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

Journal of Cancer Metastasis and Treatment 2019年第4期4卷 17-25页

作者： Sarah Mudra Shruti Bhandari Prashant Tripathi Neal Dunlap Goetz Kloecker University of Louisville School of Medicine LouisvilleKY 40202USA Department of Internal Medicine Division of Hematology and Medical OncologyJames Graham Brown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKY 40202USA Division of Infectious Disease University of Louisville School of MedicineLouisvilleKY 40202USA Department of Radiation Oncology James Graham Brown Cancer CenterUniversity of Louisville School of MedicineLouisvilleKY 40202USA

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.

关键词： Lung cancer stereotactic radiosurgery brain metastasis tyrosine kinase inhibitors immunotherapy

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

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Chinese Medical Journal 2008年第12期121卷 1076-1079页

作者： LIU Wei-ming YE Xun ZHAO Yuan-li WANG Shuo ZHAO Ji-zong Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University Beijing 100050 China

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.

关键词： cerebral arteriovenous malformations stereotactic radiosurgery microsurgery complications

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

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Cancer Communications 2019年第1期39卷 623-631页

作者： Christian D.Diehl Ehab Shiban Christoph Straube Jens Gempt Jan J.Wilkens Markus Oechsner Carmen Kessel Claus Zimmer Benedict Wiestler Bernhard Meyer Stephanie E.Combs Department of Radiation Oncology Klinikum rechts der Isar HospitalTechnical University of MunichIsmaninger Straße 2281675 MunichGermany Department of Radiation Sciences Institute of Innovative Radiotherapy85764 NeuherbergGermany Department of Neurosurgery Klinikum rechts der Isar HospitalTechnical University of Munich81675 MunichGermany Department of Diagnostic and Interventional Neuroradiology Klinikum rechts der Isar HospitalTechnical University of Munich81675 MunichGermany

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

关键词： Cancer Intracerebral metastasis stereotactic radiosurgery Fractionated stereotactic radiation therapy Microsurgical resection Neoadjuvant radiation therapy Maximum tolerated dose Protocol

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

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International Journal of Medical Physics, Clinical Engineering and Radiation Oncology 2022年第1期11卷 84-97页

作者： Jenghwa Chang Department of Radiation Medicine Northwell Health and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell New York USA Department of Physics and Astronomy Hofstra University New York USA

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).

关键词： stereotactic radiosurgery PTV Margin Coverage Probability

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Pre-operative stereotactic radiosurgery treatment is preferred to post-operative treatment for smaller solitary brain metastases

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Chinese Neurosurgical Journal 2017年第4期3卷 205-212页

作者： Hamidreza Aliabadi Arian M. Nikpour David S. Yoo James E. Herndon II John H. Sampson John P. Kirkpatrick Spine and Neurosurgery Associates 1301 Secret Ravine Parkway Suite 200Roseville CA 95661 USA Department of Radiology UC Davis MedicalCenter UC Davis School of Medicine Sacramento CA USA Department ofRadiation Oncology Duke University Medical Center Durham NC USA Department of Biostatistics and Bioinformatics Duke University MedicalCenter Durham NC USA Department of Surgery Division of NeurosurgeryDuke University Medical Center Durham NC USA

While the optimal combination of whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and surgical resection in the treatment of brain metastases, is controversial, the addition of SRS to surgical resction of solitary metastasis may enhance local control while potentially minimizing toxicity associated with adjuvant WBRT. This study seeks to determine whether pre-operative SRS to the lesion versus post-operative SRS to the resection bed may reduce irradiation of adjacent normal brain tissue. A retrospective study of 12 patients with 13 surgically resected cerebral metastases was performed. The pre-operative contrast-enhancing tumors and post-operative resection cavities plus any enhancing residual disease were contoured to yield the gross target volume (GTV). In turn these GTV’s were uniformly expanded by 3-mm to generate the pre-operative, as well as post-operative planning target volume (PTV.) For each lesion, a 7-static-conformal-beam, non-coplanar plan utilizing 6 MV photons was generated to encompass the PTV within the 85% isodose line. Excess normal brain volume irradiated was defined as the volume outside the GTV receiving the prescribed dose. When lesions were divided into two groups - Group A (pre-operative GTV’s 15 cc, n = 4) - the average volume of normal brain irradiated was significantly smaller if pre-operative SRS was used for treatment of lesions in Group A (9.5 vs. 16.8 cc, paired t-test, p = 0.0045). In contrast, this volume was smaller for Group B lesions if post-operative SRS was used for treatment of these lesions (27.6 vs. 51.2 cc, p = 0.252). A comparison of groups with respect to mean volume differences between pre- and post-operative SRS was significantly different (two-sample t-test p = 0.016). GTV and the difference between pre- and post-operative volume were highly correlated (Pearson correlation = −0.875, p < 0

关键词： stereotactic radiosurgery Brain metastases Pre-operative Solitary brain metastases

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Leptomeningeal seeding after surgical resection or stereotactic radiosurgery for brain metastases: Analysis of risk factors

Leptomeningeal seeding after surgical resection or stereotac...

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第五届韩-中神经肿瘤会议

作者： Jun Hyong Ahn Sang Hyun Lee Heon Yoo Seung Hoon Lee Jungnam Joo Sohee Kim Ho-Shin Gwak Department of Neurosurgery Seoul National University College of Medicine National Cancer Center Korea Department of diagnostic radiology National Cancer Center Korea Neuro-oncology Clinic and National Cancer Center Korea Department of Medical statistics National Cancer Center Korea

Background: Leptomeningeal seeding （LMS） is a devastating complication of malignancy. Among several pathogenesis, surgical spillage has been one of the iatrogenic factors for the development of LMS. We retrospectively analyzed various surgical factors affecting the development of LMS. Patients and Methods: We identified 294 patients with brain metastasis who had been treated using surgery between 2001 and 2009. We classified the tumor location into subcortical, pial, epipial, juxtaventricular and ventricular. The description of surgical resection was divided into piecemeal and en-bloc and the risk of using cavitron ultrasonic aspirator （CUSA） were investigated. Results: A total 44 of the 294 patients （15%） developed LMS after undergoing index procedure. The median time to LMS development was 6months （range, 1.0-42.0）. Among the 294 surgical patients, seven out of 101 en-bloc removal patients （6.9%） developed LMS, whereas 37 out of 193 piecemeal removal patients （19.2%） developed LMS, and the incidence of LMS was significantly different between these two surgical resection modes （p = 0.005）.The adjusted hazard ratio （HR） for patients whose tumors were resected by piecemeal compared to en-bloc was 3.12 （95% CI, 1.4-7.0;p = 0.006）. The incidence of LMS was significantly higher （p ＜ 0.001） in patients whose tumors were resected by CUSA, and the HR of using CUSA was 4.18 （95% CI, 1.9-9.4;p = 0.001）. The location of tumor at high-risk of CSF exposure （epipial and ventricular） conferred increased risk of LMS after the treatment compared to low-risk group with the HR 2.52 （95% CI, 1.4-4.7;p = 0.004）. On the other hand, the location of tumor at low-risk of CSF exposure （subcortical） showed significantly reduced risk of LSM compared to the other locations （HR=0.27;95% CI 0.12-0.65;p-value = 0.003）. Conclusion: The piecemeal resection mode and the use of CUSA were found to increase risk of LMS in this retrospective study. Therefore, the piecemeal resection using CUSA should be limited for the risk of post-surgical LMS espec

关键词： Leptomeningeal carcinomatosis Neoplasm seeding surgery stereotactic radiosurgery

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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

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Chinese Medical Journal 2018年第10期131卷 1206-1213页

作者： Shuai Liu Peng Chen Yan-Wei Liu Xue-Nan GU Xiao-Guang Qiu Bo Li Department of Radiation Oncology BeijLng Tiantan Hospital Capital Medical University Beijing 100050 China Department of Thoracic Oncology Tianjin Medical University Cancer Institute and Hospital Tianjin 300060 China

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.

关键词： Chemotherapy Non-Small Cell Lung Cancer Recursive Partitioning Analysis stereotactic radiosurgery Tyrosine Kinase Inhibitors Whole-Brain Radiation Therapy

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

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Chinese Medical Journal 2017年第24期130卷 2916-2921页

作者： Bo Li Zhao-Xia Dai Yi-Dong Chen Yan-Wei Liu Shuai Liu Xue-Nan Gu Xiao-Guang Qiu Department of Radiation Oncology Beijing Tiantan Hospital Affiliated to Capital Medical University Beijing 100050 China Department of Medical Oncology The Second Hospital of Dalian Medical University Dalian Liaoning 116027 China Capital Medical University Cancer Center Beijing Shijitan Hospital Capital Medical University Beijing 100038 China

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.

关键词： Brain Metastasis stereotactic radiosurgery Systemic Therapy Whole-brain Radiation Therapy

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Radiotherapy of brain metastases from non-small cell lung cancer

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Journal of Cancer Metastasis and Treatment 2019年第2期4卷 39-50页

作者： Esra Korkmaz KirakIi Ufuk YiImaz Department of Radiation Oncology Dr.Suat Seren Chest Disease and Surgery Training and Research Hospitalİzmir 35200Turkey Department of Pulmonology University of Health ScienceDr.Suat Seren Chest Disease and Surgery Training and Research Hospitalİzmir 35200Turkey

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.

关键词： Radiotherapy whole-brain radiotherapy stereotactic radiotherapy stereotactic radiosurgery brain metastases lung cancer

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

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World Journal of Clinical Oncology 2021年第12期12卷 1089-1100页

作者： Angel Cilleruelo-Ramos Esther Cladellas-Gutiérrez Carolina de la Pinta Laura Quintana-Cortés Paloma Sosa-Fajardo Felipe Couñago Xabier Mielgo-Rubio Juan Carlos Trujillo-Reyes Department of Thoracic Surgery Clinic Universitary HospitalValladolid 47005Spain Department of Surgery Universidad de ValladolidValladolid 47001Spain Department of Thoracic Surgery Hospital de la Santa Creu i Sant PauBarcelona 08029Spain Department of Radiation Oncology Hospital Universitario Ramón y CajalMadrid 28034Spain Department of Medical Oncology Hospital Don Benito-VillanuevaBadajoz 06400Spain Department of Radiation Therapy Complejo Hospitalario UniversitarioSantiago de CompostelaLa Coruña 15706Spain Department of Radiation Oncology Hospital Universitario Quirónsalud MadridMadrid 28223Spain Department of Radiation Oncology Hospital La LuzMadrid 28223Spain Department of Medicine School of Biomedical SciencesUniversidad EuropeaMadrid 28223Spain Department of Medical Oncology Unit Hospital Universitario Fundación AlcorcónMadrid 28922Spain Department of Surgery Universitat AutónomaBarcelona 08029Spain

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.

关键词： Video-assisted thoracoscopic surgery Sublobar resection Radiofrequency ablation stereotactic radiosurgery Early stage Lung cancer

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