A Statistical Index for Evaluating the CTV Coverage Loss of Brain Stereotactic Radiosurgery When the PTV Margin Is Zero

Purpose: To develop a new statistical index “percent CTV (clinical target vo-lume) coverage probability” (%CCP), defined as the probability that a specific percent (e.g., 95%) of the CTV can be reliably covered by the prescription dose, for evaluating the coverage loss of brain (fractionated) stereotactic radiosurgery (SRS/fSRS) when the PTV (planning target volume) margin is zero. Methods: The random variable Q for CTV percent coverage was derived using a previously developed model for CTV random motion that follows a three-dimensional (3D) independent normal distribution with a zero mean and a standard deviation of 𝜎𝑆(for translation) or 𝜎𝛿(for rotation). Assuming both CTV and PTV are spherical with the same diameter dCTV, the cumulative distribution function of Q could be obtained analytically using the relation of sphere-sphere intersection. The %CCP was then derived as the reliability function of Q and was used to quantify the coverage loss for selected dCTV. Results: The 95%-95% clinical goal (95% of the times, at least 95% of the CTV is covered) is not achievable with dCTV mm. For common CTVs (dCTV mm) encountered in SRS/fSRS, only 60%-90% of the CTV could be reliably covered by the prescription dose 95% of the time. For 𝜎𝑆=0.5mm and 𝜎𝛿 =0.4˚, the 95% CCP was the highest when the distance between the CTV and the isocenter 𝑑𝐼⇔𝑇=0 and gradually decreased with the increasing 𝑑𝐼⇔𝑇. Conclusions: The %CCP was successfully derived for evaluating the CTV coverage loss for brain SRS/fSRS. When the PTV margin is zero, the 95%-95% clinical goal cannot be achieved for most targets (dCTV mm).

Observations on the role of brain stereotactic radiosurgery

As a research paradigAs a research paradigm （1） evaluated measures of animal performance correlated with markers of microglia activation and inflammation as they sought to see the effects of more focused radiation in two-month-old male athymic nude rats.The authors used intensity modulated radiation therapy （IMRT） and volumetric modulated arc therapy （VMAT） to irradiate the hippocampus either unilaterally or bilaterally.Treatment plans delivered a total dose of 10 Gy to either one or both hemispheres of the rat brain.Their data suggests that specific behavioral tasks could be reduced by focused radiation delivered to the hippocampus,and in unilaterally treated animals,the contralateral brain seemed to up-regulate repair mechanisms.This report provides additional information relative to the mechanisms of radiobiological effect using targeted radiation.

Clinical and pathological changes in cerebral arteriovenous malformations after stereotactic radiosurgery failure

Background Stereotactic radiosurgery is an altemative to resection of intracranial cerebral arteriovenous malformations （AVMs）, while it will fail in some cases. This study aimed to evaluate the changes after stereotactic radiosurgery for AVMs.Methods Nineteen cases with cerebral AVMs had failure after stereotactic radiosurgery therapy. The symptoms and angiography were assessed. All patients underwent microsurgery. Pathologic examination was performed for all cases and electron microscopic examination was carried out in 6 patients.Results Seven cases had hemorrhage from 12 to 98 months after stereotactic radiosurgery, 5 had headache, 4 had refractory encephalon edema, 2 had epilepsy as a new symptom and 1 had a pressure cyst 5 years after radiosurgery. Angiography in 18 cases, 8-98 months after radiation therapy, demonstrated no significant changes in 5 cases, slight reduction in 9, near complete obliteration in 1 and complete obliteration in 3. An abnormal vessel was found on pathologic examination in 17 cases, even one case had obliterated in angiography. Electron microscopy examination showed vessel wall weakness, but the vessels remained open and blood circulated. One case died because of a moribund state before surgery. The other 18 cases had no new neurological deficiencies, seizure control and no hemorrhage occurred after microsurgery at an average follow-up of 3 years.Conclusion Stereotactic radiotherapy for AVMs should have a long period follow-up. If serious complications occur, microsurgery can be performed as salvage treatment.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors(NepoMUC):a phase I dose escalation trial

Background:More than 25%of patients with solid cancers develop intracerebral metastases.Aside of surgery,radia-tion therapy(RT)is a mainstay in the treatment of intracerebral metastases.Postoperative fractionated stereotactic RT(FSRT)to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recur-rence.However,FSRT has to be delayed until a sufficient wound healing is attained;hence systemic therapy might be postponed.Neoadjuvant stereotactic radiosurgery(SRS)might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy.Here,we conducted a study to find the maximum tolerated dose(MTD)of neoadjuvant SRS for intracerebral metastases.Methods:This is a single-center,phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital,Technical University of Munich.The rule-based traditional 3+3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied.The primary endpoint is the MTD for which no dose-limiting toxicities(DLT)occur.The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0 continuously during the study until the first follow-up visit(4-6 weeks after surgery).Secondary endpoints include local control rate,survival,immunological tumor characteristics,quality of life(QoL),CTCAE grade of late clinical,neurological,and neurocognitive toxicities.In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS.Depending on the occurrence of DLT up to 72 patients will be enrolled.The recruitment phase will last for 24 months.Discussion:Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity,such as better target volume definition with subsequent higher efficiency of eliminating tumor cells,and lower damage to surrounding healthy tissue,and much-needed systemic chemotherapy could be initiated more rapidly.

Stereotactic radiosurgery in the era of novel systemic therapy for lung cancer brain metastases

The emergence of novel systemic therapies has spurred a dramatic paradigm shift in lung cancer treatment.Research has revealed greater intracranial efficacy in targeted agents and immune checkpoint inhibitors(ICI)compared to conventional chemotherapy.Concurrently,advances in stereotactic radiosurgery(SRS)have contributed to the increased use of this highly localized,minimally-invasive treatment modality for local tumor control.In this era of precision medicine,the combination of these novel agents and SRS demands further prospective exploration-particularly as questions regarding their sequence of administration and the risk of neurotoxicity remain unanswered.Presently,although data are limited and largely retrospective,literature supports the concurrent administration of ICI and radiation,with no observed increases in immune-related adverse events or acute neurologic toxicities.In the case of patients with driver mutations,newer generations of tyrosine kinase inhibitors(TKI)display improved intracranial efficacy and are currently preferred alone upfront in patients with asymptomatic brain metastases(BM)due to lack of data.Evidence of combining TKI and SRS is limited with mixed results.In this review,we explore the evidence regarding the use of novel systemic agents and SRS for treatment of lung cancer BM.Clinical practice will continue to be refined as larger,prospective studies yield results.

Stereotactic radiosurgery in the treatment of primary central nervous system lymphoma

Objective To explore the therapeutic alternatives and evaluate the related clinical results of patients with primary central nervous system lymphoma (PCNSL) treated with gamma knife radiosurgery (GKS).Methods From January 1995 to December 2001,44 patients suffering from PCNSL,who had undergone stereotactic biopsy or craniotomy,and who had received a confirmed dignosis through pathological examination,were treated with GKS. All cases were followed up for 1-46 months with an average postoperative period of 27 months. The clinical materials,image features,treatment methods and results of follow-up,were retrospectively reviewed.Results The symptoms and signs of the patients were markedly improved within 1-3 weeks after GKS. The Kanofsky performance status was also improved from a preoperative average of 40% to a postoperative one of 90%. Thiry-eight patients (86.36%) were in complete remission (CR),the other six (13.63%) were in partial remission (PR). The local control rate reached 100%,and the median survival time was 26.5 months. The main side effect was brain edema,which can be treated with dexamethasone and mannitol. Conclusion GKS is a safe and effective method in multimodality treatment of PCNSL. A stereotactic biopsy coupled with GKS is the first choice for diagnosis and treatment. Adjuvant chemotherapy or radiotherapy should then be given according to the patient’s condition.

Concise review of stereotactic irradiation for pediatric glial neoplasms:Current concepts and future directions

Brain tumors,which are among the most common solid tumors in childhood,remain a leading cause of cancer-related mortality in pediatric population.Gliomas,which may be broadly categorized as low grade glioma and high grade glioma,account for the majority of brain tumors in children.Expectant management,surgery,radiation therapy(RT),chemotherapy,targeted therapy or combinations of these modalities may be used for management of pediatric gliomas.Several patient,tumor and treatment-related characteristics including age,lesion size,grade,location,phenotypic and genotypic features,symptomatology,predicted outcomes and toxicity profile of available therapeutic options should be considered in decision making for optimal treatment.Management of pediatric gliomas poses a formidable challenge to the physicians due to concerns about treatment induced toxicity.Adverse effects of therapy may include neurological deficits,hemiparesis,dysphagia,ataxia,spasticity,endocrine sequelae,neurocognitive and communication impairment,deterioration in quality of life,adverse socioeconomic consequences,and secondary cancers.Nevertheless,improved understanding of molecular pathology and technological advancements may pave the way for progress in management of pediatric glial neoplasms.Multidisciplinary management with close collaboration of disciplines including pediatric oncology,surgery,and radiation oncology is warranted to achieve optimal therapeutic outcomes.In the context of RT,stereotactic irradiation is a viable treatment modality for several central nervous system disorders and brain tumors.Considering the importance of minimizing adverse effects of irradiation,radiosurgery has attracted great attention for clinical applications in both adults and children.Radiosurgical applications offer great potential for improving the toxicity profile of radiation delivery by focused and precise targeting of well-defined tumors under stereotactic immobilization and image guidance.Herein,we provide a concise review of stereotactic irradiation for pediatric glial neoplasms in light of the literature.

Advances and controversies in the management of early stage nonsmall cell lung cancer

Complete resection continues to be the gold standard for the treatment of earlystage lung cancer.The landmark Lung Cancer Study Group trial in 1995 established lobectomy as the minimum intervention necessary for the management of early-stage non-small cell lung cancer,as it was associated with lower recurrence and metastasis rates than sublobar resection and lower postoperative morbidity and mortality than pneumonectomy.There is a growing tendency to perform sublobar resection in selected cases,as,depending on factors such as tumor size,histologic subtype,lymph node involvement,and resection margins,it can produce similar oncological results to lobectomy.Alternative treatments such as stereotactic body radiotherapy and radiofrequency ablation can also produce good outcomes in inoperable patients or patients who refuse surgery.

Commissioning of the TrueBeam STx 6 MV FFF Beam in the RayStation Treatment Planning System for SRS and SBRT Treatments

Purpose: The purpose of this study is to provide technical information on commissioning the TrueBeam STx 6 MV flattening-filter free (FFF) beam in the RayStation treatment planning system (TPS) for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) treatments. Methods: For beam modeling, percent depth dose curves, profiles and output factors for jaw-collimated fields and stereotactic cones as well as X-jaws transmission were measured. For multi-leaf collimator (MLC) modeling, MLC model parameters such as offset, gain, curvature, leaf tip width, tongue and groove and transmission were determined and output factors for MLC-collimated fields were measured. Absolute dose calibration was also performed. For beam model and MLC model validation, the American Association of Physicists in Medicine Task Group-119 plans, clinical SRS and SBRT plans and end-to-end testing were performed. Results: Beam characteristics of the 6 MV FFF beam agreed well with those in the literature. Validation results showed that our beam model and MLC model were acceptable for SRS and SBRT treatments. Conclusions: The technical information and dosimetric data provided in this study will be a useful reference for other clinics/institutions which will commission the same machine energy in the RayStation TPS.

Role of Recursive Partitioning Analysis and Graded Prognostic Assessment on Identifying Non-Small Cell Lung Cancer Patients with Brain Metastases Who May Benefit from Postradiation Systemic Therapy

Background：The role ofpostradiation systemic therapy in non-small cell lung cancer （NSCLC） patients with brain metastasis （BM） was controversial.Thus,we explored the role of Radiation Therapy Oncology Group recursive partitioning analysis （RTOG-RPA） and graded prognostic assessment （GPA） in identifying population who may benefit from postradiation systemic therapy.Methods：The clinical data of NSCLC patients with documented BM from August 2007 to April 2015 of two hospitals were studied retrospectively.Cox regression was used for multivariate analysis.Survival of patients with or without postradiation systemic therapy was compared in subgroups stratified according to RTOG-RPA or GPA.Results：Of 216 included patients,67.1% received stereotactic radiosurgery （SRS）,24.1% received whole-brain radiation therapy （WBRT）,and 8.8% received both.After radiotherapy,systemic therapy was administered in 58.3% of patients.Multivariate analysis found that postradiation systemic therapy （yes vs.no） （hazard ratio [HR] =0.36 l,95% confidence interval [CI] =0.202-0.648,P =0.001）,radiation technique （SRS vs.WBRT） （HR =0.462,95% CI =0.238-0.849,P =0.022）,extracranial metastasis （yes vs.no） （HR =3.970,95% CI =1.757-8.970,P =0.001）,and Kamofsky performance status （〈70 vs.≥70） （HR =5.338,95% CI =2.829-10.072,P 〈 0.001） were independent factors for survival.Further analysis found that subsequent tyrosine kinase inhibitor （TKI） therapy could significantly reduce the risk of mortality of patients in RTOG-RPA Class IⅡ （HR =0.411,95% CI =0.183-）.923,P =0.031） or with a GPA score of 1.5-2.5 （HR =0.420,95% CI =0.182-0.968,P =0.042）.However,none of the subgroups stratified according to RTOG-RPA or GPA benefited from the additional conventional chemotherapy.Conclusion：RTOG-RPA and GPA may be useful to identify beneficial populations in NSCLC patients with BM ifTKIs were chosen as postradiation systemic therapy.

Systemic Therapy after Radiotherapy Significantly Reduces the Risk of Mortality of Patients with 1-3 Brain Metastases： A Retrospective Study of 250 Patients

Background：For patients with a brain metastasis （BM）,systemic therapy is usually administered after the completion of radiotherapy,especially in cases of multiple BMs.However,the role of systemic therapy in patients with a limited number of BMs is not clear.Therefore,we conducted a retrospective study to explore this question.Methods：Consecutive patients with a pathologically confirmed malignancy and 1-3 intracranial lesions that had been documented within the last decade were selected from the databases of three hospitals in China.Results：A total of 250 patients were enrolled;of them,135 received radiotherapy alone and 115 received radiotherapy plus systemic therapy.In patients receiving whole-brain radiation therapy （WBRT） as radiotherapy,28 received WBRT alone and 35 patients received WBRT plus systemic therapy.Of the patients treated with stereotactic radiosurgery （SRS）,107 received SRS alone and 80 received SRS plus systemic therapy.Multivariate analysis revealed that systemic therapy significantly reduced the risk of mortality compared with radiotherapy alone （hazard ratio [HR] =0.294,95% confidence interval [CI] =0.158-0.548）.Further,when the analysis was conducted in subgroups ofWBRT （HR =0.230,95% CI =0.081-0.653） or SRS （HR=0.305,95% CI=0.127-0.731）,systemic therapy still showed the ability to reduce the risk of mortality in patients with BMs.Conclusion：Systemic therapy after either SRS or WBRT radiotherapy may significantly reduce the risk of mortality of patients with 1-3 BMs.

Radiotherapy of brain metastases from non-small cell lung cancer

Brain metastases risk at the time of diagnosis or during the course of disease is high in non-small cell lung cancer (NSCLC). Even the incidence of brain metastases has increased in recent years, due to detection of smaller asymptomatic lesions with MRI screening as well as improved survival as a consequence of developments in systemic therapies. In the last decade, there have been many trials in the management of NSCLC patients with brain metastases, questioning the role of adjuvant whole brain radiotherapy (WBRT) after surgery or stereotactic radiosurgery (SRS), WBRT, compared to best supportive care in patients not amenable to surgery, aggressive local therapies in solitary brain metastases, postsurgical cavity SRS, SRS in non-oligometastatic patients, cranial radiotherapy in patients with driver mutations, thyrosine kinase inhibitors, immune check point inhibitors and the impact of therapies on neurocognitive functions and quality of life. The main objective of this review is to provide an update on current trends in radiotherapy in the management of newly diagnosed brain metastases from NSCLC.

Diagnosis and management of brain metastases:an updated review from a radiation oncology perspective

Brain metastasis are the most common intracranial malignancy in the adult population. Their incidence has increased dramatically over the last 20 years, as a result of the increasing number of cases stemming from lung and breast cancer together with the higher cancer survival rates due to diagnostic and therapeutic advances. More than 40%of cancer patients develop brain metastases during the course of their disease: specifically, they appear in 50%of patients with lung cancer, more than 25% of patients with breast cancer, and 20% of patients with melanoma. Diagnosis is made using different imaging approaches, such as computed tomography and magnetic resonance imaging, accompanied by clinical manifestations and a history of malignancy supporting the diagnosis of a brain metastasis. Current treatment options should be oriented to the patient's current performance, the number of intracranial and extracranial lesions, and related factors. Although surgical resection and whole-brain radiotherapy have been standard treatments for many years, numerous treatment modalities have become more easily available and accepted worldwide, producing more favorable and reliable results. Among these is stereotactic radiosurgery, and the latest clinical trials support this treatment.