of HSRT and IMRT with temozolomide can benefit the patients after surgery with good survival, acceptable toxicity, and reduced treatment time. TRIAL REGISTRATION: NCT04547621 . Registered on 14 September 2020.

Safety and efficacy of Hypofractionated stereotactic radiosurgery for high-grade Gliomas at first recurrence: a single-center experience.

BACKGROUND: The optimal treatment for recurrent high-grade gliomas (rHGGs) remains uncertain. This study aimed to investigate the efficacy and safety of hypofractionated stereotactic radiosurgery (HSRS) as a first-line salvage treatment for in-field recurrence of high-grade gliomas. METHODS: Between January 2016 and October 2019, 70 patients with rHGG who underwent HSRS were retrospectively analysed. The primary endpoint was overall survival (OS), and secondary endpoints included both progression-free survival (PFS) and adverse events, which were assessed according to Common Toxicity Criteria Adverse Events (CTCAE) version 5. The prognostic value of key clinical features (age, performance status, planning target volume, dose, use of bevacizumab) was evaluated. RESULTS: A total of 70 patients were included in the study. Forty patients were male and 30 were female. Forty-nine had an initial diagnosis of glioblastoma (GBM), and the rest (21) were confirmed to be WHO grade 3 gliomas. The median planning target volume (PTV) was 16.68 cm3 (0.81-121.96 cm3). The median prescribed dose was 24 Gy (12-30 Gy) in 4 fractions (2-6 fractions). The median baseline of Karnofsky Performance Status (KPS) was 70 (40-90). With a median follow-up of 12.1 months, the median overall survival after salvage treatment was 17.6 months (19.5 and 14.6 months for grade 3 and 4 gliomas, respectively; p = .039). No grade 3 or higher toxicities was recorded. Multivariate analysis showed that concurrent bevacizumab with radiosurgery and KPS > 70 were favourable prognostic factors for grade 4 patients with HGG. CONCLUSIONS: Salvage HSRS showed a favourable outcome and acceptable toxicity for rHGG. A prospective phase II study (NCT04197492) is ongoing to further investigate the value of hypofractionated stereotactic radiosurgery (HSRS) in rHGG.

A new classification and clinical results of Gamma Knife radiosurgery for cavernous sinus hemangiomas: a report of 53 cases.

BACKGROUND: Cavernous sinus hemangiomas (CaSHs) are rare vascular lesions in the cavernous sinus(CS). Gamma Knife radiosurgery (GKS) provides a treatment modality alternative to microsurgery. This study was conducted to describe a new classification of CaSHs based on their magnetic resonance (MR) imaging findings and determine the efficacy and safety of GKS in a large series of CaSH patients. METHODS: From April 2007 to November 2012, 53 patients harboring CaSHs were treated using Leksell Gamma Knife model C (before April 2012) or Perfexion (from May 2012 ) at the Gamma Knife Center of Huashan Hospital. Of the 53 patients, 15 with definitive histopathologic diagnoses after surgery, 38 were diagnosed based on their MR imaging findings. There were 15 male and 38 female patients with a mean age of 52 (range, 25-76) years old. The characteristics of MR images of CaSHs were their extremely high homogeneous intensity on T2-weighted and FLAIR images: as bright as cerebrospinal fluid signal. According to the relationship between the carotid line and their location, CaSHs were classified into three types: the intrasellar, parasellar and mixed type. The mean volume of the tumors was 13.2 ± 8.2 cm(3) (range, 1-41 cm(3)). A mean marginal dose of 13.3 Gy (range, 8-15 Gy) was directed to the 49%-64% isodose line (mean 53%). RESULTS: Of the 53 tumors, 6 (11%) were classified as intrasellar type. Eight (15%) were parasellar type and the other 39 cases(74%) mixed type. The mean radiological and clinical follow-up time of this study was 24 (range, 2-67 months) and 34 months (range, 2-73 months), respectively. The tumor control rate was 100%. The mean tumor volume reduction was 79.5% (range, 16.5%-100%) compared with the pre-GKS volume. Six months after GKS, MR imaging revealed an average of 60.2% tumor volume reduction (range, 16.5%-89.2%). Twenty-nine cases (55%) showed a >80% tumor volume decrease. Neurologically, only two of these patients showed clinical deterioration, and 33 patients demonstrated an obvious improvement in ocular or endocrine disorders. At last follow-up, there were no more complications related to GKS, and none of the tumors progressed. CONCLUSIONS: Our study showed that GKS is a useful and safe therapeutic method for CaSHs as both a primary and adjuvant treatment. The new classification of CaSHs may help predict their clinical course during tumor development and treatment response after GKS. Further studies with long-term follow-up and larger numbers of cases are necessary to optimize the treatment conditions and verify the benefit of this treatment.

[Multisession cyberknife radiosurgery for cavernous sinus hemangiomas: medium- and long-term outcomes].

OBJECTIVE: To investigate the medium- and long-term outcomes of multisession cyberknife radiosurgery intreating cavernous sinus hemangiomas (CSH). METHODS: Between January 2008 and February 2012, 45 patients with CSH, including 35 female and 10 male patients with a mean age of 53 years (range: 26-80 years), underwent multisession cyberknife radiosurgery. The mean diameter of the CSH was 47.0 mm (range: 23.0-75.0 mm). The tumor volume ranged from 2.9 to 140.1 cm³, with a mean of 40.1 cm³. Eleven giant CSH with tumor volume ≥ 40.0 cm³ were irradiated by cyberknife in 4 fractions, 28 large tumors with tumor volume 10.0-40.0 cm³ in 3 fractions, 4 tumors with tumor volume 5.0-10.0 cm³ in 2 fractions, 2 small tumors with tumor volume ≤ 5.0 cm³ in 1 fraction. After the treatment, all patients had regular clinical and radiological follow-up at 6-month intervals. A combination of the neurologic examination and MRI information was used to evaluate the overall response. RESULTS: All patients were followed up for 22-70 months with a mean of 37.7 months. One patient died of stroke 3 years post cyberknife, but the follow-up MRI showed that the CSH shrank in volume. Eight patients with giant CSH had slight headache after finishing cyberknife radiosurgery, and relieved with mannitol and dexamethasone treatment. Neurological deficits in patients had improved or disappeared at 6 to 12 months post cyberknife. None of these patients showed any deterioration in symptoms or new cranial nerve deficits during the follow-up. Latest follow-up imaging demonstrated that tumors decrease > 80% in 15 patients, > 60% to 80% in 18 patients (including the death patient), 40%-60% in 12 patients post cyberknife. Two patients reported occurrence of seizures and maintaining seizure control after antiepileptic drugs administration. CONCLUSIONS: Multisession cyberknife radiosurgery is confirmed to provide medium and long-term local tumor control and symptom improvement. It is a safe and effective treatment modality for CSH, and may serve as a promising treatment option in the future.

A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema.

Bevacizumab blocks the effects of vascular endothelial growth factor in leakage-prone capillaries and has been suggested as a new treatment for cerebral radiation edema and necrosis. CyberKnife is a new, frameless stereotactic radiosurgery system. This work investigated the safety and efficacy of CyberKnife followed by early bevacizumab treatment for brain metastasis with extensive cerebral edema. The eligibility criteria of the patients selected for radiosurgery followed by early use of adjuvant bevacizumab treatment were: (1) brain tumors from metastasis with one solitary brain lesion and symptomatic extensive cerebral edema; (2) >18 years of age; (3) the patient refused surgery due to the physical conditions and the risk of surgery; (4) no contraindications for bevacizumab. (5) bevacizumab was applied for a minimum of 2 injections and a maximum of 6 injections with a 2-week interval between treatments, beginning within 2 weeks of the CyberKnife therapy; (6) Karnofsky performance status (KPS) ≥30. Tumor size and edema were monitored by magnetic resonance imaging (MRI). Dexamethasone dosage, KPS, adverse event occurrence and associated clinical outcomes were also recorded. Eight patients were accrued for this new treatment. Radiation dose ranged from 20 to 33 Gy in one to five sessions, prescribed to the 61-71 % isodose line. Bevacizumab therapy was administered 3-10 days after completion of CyberKnife treatment for a minimum of two cycles (5 mg/kg, at 2-week intervals). MRI revealed average reductions of 55.8 % (post-gadolinium) and 63.4 % (T2/FLAIR). Seven patients showed significant clinical neurological improvements. Dexamethasone was reduced in all patients, with five successfully discontinuing dexamethasone treatment 4 weeks after bevacizumab initiation. Hypertension, a bevacizumab-related adverse event, occurred in one patient. After 3-8 months, all patients studied were alive and primary brain metastases were under control, 2 developed new brain metastases and underwent salvage CyberKnife treatment. Recurrent edema and emerging radiation necrosis were not observed. CyberKnife radiosurgery followed by early use of bevacizumab is promising and appears safe for treatment of brain metastases with extensive cerebral edema.

[Cyberknife radiosurgery for cerebral arteriovenous malformations: outlining of the radiosurgical target and obliteration].

OBJECTIVE: To explore the therapeutic outcomes of cyberknife for patients with arteriovenous malformations (AVM) and outline the content of AVM targets. METHODS: Between January 2008 and October 2011, 51 patients underwent cyberknife radiosurgery for cerebral AVMs. The mean age was 27 (8-47) years. The procedures included prior embolization (n = 24), gamma knife before cyberknife (n = 2) and cyberknife initially (n = 25). The delineation of AVM targets was as follows: AVM with prior embolization, radiosurgical targets included AVM nidus, embolization areas and some small draining veins. However, low radiation dose was delivered to embolization parts and draining veins. For 25 patients without embolization, the radiosurgical target was AVM nidus. The mean target volume was 7.8 (1.2-22.0) cm³ and 15 of them were larger than 10.0 cm³. In patients harboring AVM with target volumes < 4 cm³, cyberknife radiation was delivered in a single session. And the remainder had 2 (n = 25) or 3 (n = 19) sessions. The mean marginal dose was 23(18-28) Gy. RESULTS: AVM obliteration was confirmed by magnetic resonance imaging (MRI) or angiography in 40 (78%) patients during a mean follow-up of 46 (36-70) months. Marked size reduction of AVM was obtained in 11 incompletely obliterated patients. Among them, there were second cyberknife treatment (n = 3), third embolization for complex AVM (n = 1), gamma knife (n = 1) and further follow-ups (n = 6). The higher obliteration rate of AVM was correlated with small volume of AVM in noncritical areas, prior embolization and radiation target of embolization areas. Three patients had hemorrhage during the follow-up period and recovered. Brain edema was found in patients with basal ganglion or parietal AVMs. A permanent neurological deficit (paralysis) due to adverse radiation effects developed in 1 patient. CONCLUSION: Cyberknife radiosurgery is particularly effective for patients with smaller AVMs in noncritical areas of brain. In patients with prior embolization, delineation of AVM targets including embolization areas is essential for a higher rate of obliteration.

The role of stereotactic radiosurgery in cavernous sinus hemangiomas: a systematic review and meta-analysis.

Cavernous sinus hemangioma is a rare and complex vascular tumor. A direct microsurgical approach usually results in massive hemorrhage. Stereotactic radiosurgery has emerged as a treatment alternative to microsurgery. To conduct a meta-analysis assessing the effect and complications of stereotactic radiosurgery in cavernous sinus hemangioma, a systematic review and meta-analysis of all cases of cavernous hemangioma in the cavernous sinus treated with stereotactic radiosurgery was performed. The search revealed ten papers with a total enrollment of 59 patients. Tumor size ranged from 1.5-51.4 cm(3) (mean 9.6 cm(3)). The mean follow-up period was 49.2 months (range 6-156 months). The most recent MR images demonstrated remarkable tumor shrinkage in 40 patients (67.8%), partial shrinkage in 15 patients (25.4%), and no change in four patients (6.8%). There was no significant correlation between lesion volume and tumor shrinkage. Patients with remarkable tumor shrinkage received higher doses than those with partial or no change tumor shrinkage (P = 0.031). Thirteen patients (22.0%) had no cranial nerve impairments before stereotactic radiosurgery. Among those 46 patients with cranial nerve impairments before stereotactic radiosurgery, complete resolution was achieved in seven patients and improvement in 28, and these impairments remained essentially unchanged in 11 patients. Only one patient had additional trigeminal nerve disturbance. There is no statistical significance in tumor control between patients treated with or without surgery (P = 0.091). The meta-analysis suggests stereotactic radiosurgery avoids the complications associated with attempted microsurgical resection. Stereotactic radiosurgery is an alternative for cavernous sinus hemangiomas confirmed by typical imaging.

Safety and Efficacy of Hypofractionated Stereotactic Radiotherapy with Anlotinib Targeted Therapy for Glioblastoma at the First Recurrence: A Preliminary Report.

(1) Background: Hypofractionated stereotactic radiotherapy (HSRT) and anti-vascular endothelial growth factor (VEGF) antibodies have been reported to have a promising survival benefit in recent studies. Anlotinib is a new oral VEGF receptor inhibitor. This report describes our experience using HSRT and anlotinib for recurrent glioblastoma (rGBM). (2) Methods: Between December 2019 and June 2020, rGBM patients were retrospectively analysed. Anlotinib was prescribed at 12 mg daily during HSRT. Adjuvant anlotinib was administered d1-14 every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS) after salvage treatment, and toxicity. (3) Results: Five patients were enrolled. The prescribed dose was 25.0 Gy in 5 fractions. The median number of cycles of anlotinib was 21 (14-33). The ORR was 100%. Three (60%) patients had the best outcome of a partial response (PR), and 2 (40%) achieved a complete response (CR). One patient died of tumour progression at the last follow-up. Two patients had grade 2 hand-foot syndrome. (4) Conclusions: Salvage HSRT combined with anlotinib showed a favourable outcome and acceptable toxicity for rGBM. A prospective phase II study (NCT04197492) is ongoing to further investigate the regimen.

Dose-staged Gamma Knife radiosurgery for meningiomas: A retrospective study in a single center.

Objective: This study aimed to study the efficiency and safety of a dose-staged Gamma Knife radiosurgery strategy for large meningiomas or meningiomas close to important nerve structures. Methods: This study evaluates the outcome of a prospectively accrued series of 71 consecutive patients with meningiomas treated with staged dose-fractionated Gamma Knife radiosurgery. The average peripheral doses for the first and second fractions were 9.0 ± 0.9 Gy (8-12 Gy) and 8.6 ± 0.7 Gy (range, 7-10 Gy), respectively. The interval between fractions was 6.1 ± 1.9 months (range, 3-12 months). The median follow-up time was 36 months (12-96 months). Results: During the follow-up period after the second fraction, 97.2% achieved tumor control in our series. A total of 2 patients exhibited local recurrence at 30 and 60 months after the second fraction, respectively. No treatment-related complications or new long-term neurological dysfunctions were reported. MRIs observed slightly or moderately increased peritumoral edema in six patients, but no specific neurological complaints are attributed to this finding. Conclusion: This study investigates the efficiency and safety of dose-staged Gamma Knife radiosurgery as an alternative option for meningiomas that were large in volume, adjacent to crucial structures, or in patients with contraindications to craniotomy.

Hypofractionated Radiosurgery Plus Bevacizumab for Locally Recurrent Brain Metastasis with Previously High-Dose Irradiation.

BACKGROUND: Selection of appropriate treatment for patients with recurrent brain metastasis (BM) remains uncertain. Recent studies have demonstrated a significant response rate and acceptable toxicity using fractionated stereotactic radiosurgery (FSRS) in patients with locally recurrent large BM. The aim of this study was to evaluate efficacy and toxicity of FSRS with bevacizumab as a new salvage treatment for locally recurrent BM with previous high-dose irradiation. METHODS: Patients with recurrent BM previously irradiated were enrolled. Salvage FSRS dose was 9.5-29 Gy (2-5 fractions) with 62%-75% isodose line by CyberKnife according to the brain tumor volume, site, and previous dose. Bevacizumab was prescribed for 4 cycles (5 mg/kg, every 3 weeks). The primary objective was to identify the overall survival after salvage treatment. Secondary objectives included clinical response (Karnofsky performance scale), imaging response (magnetic resonance imaging) and treatment-related adverse events. RESULTS: From December 2009 to October 2016, 24 patients were enrolled. The 1-year overall survival after salvage stereotactic radiosurgery was 87.5%. Twenty-three (96%) patients had a positive imaging response with a T2 volume reduction range of 6-22 cm3 (median 14 cm3, P = 0.032, paired t test). Significant clinical improvement was achieved (best Karnofsky performance scale score, P < 0.05, paired t test). Grade 1/2 fatigue was observed in 8 (33%) patients. Grade 3 fatigue and headache occurred in 1 patient. CONCLUSIONS: FSRS with adjuvant bevacizumab treatment showed favorable clinical and radiologic control as a salvage treatment regimen. The diagnoses of radiation necrosis and local recurrence after salvage FSRS warrant further study.