Stereotaxic Radiosurgery Research Articles

SURG-40. AWAKE CRANIOTOMY IN A MIDDLE-INCOME COUNTRY. CHALLENGES AND TECHNICAL NUANCES

Abstract OBJECTIVES Describe the first experience in this technically challenging procedure RESULTS on morbidity INTRODUCTION Awake craniotomy allows for maximal safe resection and lower incidence of adverse events. Nonetheless, it represents a technical challenge. METHODS We enroll forty patients, 18 women, and 22 men. Due to the lack of a navigation system, craniometrics points became paramount to craniotomy planning. Ultrasound is used to compensate for brain shift and confirm the tumor's exact location. We engaged in cortical and subcortical mapping and clinical evaluation of motor and sensory functions. Linguistic tests were applied. The first 24 hours are in the ICU, and an MRI is obtained. RESULTS The mean age was 51, and the mean Karfnosky scale was 80. The median size was 12 cm3. Locations were: Thirteen precentral gyri. Ten insular cortex. Eight cingulate gyri. Six supplementary motor gyri Two Supramarginal gyri. One paracentral lobe tumor. Four patients had obese morbidity, three had depression, and two had a midline displacement treated with steroids. Intraoperative, we encountered three seizures managed with cold saline, two speech arrest, and one transient hand motor deficit. Post-op adverse events were one central facial paralysis, one upper limb, and one lower limb paresthesias; all improved after 72 hours. The median length of stay is 48 hours. The median extent of resection is 93%. The mean KPS was 80 at discharge. We undertook a median of 18 months follow-up. 38 Glioblastomas(GMB) and 2 Low-Grade Gliomas(LGG) were found. The standard oncology treatment was Temozolomide and stereotaxic radiosurgery(SRS). The median time from surgery to SRS was 4.3 months. The median SRS marginal and maximal dose were 15Gy and 26Gy. The median overall survival(OS) was sixteen months, and the Progression-free survival(PFS) was ten months. CONCLUSION An awake craniotomy without the navigation system is possible; however, careful planning is essential.

Outcomes of single brain metastasis treated with gamma knife stereotaxic radiosurgery(GKSR). Our experience on 103 cases.

Brain metastases (BM) occur in the natural course of malignant tumors in 18-40% of cases. Their management has changed considerably over the past decade thanks to the advent of Gamma knife Stereotactic Radiosurgery (GKSR). We report our experience on Single Brain metastasis treated with (GKSR). Patients treated by Gamma Knife stereotaxic radiosurgery (GKSR) in our institution between 2009 and 2021 for Single BM were recorded retrospectively. A total of 103 patients (n=52; 50.5% females) were included, with a mean age of 56.33±11.33. Breast (n=39, 37.9%) and lung (n=36, 35%) were the common original location for the primary tumors. GKSR alone without prior surgery, radiotherapy, or chemotherapy was achieved in 81.5% (n=84). Thirteen patients (15.1%) progressed in BM volume while finding the appearance of de novo BM in 5 (5.8%) patients. The median percentage of tumor control after radiosurgery treatment was 70% (IQR: 65-78) and only 26.2% (n=27) of patients had >80% tumor control and stability over the median follow-up time of 5 (95% CI, 4-6) months. We found only two cases of radionecrosis (1.9%). The median survival time was 5.21 (IQR, 3-8) months. Retreatment, recursive partitioning analysis (RPA) class, and tumor stability influenced the overall survival of BM respectively (Hazard Ratio adjust (HRa)=5.610,p=0.045; HRa=6.133,p=0.031; HRa=22.463, p=0.036). Stereotaxic Radiosurgery provides good results in terms of Overall survival with fewer neurocognitive disorders.RPA class and tumor control (stability) influenced the overall survival of single BM.

Influence of clinical and neurophysiological parameters on the function outcome of the facial nerve after vestibular schwannoma surgery

Introduction: Vestibular schwannomas are benign neoplasms of the nerve seath, and they represent the third most common endocranial tumour, following the meningioma and the pituitary adenomas. The primary symptoms of vestibular schwannomas are hearing loss, tinnitus as well as a balance disorder. The therapy of vestibular schwannoma consists of observation, surgery and radiosurgery. The majority of patients who are good candidates for surgery are already affected by significant hearing impairment, thus one of the primary goals of the surgery is the preservation of facial nerve function. Aim: To analyze the outcome of facial nerve function one-year post-surgery using clinical and neuropsychological parameters. Material and methods: This study analyzed the patient's clinical status on admission along with the neuroradiological characteristics of tumours and the neurophysiological intraoperative parameters and their effect on the facial nerve function in the early postoperative period as well as one year after the surgery using the House–Brackmann scale. Results: A total of 30 patients who underwent surgery from January 1st 2015 to December 31st 2018 at the Clinical Centre of Serbia, Neurosurgery Clinic for vestibular schwannomas were examined. The median age of the patients was 51 years. Hearing loss was present in all patients. Sensitivity drop in the innervation region of n. trigeminus was present in 7 (23.3%) patients, as was tinnitus. Cerebellar symptomatology (76%) was present in the highest percentage of patients. Conclusion: We can conclude that the most important aspects of the facial nerve function are the preoperative state of the facial nerve and the electrophysiological parameters. Although the radical procedure of surgery led to an immediate postoperative outcome, it was not significant for the ultimate outcome of treatment. Thus, radical surgery may be considered to carry the same risk of definitive impairment of the facial nerve function, just like a combination treatment with subtotal resection and stereotaxic radiosurgery.

Management of Recurrent Meningiomas: State of the Art and Perspectives

Simple SummaryIntracranial meningiomas account for 30% to 40% of the primary lesions of the central nervous system. Surgery is the mainstay treatment whenever symptoms related to an intra-cranial meningioma are encountered. However, the management of recurrences after initial surgery, which are not uncommon, is still a matter of debate. Here, we present the alternatives described in the management of meningioma recurrence (radiotherapy, stereotaxic radiosurgery, protontherapy, and chemotherapy, among others). Their overall results are compared to surgery and future perspectives are presented.Background: While meningiomas often recur over time, the natural history of repeated recurrences and their management are not well described. Should recurrence occur, repeat surgery and/or use of adjuvant therapeutic options may be necessary. Here, we summarize current practice when it comes to meningioma recurrence after initial surgical management. Methods: A total of N = 89 articles were screened. N = 41 articles met the inclusion criteria and N = 16 articles failed to assess management of meningioma recurrence. Finally, N = 24 articles were included in our review. Results: The articles were distributed as follows: studies on chemotherapy (N = 14), radiotherapy, protontherapy, and stereotaxic radiosurgery (N = 6), boron-neutron capture therapy (N = 2) and surgery (N = 3). No study seems to provide serious alternatives to surgery in terms of progression-free and overall survival. Recurrence can occur long after the initial surgery and also affects WHO grade 1 meningiomas, even after initial gross total resection at first surgery, emphasizing the need for a long-term and comprehensive follow-up. Conclusions: Surgery still seems to be the state-of-the-art management when it comes to meningioma recurrence, since none of the non-surgical alternatives show promising results in terms of progression-free and overall survival.

Stages of stereotactic radiosurgery in the treatment of recurrent glioblastomas

Objective: to evaluate the effectiveness of stereotactic radiosurgery as a therapy method taking into account overall survival in patients with recurrent glioblastoma at all stages of treatment. Materials and methods. A sample of patients (66 ailments) who were treated in 2016-2021 with a molecularly confirmed diagnosis of wild-type glioblastoma was analyzed. Only patients, who, were treated in several stages and as a rule, underwent stereotaxic radiosurgery (SRS), or SRS alone after a biopsy, or SRS in case of relapse, after surgery and radiotherapy, or SRS for subsequent relapses were selected. When evaluating the results, the following were taken into account: 1) age at the diagnosis, 2) volume of surgical resection, 3) use of radiation therapy, 4) use of adjuvant chemotherapy after SRS and response evluation criteria in solid tumors. Overall survival (OS) was assessed after diagnosis and at the time of SRS. Results. Patients received SRS at an average 10 months after initial diagnosis. Median duration of follow-up was 8 months after SRS and 12 months after diagnosis, median OS for all patients was nine months (1 to 42 months) after SRS and 20 months (4 to 64 months) respectively. The median survival after SRS was 9 months (p=0.008; χ2=7.008). The median OS for younger patients (<50 years) was 32.5 months, for elderly patients (>50 years) was 14.8 months (p=0.04; χ2=3.870). The median overall survival rate was 32.2 months in patients who received SRS 10 months after the diagnosis was made, and 16 months in those who received SRS earlier than 10 months (p=0.004, χ2=8.145). Radiosurgical doses ≥15 Gy were correlated with a mean survival rate of nine months and seven months in patients treated at doses <15 Gy (p=0.01; χ2=6.756). In patients who received adjuvant therapy with bevacizumab and/or chemotherapy after SRS, the median OS was 12 months, in patients who did not receive additional therapy after SRS, it was 7 months (p=0.04, χ2=4.19). Conclusions. Stereotactic radiosurgery promotes the effectiveness of glioblastoma treatment due to the possibility of carrying out this method at various stages of treatment. The overall survival of our patients depended on the period of SRS after diagnosis, patient age, radiation dose, and adjuvant chemotherapy.

Cavernous malformations of the brain and modern views on their treatment

Cavernous malformations of the brain have become an increasingly common pathology in recent years, thanks to the advancement of modern methods of neuroimaging. Despite the benign nature of the course in most cases, these formations can cause convulsions and serious neurological disorders. Typically, clinical manifestations are caused by hemorrhages in the structure of the cavernous and surrounding parenchyma of the brain. The management strategy chosen for patients with cerebral cavernous malformations is determined by the type of malformation, its size, localization, the presence of repeated hemorrhages, and the clinical picture. This literature review focuses on modern methods of treating cerebral cavernous malformations. The main methods of treatment for cavernous malformations of the brain, particularly surgical treatment, have been analyzed. If surgical intervention is not possible, alternative methods of treatment include radiation therapy, such as stereotaxic radiosurgery, and proton therapy, in cases of deep location of foci in functionally significant areas of the brain, which are characterized by the highest risk of complications. Thе possibilities, efficacy, and safety of stereotactic radiosurgical treatment are discussed, as well as the use of proton therapy in the treatment of cavernous malformations. Furthermore, radiation therapy has been shown to be beneficial for cavernous malformations.

Dual-time point brain FDG PET to differentiate tumor progression from radionecrosis after stereotactic radiotherapy for brain metastases

Dual phase 18[F]-FDG brain PET (dual-PET) is useful to distinguish tumor recurrence (TR) from radionecrosis (RN) after stereotaxic radiosurgery (SRS) of brain metastases, when contrast-enhanced MRI is inconclusive. We aimed to compare six different visual and quantitative interpretation criteria to enhance diagnostic performances. In this retrospective french multicentric study (Clermont-Ferrand, Montpellier, Rennes), we evaluated 45 patients previously treated with SRS for BM, addressed for a dual-PET by the local neuro-oncological committees for an evolving lesion on MRI inconclusive between TR and RN, at least 3 months after the last SRS session. Dual-PET included both an “early” and a “delayed” acquisition, respectively 30 to 60 minutes and 4 to 5 hours after 18[F]-FDG injection. After measuring SUVmax values of both lesion (L) and mirror contralateral grey matter (GM) at early (1) and delayed (2) acquisitions, three quantitative metrics were calculated: ratios of L SUVmax to GM SUVmax at “early” (L1/GM1) and “delayed” (L2/GM2) acquisitions and the retention index which is the variation over time of the standardized SUVmax ratio (RI = [(Delayed-Early)/Early]). Visual analysis was also conducted using a subjective 6 points visual scale of the lesion uptake at both acquisitions. The five interpretation criteria were compared according to their area under the ROC curve (AUC), and to their diagnostic accuracy applying the best cut off value (maximizing the Youden's index) by the Cochran Q test. The final diagnosis was based on pathology, or by default radiological and clinical follow-up criteria after at least 6 months. Final diagnoses were TR for 24 patients and RN for 21 patients. There was no statistically significant difference regarding AUC between the different interpretation methods. AUC ranged from 0,78 [95 %CI 0,63; 0,89] with the L1/GM1 Ratio, to 0.85 [95 %CI 0.72; 0.94] with the L2/GM2 ratio. Visual analyses AUC were excellent at both early (0.835 [95 %CI 0.7; 0.93]) and delayed acquisitions (0.83 [95 %CI 0.69; 0.92]). There was no statistically significant difference between accuracies ( p = 0.87) ranging from 0.71 with the RI ratio to 0.80 with both the “delayed” visual and quantitative analyses. Dual-PET protocol distinguishes RN and TR after SRS with robust diagnostic performances in case of doubtful MR, with an accuracy up to 80 %.

The benefits of vestibular schwannoma treatment by the means of gamma knife radiosurgery. Literature review

Domantas Jakštas1, Gabija Pajedienė1, Monika Martusevičienė2 1Lithuanian University of Health Sciences, Medical Academy, Faculty of Medicine 2Lithuanian University of Health Sciences, Kaunas Hospital Abstract Vestibular schwannoma (VS), also known as acoustic neuroma, is a benign, slow-growing tumor that develops due to hyperproduction of Schwan‘s cells surrounding the balance and auditory nerves in the inner ear. Symptoms such as asymmetric hearing loss, tinnitus, dizziness, and imbalance occur as the tumor grows. Significant enlargement of the tumor may exhibit pressure on the surrounding brain structures, leading to various neurological deficits and life-threatening damage to the brain stem. Due to the complex localization of the tumor, surgical treatment is associated with a high risk of complications and more difficult recovery, leading to the increasing use of radiosurgical treatments. Gamma knife stereotaxic radiosurgery is a promising and effective treatment method that is increasingly used to treat VS. Aim: to collect publications on the treatment of vestibular schwannoma with stereotaxic radiosurgery using Gamma knife and to systematically evaluate the benefits provided by this method over traditional microsurgery. Methods. A comprehensive search of English-language literature in the PubMed database was performed. The search was performed using MeSH terms: Gamma knife, radiosurgery, stereotactic radiosurgery, vestibular schwannoma, acoustic neuroma. Article inclusion criteria: Article was published in English Article was not older than 15 years Article was describing the results of vestibular schwannoma treatment by the means of Gamma knife (LINAC radiosurgery and CyberKnife were excluded) Exclusion criteria: Articles, describing the use of other radiosurgery modalities, such as LINAC and CyberKnife Results: with the use of chosen keywords, 60 studies were found. After implementing inclusion and exclusion criteria, 31 articles were selected for further evaluation. After analyzing the information, presented in these articles, we have come to conclusion that Gamma Knife is an effective method of VS treatment, with an advantage as this method can avoid many of the complications associated with open surgical treatment, such as hearing loss, facial or trigeminal nerve dysfunction. Keywords: vestibular schwannoma, gamma knife, stereotactic radiosurgery. https://doi.org/10.53453/ms.2021.06.12

Differential diagnosis between progression and radionecrosis in brain metastases after stereotactic radiosurgery using hybrid FDG-PET and MRI coregistered images

IntroductionDual phase 18 FDG brain PET is helpful to assess brain metastases (BM) as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory processes. This is useful when MRI can’t discriminate brain tumor recurrence (TR) rom radionecrosis (RN) after stereotaxic radiosurgery (SRS) for BM. Many studies have sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many biases, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers. Materials and methodsWe retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET consisted in an “early” and “delayed” acquisition, respectively 30minutes and 4h after injection. MRI included permeability and perfusion sequences. PET and MRI data were all coregistered on the contrast enhanced T1 MRI images. Semi-automated Volumes of Interest (VOI) of the tumor were drawn on the BM and a reference contralateral white-matter ROI (WM) was drawn for standardization; every metric was calculated inside these ROIs, in particular the tumor SUVmax and its variation in time. A 20% increase in the tumor SUVmax was in favor of TR while a modification of less than 100% was in favor of RN. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up. ResultsNine patients were ruled out as TR and 6 as RN. After standardization, there was a significant difference between groups for VP (P=0.042), Washin (P=0.035), Peak Enhancement (P=0.037), standardized delayed SUVmax (P=0.008) and RI (P=0.016). Semi-quantitative analysis found respectively for PET and MRI a Sensitivity of 100% and 87.5% and a Specificity of 100% and 85.71%. ConclusionCoregistered PET-MRI images accurately discriminate between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.

GAMMA KNIFE RADIOSURGERY ROLE IN THE MANAGEMENT OF BRAIN STEM CAVERNOUS ANGIOMAS

Background: Cavernous angioma or cavernoma is a benign vascular malformation, which can be found at any region within the brain. Brain stem cavernous angioma is rare. Although the optimal management of intracranial cavernous angiomas is open resection, Gamma Knife radiosurgery (GKR) has played an important role in treating these deeply seated and high surgical risk malformations throughout the past 20 years. Aim of the study: Our study aimed to evaluate the efficacy, and safety of Gamma Knife radiosurgery in the management of brainstem cavernous angiomas.Patients and Methods: Our retrospective study was conducted on 22 patients with brainstem cavernous hemangioma who underwent gamma knife at the Gamma Knife center (GKC), Nasser Institute Hospitals, Cairo in collaboration with department of neurosurgery, Ain Shams University. Follow up period 24-132 months, mean follow up period 51 months.Results: In the present series we have satisfactory results as regards reducing rebleeding rate, we have post radiosurgeryrebleeding rate of 2.8%. It represents the sum of the bleeding rate for all patients in the study including those who have rebleeding rate 30% preradiosurgical. As regards control of improvement of presenting manifestations, we have also excellent results in the present series (75%) of patients showed improvement of the symptoms, (25%) remained stable clinically. Reduction of cavernoma size after treatment was observed also in our series for 77.3% of the lesions. There was no permanent morbidity post gamma knife, only 3 transient morbidities were happened due to edema and bleeding.Conclusion: As the development of stereotaxic radiosurgery and more experience accumulated, GKR has become an effective and safe alternative method for brainstem cavernous angiomas treatment.

Distinguishing tumor recurrence from radionecrosis in brain metastases after stereotactic radiosurgery using hybrid FDG-PET and MRI coregistered images

Objectives Dual phase 18 FDG-PET has been proven helpful to assess FDG-avid cerebral tumors as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory process. This is useful when MRI can’t discriminate brain tumor recurrence (TR) from radionecrosis (RN) after stereotaxic radiosurgery (SRS) for brain metastases (BM). Many studies sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many bias, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers. Methods We retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET comprised a one hour “based image” (H1) followed by a 4 hours “delayed image” (H4). MRI included contrast enhanced T1 (T1), FLAIR, ASL (BAT,CBF), T1 Perfusion (ktrans, SER) and T2* Permeability (k2, rBF, rBV). PET and MRI data were all coregistered on the T1 images. Semi-automated Regions of Interest (ROI) of the tumor were drawn on the T1 MRI, H1 and H4 FDG-PET images; a reference contralateral white-matter ROI (WM) was drawn for standardization. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up. Results Eleven patients matched the inclusion criteria; 7 with TR and 4 with RN; no additional treatment was introduced. On visual analysis, FDG-PET and MRI respectively obtained 100% and 83% Sensitivity and 100% and 80% Specificity. The two MRI-false negative diagnoses were subsequently identified on follow-up (1 patient, RN) and histology (1 patient, TR). When standardized on WM, PET SUVmax values were significantly different across groups at H1 (P Conclusion Coregistered PET-MRI images accurately discriminates between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.

DIFFERENTIAL DIAGNOSTICS OF A RADIONECROSIS AND LOCAL TUMORAL RECURRENCE ACCORDING TO ARTERIAL SPIN LABELLING AFTER RADIOSURGERY TREATMENT OF MALIGNANT GLIOMAS OF A BRAIN

The aim: Assessment of a possibility of performing differential diagnostics of the post-beam radio necrosis (PBRN) and the local recurrence (LR) after the carried-out stereotaxic radio surgery (SRS) according to perfusion on the basis of non-contrast pulse arterial backs markings (PASL). Materials and methods: In our research, we consider results of the stereotactic radiosurgery (SRS) which is carried out to 20 patients with the diagnosis the malignant glioma of a brain (MGB) in respect differential diagnostics of a local tumor recurrence and radionecrosis according to perfusion non-contrast MRT of a research on the basis of the sequence of PASL. The diagnosis of MGB before carrying out SRS was established to all 20 patients on the basis of a histologic research on data of a biopsy. From them the anaplastic astrocytoma (AnASTs, grade III) and at 14 - a glioblastoma was diagnosed for 6 patients (GBM, grade IV). Confirmations of the post-beam diagnosis it was carried out on the basis of a histologic research on results of a stereotactic biopsy or a surgical resection. Traditional methods of medical statistics were applied to processing of the statistical information obtained in a research at all its stages (calculation of average and relative sizes with their errors), also graphic and tabular methods were applied to rational evident statement of the received results. Results: The diagnosis of a local tumor recurrence according to a relative regional blood-groove on the basis of PASL was exposed to 8 patients and confirmed histologically (to 5 patients underwent surgical resection, 3 - according to biopsy data). Patients with a confirmed diagnosis of relapse according to biopsy were performed in 1 case, repeated radiosurgery and in 2 cases (with a diagnosis of multifocal continued growth of glioblastoma) - irradiation of the entire brain. Radionecrosis was diagnosed in 12 cases. In 6 cases, it was confirmed on the basis of clinical diagnostic data of dynamic observation of patients, in 3 cases - according to surgical resection, and in 3 cases - according to stereotactic biopsy. According to our data, the average rrCBF based on arterial spin labelling (PASL) rTPmean ≤ 0.8ml / 100g / minute most likely testified in favor of radionecrosis, average ≥ 1.5ml / 100g / min - in favor of tumor progression, the maximum rTPmax ≤ 1.3ml / 100g / min most likely testified in favor of radio-necrosis, the maximum indicator rTPmax≥ 1.8ml / 100g / min - in favor of tumor progression. Conclusions: According to a relative regional blood flow of rrCBF based on non-contrast PASL perfusion, it is possible to reliably carry out a differential diagnosis of radionecrosis and local tumor recurrence in patients undergoing radiosurgical treatment for malignant gliomas of the brain.

Abstract CT065: A Phase I clinical trial: Use of 4-demethyl-4-cholesteryl- oxycarbonyl-penclomedine (DM-CHOC-PEN) plus radiation as treatments for cancers involving the CNS

Abstract Purpose: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase II studies [AACR, #CT129, 2017] in subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy with 39-98.8 mg/m2 of drug. DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor. Thus, the drug penetrates the CNS and tumors and is available to act as a radiosensitizer; the latter has been supported with in vitro studies [AACR, #4746, 2017]. The current presentation reviews Phase I clinical data that supports the safety, dose-tolerance and use for DM-CHOC-PEN plus radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once to subjects with advanced cancer involving the CNS. A single dose (39 mg/m2 to 98.7 mg/m2 in escalating Phase I scheme) was administered once 3-weeks prior to receiving stereotaxic radio-surgery (SRS), gamma knife or whole brain irradiation (WBRT) therapy. Radiation was administered in doses of 15-30 Gy depending on the size and number of lesions. Results: Thirteen (13) subjects with cancer involving the CNS have been treated to date with DM-CHOC-PEN (6-NSCLC, 1-breast, 1-melanoma, 2-GBM & 3-sarcomas). Subjects received 39, 50, 70, 86.8 or 98.7 mg/m2 and 15-30 Gy of radiation. The drug/radiation combination was well tolerated. One (1) subject with NSCLC did develop vasogenic edema and tumor necrosis which resolved and the subject is in complete remission 42+ mos. A second subject with a recurrent GBM with confusion progressed - Gr-3. Ten (10) of the thirteen (13) subjects have had objective results (OS 8-54+ mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. The same phenomenon was observed with RBCs (estimation using Monolix 3.2). DM-CHOC-PEN was detected bound to RBCs for 3-days (after 70 mg/m2) and was also detected in the urine (Cmax=17.5 µg/mL) until day 15. The AUC was linear for all doses. Pre-clinical radiosensitization in vitro studies [AACR #1917, 2017] support the present trial study result. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed as a MOA. Conclusion: Data is presented that documents effectiveness and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during Phase I/II clinical trials with DM-CHOC-PEN alone supported the drug’s persistent presence in human tumors after systemic administration and possible positive effects on response to subsequent radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-02 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: RS Weiner, T Mahmood, Lee Roy Morgan, K. Harris, A. Baghian, SJ DiBiase, P. Friedlander, ML Ware, R. Kawauchi, J. Herman, M. Bhandari. A Phase I clinical trial: Use of 4-demethyl-4-cholesteryl- oxycarbonyl-penclomedine (DM-CHOC-PEN) plus radiation as treatments for cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT065.

P3.01-79 Intracerebral Efficacy of Immune Check-Point Inhibitors in NSCLC Patients with Brain Metastases

The brain is a common site of metastatic disease in patients with non-small cell lung cancer (NSCLC). Approximately 30–50% of patients will develop brain metastases during the course of treatment. Several immune check-point inhibitors (ICIs) have shown efficacy against non–small-cell lung cancers (NSCLCs) and approved in second line setting. However, regarding ICIs intracerebral efficacy and tolerability in NSCLC patients with active brain metastases (BMs) remains unknown. We reviewed the medical charts of 49 patients with advanced NSCLC treated with ICIs between January 2016 and March 2018. The intracranial activity of ICIs in patients with brain metastases was assessed by brain magnetic resonance imaging (MRI) using RECIST v. 1.1 criteria. The primary endpoint was intracerebral objective response rate (IORR). Secondary endpoints included intracerebral control rate, intracerebral and general progression-free survival (PFS), overall survival (OS) and tolerance. Ten NSCLC patients with BMs were identified. The median age of patients was 61 years (range 44–80 years) and the majority of patients were male (n = 9; 90%). All patients were pretreated with stereotaxic radiosurgery (n = 7) or whole brain radiation therapy (n = 3). All but one patients received prior systemic treatment for NSCLC. Three patients received two prior lines of systemic therapy. Two patients were treated with pembrolizumab. Median follow-up was 5.7 (95% CI: 2.7–8.4) months. IORR and extracerebral response rate were, respectively, 0% (95% CI: 0–25.9%) and 20% (95% CI: 2.5–55.6%). Intracerebral control rate was 60% (95% CI: 26.2–87.8%). Median intracerebral and general PFS lasted 1.8 (95% CI: 0.9–7.1) and 2.8 (95% CI: 1.8–4.6) months, respectively. Median OS was 8.9 (95% CI: 4.9–not reached) months. No neurological adverse events occurred. ICIs might have the efficacy and favorable safety profile in NSCLC patients with BMs.

Abstract CT119: Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS

Abstract Purpose:4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a mechanism of action (MOA) via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR, 58, #CT129, 2017] in subjects with cancers involving the CNS. Four (4) subjects in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy and DM-CHOC-PEN was identified in samples from all 4-subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Thus, the drug penetrates the CNS and concentrates in tumors. It is available, therefore, to act as a radiosensitizer as demonstrated in in vitro studies [AACR, 58, #4746, 2017]. The current presentation reviews Phase I clinical data that supports the safety, dose-tolerance, and use of DM-CHOC-PEN with radiation in subjects with cancers involving the CNS - IND 68,876. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. A single dose was administered prior to standard radiation therapy. The dose was escalated from 39 mg/m2 to 98.7 mg/m2 I.X1, then 3-weeks later the subject received stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). Total radiation administered was 15-30 Gy depending on the size and number of lesions. Results: Nine (9) subjects with cancer involving the CNS have been treated to date - (6-NSCLC, 1-breast, 1-melanoma & 1-sarcoma). Subjects received 39, 55, 70, 86.8 or 98.7 mg/m2 followed by 15-30 Gy of radiation. The drug/radiation combination was well tolerated. One (1) subject with NSCLC developed vasogenic edema and tumor necrosis which resolved; that subject is in complete remission 31+ mos. Six out of nine subjects have had objective responses (OS 4 - 42+ mos.) Bioavailability for DM-CHOC-PEN revealed a rebound phenomenon @ ~ 50 hours post-infusion with a T-release of 26.7 h. The same phenomenon was observed with RBCs (estimation using Monolix 3.2). DM-CHOC-PEN was detected bound to RBCs for 3-days (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. The AUC was linear for all doses. Pre-clinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL. For radiation alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) plus radiation (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports enhanced cytotoxicity and safety of DM-CHOC-PEN plus radiation as therapy for subjects with cancers involving the CNS. Observations during Phase I/II clinical trials with DM-CHOC-PEN alone support the drug's persistent presence in human tumors after systemic administration and possible positive effects on response to subsequent radiation. Complete data on subject responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43 CA213545-01 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: LR Morgan, T Mahmood, R S. Weiner, R Kawauchi, M Bhandari, K Devisitty, J Herman, R Summe, ML Ware, P Friedlander, AH Rodgers. Early phase I clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT119.

Abstract 4746: Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS

Abstract Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I/II studies [AACR #CT129, 2016] in subjects with cancers involving the CNS. The current presentation reviews clinical and in vitro data that support radiosensitizing properties for DM-CHOC-PEN in cancers involving the CNS. Patients & Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer involving the CNS. The dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. All subjects with resistant or new CNS lesions that did not respond to DM-CHOC-PEN were given the option of surgery, stereotaxic radio-surgery (SRS) or whole brain irradiation (WBRT). As preclinical support, human NSCLC adenocarcinoma cells (H-2086) growing in culture (106 cells/mL) were pretreated with DM-CHOC-PEN (0.1 -1.0 µg/mL) for 24 hrs, drug washed, re-fed fresh medium and then 48 h later irradiated (SRS with 6, 9 or 12 Gy). Results: Fifty-three (53) subjects with/without CNS involvement have been treated to date with DM-CHOC-PEN. Five (5) subjects (4-NSCLC & 1-sarcomas) in the Phase I/II trials required surgery for persistent CNS lesions following DM-CHOC-PEN therapy. DM-CHOC-PEN was identified in samples from all subjects - 90-212 ng/g tumor [subjects had been treated with 39-98.8 mg/m2 of drug]. Five subjects (1-sarcoma & 4-NSCLC) who had been treated with DM-CHOC-PEN for 6-wks - 8-mos had persistent NSCLC lesions involving the CNS were treated with SRS or WBRT. All five subjects had excellent objective results (OS 8+ - 29+ mos) with no CNS toxicity. Preclinical in vitro studies supported the clinical data: NSCLC cells treated with DM-CHOC-PEN (0.1 -1.0 µg/mL) demonstrated 50 & 100% cytotoxicity @ 0.4 & 1.0 µg/mL; for SRS alone (6, 9 &12 Gy) - cell kill was 20 & 65% @ 6 & 12 Gy [100% kill was not observed at this dose range]; for DM-CHOC-PEN (0.25 µg/mL) + SRS (6-12 Gy) - cell kill was 80 & 100% @ 6 & 12 Gy. Thus, in combination - less drug (0.25 µg/mL) and 12 Gy - produced a 100% cell kill, as compared to either SRS or drug, alone. Photon induced charge transfer reactions with DM-CHOC-PEN will be discussed. Conclusion: Preliminary data is presented that supports DM-CHOC-PEN’s cytotoxicity and radiosensitizing properties in cancers involving the CNS. Observations during clinical trials support the drug’s persistent presence in human tumors after systemic administration and notable positive effect on response to subsequent radiation. Complete data on patient responses and observed toxicities will be presented. Supported by - NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Lee Roy Morgan, R S. Weiner, T Mahmood, R. Kawauchi, K Devisetty, J Herman, M Bhandari, R Summe, E Benes, AH Rodgers, ML Ware, JS Hayman, J Weber, Jay J. Zou. Early clinical support for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as a radiosensitizer in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2017-4746

Metastases in cerebellopontine angle from the tumors of central nerve system

The objective of this study was to analyze the characters of the cerebellopontine angle (CPA) metastases from central nerve system (CNS) tumors. Ten patients were reviewed for the period between 2008 and 2015. The clinical and neuroimaging features, and treatment outcomes were analyzed retrospectively. The average period during primary diagnosis through the diagnosis of CPA metastases was 42.4months. Among the 10 cases, the primary tumors and metastases were found simultaneously in 3 cases, the metastases after primary tumor removal were found in 5 cases, and the metastases after stereotaxic radiosurgery were found in 2 cases. Only 4 patients presented with the symptoms and signs associated with CPA involving, one with hearing loss, one presenting facial paralysis, one suffering from tinnitus and one case with dizziness. There were 2 cases with the miliary metastases and 8 cases with massive metastases. There existed 3 cases with single CPA metastases, whereas 7 cases with multiple metastatic foci. Among the 8 cases of massive metastatic foci, 6 tumors presented the solid features and the other 2 cases exhibited cystic and solid features. In this cohort of cases, 4 cases were involved in the bilateral and 6 cases presented unilateral metastatic foci. The three CPA metastases were removed in this group, 6 case performed with radiotherapy, and 5 cases received chemotherapy. In the current group 5 patients have been dead, 3 patients kept stable and 2 cases experienced improvement. In spite of seldom previous reports regarding the metastases from CNS tumors occurring in the CPA are existent, this rare form of the disease should be considered in future evaluation as a differential diagnosis.

Clinical outcomes of a cohort of patients with central nervous system metastases from thyroid cancer.

IntroductionMetastases to central nervous system (M1-CNS) are rarely reported in thyroid cancer (TC) patients. We aimed to characterize patients with M1-CNS from TC followed in our department.MethodsReview of the medical records of 27 patients with TC-related M1-CNS.ResultsMean age at TC diagnosis was 56.9 ± 19.1 years. Papillary TC (55.6%) was the commonest histological type, followed by poorly differentiated (18.5%), medullary (11.1%), follicular (7.4%) and Hürthle cell (7.4%) carcinomas. Angioinvasion and extrathyroidal extension were observed in a high number of patients. At M1-CNS diagnosis, other distant metastases were already present in 77.8% of the patients. Treatment directed to M1-CNS was offered to 20 (74%) patients: 1 was submitted to surgery, 18 to radiotherapy (either whole-brain radiotherapy or stereotaxic radiosurgery or both) and 4 to surgery and radiotherapy. Four patients received cytotoxic chemotherapy and one was submitted to 131I. Median survival since M1-CNS detection was 5.0 months. The only factor associated with better survival was surgery to brain metastases (P = 0.012).ConclusionsThe management of these patients is very challenging given the inexistence of effective treatments, except for brain surgery in selected cases.

Timing of Whole Brain Radiotherapy on Survival of Patients with EGFR-mutated Non-small Cell Lung Cancer and Brain Metastases

背景与目的全脑放疗（whole brain radiotherapy, WBRT）在表皮生长因子受体（epidermal growth factor receptor, EGFR）突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）脑转移患者治疗中何时应用尚无高级别的循证医学证据。本研究旨在探讨WBRT的参与时间对携有EGFR突变的NSCLC脑转移患者生存的影响。方法2009年8月-2015年5月在我院确诊的EGFR突变伴脑转移的晚期NSCLC共78例患者，均接受WBRT及EGFR酪氨酸激酶抑制剂（EGFR tyrosine kinase inhibitors, EGFR-TKIs）治疗的48例初治患者进入临床分析，采用Cox比例风险模型分析患者颅内无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）的影响因素。结果全组患者颅内客观缓解率（objective response rate, ORR）为81.3%，颅内疾病控制率（disease control rate, DCR）为93.8%，中位颅内PFS为10个月，中位OS为18个月。颅内PFS的多因素分析显示，美国东部肿瘤协作组评分（Eastern Cooperative Oncology Group performance status, ECOG PS）0分-1分（HR=30.436, 95%CI: 4.721-196.211, P < 0.001）及早期WBRT患者（HR=3.663, 95%CI: 1.657-8.098, P=0.001）的颅内PFS更佳。OS的多因素分析显示，ECOG PS 0分-1分（HR=57.607, 95%CI: 6.135-540.953, P < 0.001）、早期WBRT（HR=2.757, 95%CI: 1.140-6.669, P=0.024）及立体定向放射外科（stereotaxic radio surgery, SRS）的应用（HR=5.964, 95%CI: 1.895-18.767, P=0.002）是患者OS的独立预后因素。结论早期WBRT联合TKIs治疗可改善EGFR突变的NSCLC脑转移患者的预后，尚有待大样本的前瞻性临床试验验证。

SU-F-T-573: Evaluation of EBT-XD Radiochromic Films for Verification of SBRT and SRS Treatment Delivery

Purpose: To evaluate the accuracy and precision of radiochromic films EBT-XD for quality control of stereotaxic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) plan delivery. Methods: A film cut in 3×10 cm2 strips was irradiated from 0 to 20 Gy in increments of 1 to 1.5 Gy using a 15 MeV electron beam. Triple-channel film calibration was completed 24 hours later by scanning the film strips on an Epson 10000XL scanner using a well-defined protocol. Several dose measurements of increasing complexity were subsequently performed with Varian iX accelerators. Pieces of films were first irradiated in a solid water phantom with 6 MV photon beams and a static gantry to doses spanning the calibration range, either in a single field or multiple fields setup. High dose (>15 Gy per fraction) IMRT plans were then measured. Finally films were irradiated with volumetric modulated arc therapy (VMAT) plans of lung and spinal lesions with prescribed doses per fraction between 8 and 20 Gy. The dose measured with the films was compared to the calculated dose from the Eclipse planning system using the Anisotropic Analytical Algorithm (AAA). Results: 77 dose measurements were compared to either ion chamber measurements or dose calculations (reference). The average dose difference between film measurements and reference was 0.7 % and the standard deviation was 1.3%. The maximum and minimum dose differences were +3.5% and −2% in the 4 Gy to 20 Gy range. Measured dose profiles of lung and vertebra treatment plans agreed very well with the calculations. Conclusion: EBT-XD films are a useful dosimeter for quality control of SBRT and SRS plan delivery. The measurement of a full 2D dose plane with high spatial resolution and acceptable dose accuracy make it an advantageous choice compared to other detectors such as ion chambers or diodes.