Intracranial chordoma: radiosurgery,hypofractionated stereotactic radiotherapy and treatment outcomes

BackgroundThe aim of the study was to assess the results of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy (SRS/SRT) for skull base chordomas.Materials and methodsTwenty-three patients aged 12–75 were treated with SRS/SRT due to skull base chordoma. In 19 patients SRS/SRT was a part of the primary therapy, while in 4, a part of the treatment of recurrence. In 4 patients SRS/SRT was used as a boost after conventional radiotherapy and in 19 cases it was the only irradiation method applied. Patients were irradiated to total dose of 6–35 Gy and median total equivalent dose of 52 Gy.ResultsDuring median follow-up of 39 months, 4 patients died. One-, two- and five-year OS was 95%, 89% and 69%, respectively. In nine patients, progression of the disease was diagnosed during study period. One-, two- and five-year progression free survival (PFS) from the end of radiotherapy was 81%, 59% and 43%, respectively. Radiotherapy was well tolerated and only two patients in our group experienced moderate treatment-related toxicity.ConclusionSRS/SRT alone or in combination with surgery is a safe and effective method of irradiation of patients with skull base chordomas. High EQD₂ is necessary to achieve satisfactory treatment results.     

Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients

Background

The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome.

Methods

Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7–79.9 years) with a follow-up greater than five years (median 11 years, range 5.3–22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11–20 Gy) and the median tumor volume was 9.5 ml (range 2.8–51 ml).

Results

Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively.

Conclusions

Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy.     

Optimizing MRI sequences and images for MRI-based stereotactic radiosurgery treatment planning

AimDevelopment of MRI sequences and processing methods for the production of images appropriate for direct use in stereotactic radiosurgery (SRS) treatment planning.BackgroundMRI is useful in SRS treatment planning, especially for patients with brain lesions or anatomical targets that are poorly distinguished by CT, but its use requires further refinement. This methodology seeks to optimize MRI sequences to generate distortion-free and clinically relevant MR images for MRI-only SRS treatment planning.Materials and methodsWe used commercially available SRS MRI-guided radiotherapy phantoms and eight patients to optimize sequences for patient imaging. Workflow involved the choice of correct MRI sequence(s), optimization of the sequence parameters, evaluation of image quality (artifact free and clinically relevant), measurement of geometrical distortion, and evaluation of the accuracy of our offline correction algorithm.ResultsCT images showed a maximum deviation of 1.3 mm and minimum deviation of 0.4 mm from true fiducial position for SRS coordinate definition. Interestingly, uncorrected MR images showed maximum deviation of 1.2 mm and minimum of 0.4 mm, comparable to CT images used for SRS coordinate definition. After geometrical correction, we observed a maximum deviation of 1.1 mm and minimum deviation of only 0.3 mm.ConclusionOur optimized MRI pulse sequences and image correction technique show promising results; MR images produced under these conditions are appropriate for direct use in SRS treatment planning.     

Feasibility and potential advantages using VMAT in SRS metastasis treatments

BackgroundUtilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has become the technique of choice as opposed to whole brain radiation therapy (WBRT). The aim of this work is to evaluate the feasibility and potential benefits in terms of normal tissue (NT) and dose escalation of volumetric modulated arc therapy (VMAT) in SRS metastasis treatment. A VMAT optimization procedure has therefore been developed for internal dose scaling which minimizes planner dependence.Materials and methodsFive patient-plans incorporating treatment with frame-based SRS with dynamic conformal arc technique (DA) were re-planned for VMAT. The lesions selected were between 4–6 cm³. The same geometry used in the DA plans was maintained for the VMAT cases. A VMAT planning procedure was performed attempting to scale the dose in inner auxiliary volumes, and to explore the potential for dose scaling with this technique. Comparison of dose-volume histogram (DVH) parameters were obtained.ResultsVMAT allows a superior NT sparing plus conformity and dose scaling using the auxiliary volumes. The VMAT results were significantly superior in NT sparing, improving both the V₁₀ and V₁₂ values in all cases, with a 2–3 cm³ saving. In addition, VMAT improves the dose coverage D₉₅ by about 0.5 Gy. The objective of dose escalation was achieved with VMAT with an increment of the Dmean and the Dmedian of about 2 Gy.ConclusionsThis work shows a benefit of VMAT in SRS treatment with significant NT sparing. A VMAT optimization procedure, based on auxiliary inner volumes, has been developed, enabling internal dose escalation.     

Time motion study to evaluate the impact of flattening filter free beam on overall treatment time for frameless intracranial radiosurgery using Varian TrueBeam® linear accelerator

BackgroundThe aim was to study the impact of the flattening filter free (FFF) beam on overall treatment time for frameless intracranial radiosurgery using TrueBeam^® LINAC.The development of frameless stereotactic radiosurgery (SRS) is possible due to the incorporation of image guidance in the delivery of treatment. It is important to analyze the cost and benefits of FFF beams for treating SRS by understanding the impact of FFF beams in reducing the treatment time.Materials and methodsDynamic conformal arc (DCA ) and volumetric arc therapy (VMAT) plans were generated using 6 MV with a flattening filter (FF) and FFF beams. Overall treatment time was divided into beam on time (BOT) and beam off time (BFT). Percentage beam on time reduction (PBOTR) and Percentage total time reduction (PTTR) factors were defined for the comparison.ResultsBOT reduction was observed to be significant for higher dose per fraction but subjected to the treatment technique and modulation differences. PBOTR values are much higher than PTTR values. The 39.9% of PBOTR resulted in only 8% PTTR for DCA and 65.3% resulted in 15.9% PTTR for VMAT.ConclusionMajor BFT was utilized for imaging and verification. FFF beam significantly reduced the beam on time and was found to be most effective if the fractional dose was as high as that for SRS. Newly defined PBOTR and PTTR factors are very useful indicators to evaluate the efficacy of FFF beams in terms of time reduction.     

前部缺血性视神经病变患者图形视觉诱发电位与视功能改变的关系及其临床意义

目的:探究前部缺血性视神经病变(AION)患者图形视觉诱发电位(P-VEP)检查结果与预后间的关系。方法:选择2016年12月-2019年12月于我院就诊并确诊的AION患者作为研究对象,入院后接受综合治疗,治疗后评估患者的视功能,评价患者的治疗效果,采用相关性分析探究患者入院后P-VEP检查结果与经治疗后患者视功能改善值间的相关性。结果:研究组15'棋盘格和60'棋盘格P100波潜伏时均高于对照组,P100波振幅均低于对照组,差异均具有统计学意义(P0.05)。治疗后3个月AION患者最佳矫正视力和视野平均敏感度(MS)高于治疗前,视野平均缺失值(MD)低于治疗前,差异均具有统计学意义(P0.05)。AION患者治疗前后视力差值与15'棋盘格P100波振幅呈正相关,视野MD差值和视野MS差值与P-VEP四项反应值不具有相关性。结论:P-VEP检查结果 15'棋盘格P100波振幅与患者视力改善差值间存在显著的正相关性,可提示患者视功能恢复程度及预后。     

Idebenone Protects against Retinal Damage and Loss of Vision in a Mouse Model of Leber’s Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients.     

Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.     

Baseline Magnetic Resonance Imaging of the Optic Nerve Provides Limited Predictive Information on Short-Term Recovery after Acute Optic Neuritis

Background

In acute optic neuritis, magnetic resonance imaging (MRI) may help to confirm the diagnosis as well as to exclude alternative diagnoses. Yet, little is known on the value of optic nerve imaging for predicting clinical symptoms or therapeutic outcome.

Purpose

To evaluate the benefit of optic nerve MRI for predicting response to appropriate therapy and recovery of visual acuity.

Methods

Clinical data as well as visual evoked potentials (VEP) and MRI results of 104 patients, who were treated at the Department of Neurology with clinically definite optic neuritis between December 2010 and September 2012 were retrospectively reviewed including a follow up within 14 days.

Results

Both length of the Gd enhancing lesion (r = -0.38; p = 0.001) and the T2 lesion (r = -0.25; p = 0.03) of the optic nerve in acute optic neuritis showed a medium correlation with visual acuity after treatment. Although visual acuity pre-treatment was little but nonsignificantly lower if Gd enhancement of the optic nerve was detected via orbital MRI, improvement of visual acuity after adequate therapy was significantly better (0.40 vs. 0.24; p = 0.04). Intraorbitally located Gd enhancing lesions were associated with worse visual improvement compared to canalicular, intracranial and chiasmal lesions (0.35 vs. 0.54; p = 0.02).

Conclusion

Orbital MRI is a broadly available, valuable tool for predicting the improvement of visual function. While the accurate individual prediction of long-term outcomes after appropriate therapy still remains difficult, lesion length of Gd enhancement and T2 lesion contribute to its prediction and a better short-term visual outcome may be associated with detection and localization of Gd enhancement along the optic nerve.     

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS)

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.     

Microradiosurgical cortical transections generated by synchrotron radiation

PurposeMicroplanar X-ray beams (microbeams) originated by synchrotron sources have been delivered to the visual brain cortex regions in rodents to create microscopically narrow lesions. The effects of microbeams mimic those generated by microsurgical subpial transections (also known as multiple subpial transections) but are obtained in a low-invasive way.MethodsImage-guided atlas-based microbeam cortical transections have been generated on seven 1 month-old Wistar rats. An array of 10 parallel beams of 25 microns in thickness and spaced of 200 micron center-to-center was centered on the visual cortex and deposited an incident dose of 600 Gy.ResultsThe procedure was well tolerated by rats. After recovery, rats showed regular behavior, no sign of gross visual impairment and regular weight gain. After 3 months, rats were sacrificed and brains histologically examined. Cortical transections resembling those obtained through a surgical incision were found over the irradiated region. Remarkable sparing of the cortical columns adjacent to the transections was observed. No sign of radionecrosis was evident at least at this time point.ConclusionsThe visual brain cortex transected by synchrotron-generated microbeams showed an incision-like path of neuronal loss while adjacent non irradiated columns remained intact. These preliminary findings, to be further investigated also using other techniques, suggest that microbeam radiosurgery can affect the cortex at a cellular level providing a potential novel and attractive tool to study cortical function.     

Parallel Changes in Structural and Functional Measures of Optic Nerve Myelination after Optic Neuritis

IntroductionVisual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON.MethodsThirty acute ON patients were studied at 1,3,6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further.ResultsBoth latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94ms of latency delay.ConclusionA strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.     

Radiation dose to the fetus during CyberKnife radiosurgery for a brain tumor in pregnancy

PurposePregnancy during radiosurgery is extremely rare in clinical practice. We report fetal dose results during CyberKnife radiosurgery for a brain tumor in pregnancy.Methods and materialsA 26 year old pregnant woman with a rapidly growing deep-seated grade-III glioma was treated during the third trimester of gestation using CyberKnife. Ultrasound imaging was used to determine the position of the embryo prior to treatment. A dose of 1400 cGy was prescribed aiming to control tumor growth until delivery of the child. Prior to radiosurgery, the treatment was simulated on an anthropomorphic phantom. Radiation dose to the embryo was measured using a Farmer chamber and EBT3 films.ResultsFetal doses of 4.4 cGy and 4.1 cGy were measured for the embryo's head and legs, lying at 56 cm and 72 cm from the isocenter, respectively, using the Farmer chamber situated at 8.5 cm depth beneath the phantom surface. Dose results of 4.4 cGy, 3.5 cGy and 2.0 cGy were measured with the films situated at depths of 6.5 cm, 9.5 cm and 14.5 cm, respectively. An average dose of 4.2 cGy to the fetus was derived from the above values. A corresponding dose of 3.2 cGy was also calculated based on results obtained using EBT3 films situated upon the patient skin.ConclusionsThe measured fetal doses are below the threshold of 10 cGy for congenital malformations, mental and growth retardation effects. The radiogenic cancer risk to the live-born embryo was estimated less than 0.3% over the normal incidence. The treatment was administered successfully, allowing the patient to deliver a healthy child.     

Setup uncertainties in linear accelerator based stereotactic radiosurgery and a derivation of the corresponding setup margin for treatment planning

PurposeIn the present study, clinical stereotactic radiosurgery (SRS) setup uncertainties from image-guidance data are analyzed, and the corresponding setup margin is estimated for treatment planning purposes.MethodsPatients undergoing single-fraction SRS at our institution were localized using invasive head ring or non-invasive thermoplastic masks. Setup discrepancies were obtained from an in-room x-ray patient position monitoring system. Post treatment re-planning using the measured setup errors was performed in order to estimate the individual target margins sufficient to compensate for the actual setup errors. The formula of setup margin for a general SRS patient population was derived by proposing a correlation between the three-dimensional setup error and the required minimal margin.ResultsSetup errors of 104 brain lesions were analyzed, in which 81 lesions were treated using an invasive head ring, and 23 were treated using non-invasive masks. In the mask cases with image guidance, the translational setup uncertainties achieved the same level as those in the head ring cases. Re-planning results showed that the margins for individual patients could be smaller than the clinical three-dimensional setup errors. The derivation of setup margin adequate to address the patient setup errors was demonstrated by using the arbitrary planning goal of treating 95% of the lesions with sufficient doses.ConclusionsWith image guidance, the patient setup accuracy of mask cases can be comparable to that of invasive head rings. The SRS setup margin can be derived for a patient population with the proposed margin formula to compensate for the institution-specific setup errors.     

Radiosurgery dose reduction for brain metastases on immunotherapy (RADREMI): A prospective phase I study protocol

IntroductionUp to 20% of patients with brain metastases treated with immune checkpoint inhibitor (ICI) therapy and concomitant stereotactic radiosurgery (SRS) suffer from symptomatic radiation necrosis. The goal of this study is to evaluate Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) on six-month symptomatic radiation necrosis rates.MethodsThis study is a prospective single arm Phase I pilot study which will recruit patients with brain metastases receiving ICI delivered within 30 days before SRS. All patients will be treated with RADREMI dosing, which involves SRS doses of 18 Gy for 0−2 cm lesions, 14 Gy for 2.1−3 cm lesions, and 12 Gy for 3.1−4 cm lesions. All patients will be monitored for six-month symptomatic radiation necrosis (defined as a six-month rate of clinical symptomatology requiring steroid administration and/or operative intervention concomitant with imaging findings consistent with radiation necrosis) and six-month local control. We expect that RADREMI dosing will significantly reduce the symptomatic radiation necrosis rate of concomitant SRS + ICI without significantly sacrificing the local control obtained by the present RTOG 90−05 SRS dosing schema. Local control will be defined according to the Response Assessment in Neuro-Oncology (RANO) criteria.DiscussionThis study is the first prospective trial to investigate the safety of dose-reduced SRS in treatment of brain metastases with concomitant ICI. The findings should provide fertile soil for future multi-institutional collaborative efficacy trials of RADREMI dosing for this patient population.Trial RegistrationClinicaltrials.gov identifier: NCT04047602 (registration date: July 25, 2019).     

Outcomes following stereotactic radiosurgery or whole brain radiation therapy by molecular subtype of metastatic breast cancer

BackgroundThis study quantified clinical outcomes by molecular subtype of metastatic breast cancer (BC) following whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Doing so is important for patient counseling and to assess the potential benefit of combining targeted therapy and brain radiotherapy for certain molecular subtypes in ongoing trials.Materials and methodsThe National Cancer Database was queried for BC (invasive ductal carcinoma) cases receiving brain radiotherapy (divided into WBRT and SRS ). Statistics included multivariable logistic regression to determine factors associated with SRS delivery, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling.ResultsOf 1,112 patients, 186 (16.7%) received SRS and 926 (83.3%) underwent WBRT. Altogether, 410 (36.9%), 195 (17.5%), 162 (14.6%), and 345 (31.0%) were ER+/HER2−, ER+/HER2+, ER−/HER2+, and ER−/HER2−, respectively. In the respective molecular subtypes, the proportion of subjects who underwent SRS was 13.4%, 19.4%, 24.1%, and 15.7%. Respective OS for WBRT patients were 12.9, 22.8, 10.6, and 5.8 months; corresponding figures for the SRS cohort were 28.3, 40.7, 15.0, and 12.9 months (p < 0.05 for both). When comparing OS between treatment different histologic subtypes, patients with ER−/HER2+ and ER−/HER2− disease had worse OS than patients with ER+/HER2− disease, for both patients treated with SRS and for patients treated with WBRT.ConclusionsMolecular subtype may be a useful prognostic marker to quantify survival following SRS/WBRT for metastatic BC. Patients with HER 2-enriched and triple-negative disease had the poorest survival following brain irradiation, lending credence to ongoing studies testing the addition of targeted therapies for these subtypes.     

Serial pattern evoked potential recording in a case of toxic optic neuropathy due to ethambutol

Visual evoked potentials (VEPs) were studied in a patient who developed visual impairment during ethambutol treatment. The ERG and the flash VEP were normal at the time of maximal visual loss, whereas pattern reversal VEPs 2 and 5 months after onset revealed evidence of severe bilateral optic nerve involvement, especially affecting macular fibres. Seven months after onset paramacular PNP complexes with a late positivity (scotomatous response) were recorded after pattern reversal and half-field stimulation, suggesting involvement of fibres subserving central vision. At the time when visual acuity was normal there was still electrophysiological evidence of a mild involvement of the anterior visual pathway. The papillomacular bundle seems to be especially involved in ethambutol eye toxicity.