Publications by authors named "Jonathan P S Knisely"

75 Publications

Time to administration of stereotactic radiosurgery to the cavity after surgery for brain metastases: a real-world analysis.

J Neurosurg 2021 May 28:1-11. Epub 2021 May 28.

2Department of Neurosurgery.

Objective: Publications on adjuvant stereotactic radiosurgery (SRS) are largely limited to patients completing SRS within a specified time frame. The authors assessed real-world local recurrence (LR) for all brain metastasis (BM) patients referred for SRS and identified predictors of SRS timing.

Methods: The authors retrospectively identified BM patients undergoing resection and referred for SRS between 2012 and 2018. Patients were categorized by time to SRS, as follows: 1) ≤ 4 weeks, 2) > 4-8 weeks, 3) > 8 weeks, and 4) never completed. The relationships between timing of SRS and LR, LR-free survival (LRFS), and survival were investigated, as well as predictors of and reasons for specific SRS timing.

Results: In a cohort of 159 patients, the median age at resection was 64.0 years, 56.5% of patients were female, and 57.2% were in recursive partitioning analysis (RPA) class II. The median preoperative tumor diameter was 2.9 cm, and gross-total resection was achieved in 83.0% of patients. All patients were referred for SRS, but 20 (12.6%) did not receive it. The LR rate was 22.6%, and the time to SRS was correlated with the LR rate: 2.3% for patients receiving SRS at ≤ 4 weeks postoperatively, 14.5% for SRS at > 4-8 weeks (p = 0.03), and 48.5% for SRS at > 8 weeks (p < 0.001). No LR difference was seen between patients whose SRS was delayed by > 8 weeks and those who never completed SRS (48.5% vs 50.0%; p = 0.91). A similar relationship emerged between time to SRS and LRFS (p < 0.01). Non-small cell lung cancer pathology (p = 0.04), earlier year of treatment (p < 0.01), and interval from brain MRI to SRS (p < 0.01) were associated with longer intervals to SRS. The rates of receipt of systemic therapy also differed significantly between patients by category of time to SRS (p = 0.02). The most common reasons for intervals of > 4-8 weeks were logistic, whereas longer delays or no SRS were caused by management of systemic disease or comorbidities.

Conclusions: Available data on LR rates after adjuvant SRS are often obtained from carefully preselected patients receiving timely treatment, whereas significantly less information is available on the efficacy of adjuvant SRS in patients treated under "real-world" conditions. Management of these patients may merit reconsideration, particularly when SRS is not delivered within ≤ 4 weeks of resection. The results of this study indicate that a substantial number of patients referred for SRS either never receive it or are treated > 8 weeks postoperatively, at which time the SRS-treated patients have an LR risk equivalent to that of patients who never received SRS. Increased attention to the reasons for prolonged intervals from surgery to SRS and strategies for reducing them is needed to optimize treatment. For patients likely to experience delays, other radiotherapy techniques may be considered.
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http://dx.doi.org/10.3171/2020.10.JNS201934DOI Listing
May 2021

BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

Oncology 2021 May 6:1-9. Epub 2021 May 6.

Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA.

Purpose: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA).

Methods And Materials: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test.

Results: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months.

Conclusions: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.
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http://dx.doi.org/10.1159/000516168DOI Listing
May 2021

[Ga]-DOTATATE PET/MRI as an adjunct imaging modality for radiation treatment planning of meningiomas.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab012. Epub 2021 Jan 21.

Department of Radiology, Weill Cornell Medicine, New York, New York, USA.

Background: Meningiomas express high levels of somatostatin receptor 2 (SSTR2). SSTR2-targeted PET imaging with [Ga]-DOTATATE can aid with distinguishing residual meningioma from reactive changes in the postoperative setting. We present initial dosimetric analyses, acute events, and local control data utilizing [Ga]-DOTATATE PET/MRI-assisted target delineation for prospectively-treated intermediate-risk meningiomas.

Methods: Twenty-nine patients underwent DOTATATE PET/MRI meningioma evaluation in 2019. Eight patients with 9 postoperative meningiomas met RTOG 0539 intermediate-risk criteria (recurrent WHO grade I, 1/9; WHO grade II, 8/9). Target volumes were created using DOTATATE PET/MRI to determine residual disease and received a nominal dose of 35.0 Gy over 5 fractions. For comparison, cases were recontoured and planned with MRI alone per RTOG 0539 guidelines. Mean and maximum equivalent 2 Gy doses were generated for target volumes and organs at risk (OAR) within 1 cm of the PTV and compared using Wilcoxon matched pairs signed rank test.

Results: DOTATATE PET/MRI-guided planning significantly reduced mean PTV (11.12 cm compared to 71.39 cm based on MRI alone, < .05) and mean and max dose to the whole brain, optic nerves, and scalp. PET/MRI plans resulted in at least 50% reduction of mean and max doses to the lens, eyes, chiasm, cochlea, brainstem, and hippocampi. One patient experienced focal alopecia. There were no local recurrences at 6 months.

Conclusion: Incorporating DOTATATE-PET/MRI for postoperative target delineation in patients with intermediate-risk intracranial meningiomas results in PTV reduction and decreased OAR dose. Our findings warrant larger studies evaluating DOTATATE-PET/MRI in the radiotherapeutic planning of postoperative meningiomas.
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http://dx.doi.org/10.1093/noajnl/vdab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954102PMC
January 2021

Timing of Adjuvant Fractionated Stereotactic Radiosurgery Affects Local Control of Resected Brain Metastases.

Pract Radiat Oncol 2021 May-Jun;11(3):e267-e275. Epub 2021 Feb 10.

Department of Neurosurgery, Weill Cornell Medical College/New York Presbyterian Hospital, New York, New York; Department of Otolaryngology, Weill Cornell Medical College/New York Presbyterian Hospital, New York, New York; Department of Neuroscience, Weill Cornell Medical College/New York Presbyterian Hospital, New York, New York. Electronic address:

Purpose: For resected brain metastases (BMs), stereotactic radiosurgery (SRS) is often offered to minimize local recurrence (LR). Although the aim is to deliver SRS within a few weeks of surgery, a variety of socioeconomic, medical, and procedural issues can cause delays. We evaluated the relationship between timing of postoperative SRS and LR.

Methods And Materials: We retrospectively identified a consecutive series of patients with BM managed with resection and SRS or fractionated SRS at our institution from 2012 to 2018. We assessed the correlation of time to SRS and other demographic, disease, and treatment variables with LR, local recurrence-free survival, distant recurrence, distant recurrence-free survival, and overall survival.

Results: A total of 133 patients met inclusion criteria. The median age was 64.5 years. Approximately half of patients had a single BM, and median BM size was 2.9 cm. Gross total resection was achieved in 111 patients (83.5%), and more than 90% of patients received fractionated SRS. The median time to SRS was 37.0 days, and the LR rate was 16.4%. Time to SRS was predictive of LR. The median time from surgery to SRS was 34.0 days for patients without LR versus 61.0 days for those with LR (P < .01). The LR rate was 2.3% with SRS administered ≤4 weeks postoperatively, compared with 23.6% if SRS was administered >4 weeks postoperatively (P < .01). Local recurrence-free survival was also improved for patients who underwent SRS at ≤4 weeks (P = .02). Delayed SRS was also predictive of distant recurrence (P = .02) but not overall survival.

Conclusions: In this retrospective study, the strongest predictor of LR after postoperative SRS for BM was time to SRS, and a cutoff of 4 weeks was a reliable predictor of recurrence. These findings merit investigation in a prospective, randomized trial.
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http://dx.doi.org/10.1016/j.prro.2021.01.011DOI Listing
February 2021

Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases.

Neuro Oncol 2020 12;22(12):1728-1741

Department of Radiation Oncology, Keck School of Medicine of University of Southern California, Los Angeles, CA.

Background: The American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines.

Methods: The panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness.

Results: The panel agreed that SRS alone is usually appropriate for those with good performance status and 2-10 asymptomatic BM, and usually not appropriate for >20 BM. For 11-15 and 16-20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2-4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options.

Conclusions: For patients with 2-10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.
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http://dx.doi.org/10.1093/neuonc/noaa192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746939PMC
December 2020

Cancer and cardiovascular disease.

Lancet 2020 06;395(10241):1904

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

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http://dx.doi.org/10.1016/S0140-6736(20)30238-5DOI Listing
June 2020

Somatostatin receptor-2 negative meningioma: pathologic correlation and imaging implications.

Clin Imaging 2020 Oct 25;66:18-22. Epub 2020 Apr 25.

Department of Radiology, Weill Cornell Medicine-New York Presbyterian Hospital, United States of America.

Meningiomas are the most common non-malignant primary intracranial tumors, accounting for nearly 40% of all primary brain tumors, usually expressing high levels of somatostatin receptors (SSTR), particularly SSTR2. Because Ga-DOTATATE targets SSTR2, it is increasingly used clinically for meningioma evaluation. While previous apparent lack of SSTR expression in meningiomas has been reported in isolated cases, these prior studies utilized Indium-111 (In) Octreotide, which is of lesser diagnostic accuracy compared to Ga-DOTATATE, as well as Technetium-99m (Tc)-DTPA scintigraphy, which necessitates an intact blood-tumor-permeability barrier. This paper presents a histopathologic proven atypical meningioma, WHO Grade II, with low level avidity on Ga-DOTATATE PET/MRI, subsequently proven to be SSTR2-negative by immunohistochemistry, with a review and discussion of the current literature and imaging implications.
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http://dx.doi.org/10.1016/j.clinimag.2020.04.026DOI Listing
October 2020

PTEN as a Guardian of the Genome: Pathways and Targets.

Cold Spring Harb Perspect Med 2020 09 1;10(9). Epub 2020 Sep 1.

Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.

Faithful transmission of genetic information is only possible with the structural and functional integrity of the genome. PTEN has been recognized as a guardian of the genome since the identification of its noncanonical localization and function in the nucleus. Yet, the role of PTEN in guarding the genome relies on integration of diverse mechanisms elicited by its canonical activity in antagonizing PI3K as well as emerging noncanonical functions. In the nucleus, PTEN maintains the structural integrity of chromosomes and the architecture of heterochromatin by physically interacting with chromosomal and nucleosomal components. PTEN also controls the functional integrity of key genetic transmission machineries by promoting proper assembly of the replisome and mitotic spindles. Deregulation of PTEN signaling impairs genome integrity, leading to spontaneous replication/mitotic stress and subsequent stress tolerance. Identification of novel targets of PTEN signaling and illumination of the interplay of diverse PTEN pathways in genome maintenance will help us better understand mechanisms underlying tumor evolution and therapeutic resistance.
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http://dx.doi.org/10.1101/cshperspect.a036194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354882PMC
September 2020

What Would I Want Done for My Mother?

Int J Radiat Oncol Biol Phys 2019 12;105(5):941-942

Department of Radiation Oncology, Weill Cornell Medicine & New York Presbyterian, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2019.08.015DOI Listing
December 2019

Possible Abscopal Effect Observed in Frontal Meningioma After Localized IMRT on Posterior Meningioma Resection Cavity Without Adjuvant Immunotherapy.

Front Oncol 2019 18;9:1109. Epub 2019 Oct 18.

Department of Neurosurgery, North Shore University Hospital, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.

Localized radiation therapy (RT) is known to infrequently cause off-target or "abscopal" effects at distant metastatic lesions. The mechanism through which abscopal effects occur remains unknown, but is thought to be caused by a humoral immune response to tumor-specific antigens generated by RT. Combination treatment regimens involving RT and immunotherapy to boost the humoral immune response have demonstrated synergistic effects in promoting and accelerating abscopal effects in metastatic cancer. Nevertheless, abscopal effects, particularly after RT alone, remain exceedingly rare. We report the case of an 84-year-old man with an atypical meningioma, who demonstrated a radiographically significant response to an untreated second intracranial lesion, likely also a meningioma, after intensity-modulated radiation therapy (IMRT) to a separate, detatched resection cavity. Serial annual MRI imaging starting at 2- to 3.5-year (most recent) post-IMRT follow-up demonstrated a persistent decrease in both tumor size and surrounding edema in the untreated second lesion, suggestive of a possible abscopal effect. We describe here the first report of a potential abscopal effect in meningioma, summarize the limited literature on the topic of abscopal effects in cancer, and detail the existing hypothesis on how this phenomenon may occur and possibly relate to the development of future treatments for patients with metastatic disease.
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http://dx.doi.org/10.3389/fonc.2019.01109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813201PMC
October 2019

Worldwide Access to Stereotactic Radiosurgery.

World Neurosurg 2019 Oct;130:608-614

Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA.

Stereotactic radiosurgery is a safe and effective technology that can address a variety of neurosurgical conditions, but in many parts of the world, access remains an issue. Although the technology is increasingly available in the United States, Canada, Europe, and parts of Asia, poor access to central nervous system (CNS) imaging and inadequate treatment equipment in other parts of the world limit the availability of radiosurgery as a treatment option. In addition, epidemiologic data about cancer and CNS metastases in low-income countries are sparse and much less complete than in more developed countries, and the need for radiosurgery may be underestimated as a result. Current radiosurgical platforms can be expensive to install and require a substantial amount of personnel training for safe operation. Socioeconomic and political forces are relevant to limitations to and opportunities for improving access to care. Here we examine the current barriers to access and propose areas for future efforts to improve global availability of radiosurgery for neurosurgical conditions.
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http://dx.doi.org/10.1016/j.wneu.2019.04.031DOI Listing
October 2019

Historical Aspects of Stereotactic Radiosurgery: Concepts, People, and Devices.

World Neurosurg 2019 Oct;130:593-607

Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA.

Stereotactic radiosurgery is a modern discipline that emerged after World War II. It represents a synthesis of an approach to patient care that was not immediately embraced by either neurosurgeons or radiation oncologists, but which has been shown, time and again, to be advantageous for the treatment of intracranial pathology. Indeed, stereotactic radiosurgical techniques are now being rapidly adapted and adopted for the treatment of extracranial malignant and benign disease. Any examination of the individuals, devices, and technological advances that permitted stereotactic radiosurgery to become a preferred approach for patient care cannot be absolutely comprehensive but can provide insights into the evolution of the specialty and potential future prospects for further improvements in patient care. As Shakespeare wrote in The Tempest, "What's past is prologue."
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http://dx.doi.org/10.1016/j.wneu.2019.04.030DOI Listing
October 2019

A Multidisciplinary Team Approach to Brain and Spine Stereotactic Radiosurgery Conferences: A Unique Institutional Model.

World Neurosurg 2019 Nov 10;131:159-162. Epub 2019 Aug 10.

Department of Neurological Surgery, Weill Cornell Medicine, New York, New York, USA. Electronic address:

Objective: The use of multidisciplinary teams (MDTs) comprised of all members of the patient care team is becoming increasingly popular in the field of oncology. We present a single-center experience exploring the utility and uniqueness of an MDT in the care of patients undergoing brain and spine stereotactic radiosurgery (SRS).

Methods: The weekly SRS conference brought together neurosurgeons, radiation oncologists, neuroradiologists, physicists, dosimetrists, therapists, advanced practice providers, and trainees in these fields as well as researchers from a variety of disciplines with a goal of optimizing patient care. A survey of 20 conference attendees from 7 different facets of the MDT was conducted for feedback.

Results: The survey results revealed that most respondents believed the SRS conference increased educational opportunities, provided opportunities for research and collaborations, helped streamline patient care, and was beneficial to their practice.

Conclusions: We present our institutional MDT model, a framework and workflow that can be incorporated at other large academic centers. We believe that the SRS conference has educational, academic, and patient care value.
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http://dx.doi.org/10.1016/j.wneu.2019.08.012DOI Listing
November 2019

Tumor control and survival in patients with ten or more brain metastases treated with stereotactic radiosurgery: a retrospective analysis.

J Neurooncol 2019 May 3;143(1):167-174. Epub 2019 Apr 3.

Department of Radiation Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.

Introduction: To assess tumor control and survival in patients treated with stereotactic radiosurgery (SRS) for 10 or more metastatic brain tumors.

Methods: Patients were retrospectively identified. Clinical records were reviewed for follow-up data, and post-treatment MRI studies were used to assess tumor control. For tumor control studies, patients were separated based on synchronous or metachronous treatment, and control was assessed at 3-month intervals. The Kaplan-Meier method was employed to create survival curves, and regression analyses were employed to study the effects of several variables.

Results: Fifty-five patients were treated for an average of 17 total metastases. Forty patients received synchronous treatment, while 15 received metachronous treatment. Univariate analysis revealed an association between larger brain volumes irradiated with 12 Gy and decreased overall survival (p = 0.0406); however, significance was lost on multivariate analysis. Among patients who received synchronous treatment, the median percentage of tumors controlled was 100%, 91%, and 82% at 3, 6, and 9 months, respectively. Among patients who received metachronous treatment, the median percentage of tumors controlled after each SRS encounter was 100% at all three time points.

Conclusions: SRS can be used to treat patients with 10 or more total brain metastases with an expectation of tumor control and overall survival that is equivalent to that reported for patients with four or fewer tumors. Development of new metastases leading to repeat SRS is not associated with worsened tumor control or survival. Survival may be adversely affected in patients having a higher volume of normal brain irradiated.
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http://dx.doi.org/10.1007/s11060-019-03153-8DOI Listing
May 2019

Spine Radiosurgery Dosimetry-A Simple Way Forward.

Pract Radiat Oncol 2019 03 18;9(2):e127-e128. Epub 2019 Jan 18.

Weill Cornell Medicine & New York-Presbyterian, Department of Radiation Oncology, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.prro.2018.10.007DOI Listing
March 2019

Precision Medicine-Targeted Therapy.

Int J Radiat Oncol Biol Phys 2018 11 18;102(4):734. Epub 2018 Oct 18.

Weill Cornell Medicine, NewYork-Presbyterian, New York City, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2018.07.190DOI Listing
November 2018

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 2: Existing Experience and Considerations for Future Trials.

Oncology (Williston Park) 2018 03 15;32(3):e33-e37. Epub 2018 Mar 15.

The brain has long been considered an immunologically privileged site, and the role of immunotherapy in treating intracranial disease has only recently been revived-with preclinical evidence showing that the systemic immune system responds to immunotherapy for intracranial disease, and with clinical evidence demonstrating improved locoregional control and survival compared with historical outcomes when immune-directed therapies are combined with radiation. Pharmaceutical industry-supported multi-institutional drug efficacy studies routinely exclude patients with brain metastases, so current evidence for treatment of brain metastases using stereotactic radiosurgery combined with immunotherapy comes from single-institution studies. Many studies of combinations of immune checkpoint blockade (with anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 antibodies) with stereotactic radiosurgery have demonstrated promising improvements in intracranial control and survival. In addition to evaluating the optimal combination of these therapies, future studies will likely search for predictive biomarkers to better select patients whose disease is most appropriately managed with this combined-modality approach.
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March 2018

Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 1: Principles of Combined Treatment.

Oncology (Williston Park) 2018 02 15;32(2):e28-e32. Epub 2018 Feb 15.

The role of systemic therapy in the treatment of intracranial metastases has traditionally been limited by the blood-brain barrier, and radiation therapy-either with whole-brain treatment or stereotactic radiosurgery-has remained a primary treatment modality. Recent evidence has demonstrated that antigens released in the brain can inform the systemic immune system, and systemic antibodies can traverse into the brain. This has led to a renewed interest in investigating novel immunotherapy agents to treat both systemic and intracranial disease. Currently, several trials of immunotherapy, with or without sequential or concurrent radiation, have been performed in patients with brain metastases to evaluate the safety and efficacy of combined treatment. Combined use of stereotactic radiosurgery and checkpoint inhibitors appears safe and effective in the treatment of various brain metastases. Future studies will evaluate the optimal sequencing of radiosurgery and immunotherapy and assess the radiation doses and fractionations that will provide the best tumor response.
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February 2018

Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539.

J Neurosurg 2018 07 6;129(1):35-47. Epub 2017 Oct 6.

12Miami Cancer Institute Executive Office, Miami, Florida.

OBJECTIVE This is the first clinical outcomes report of NRG Oncology RTOG 0539, detailing the primary endpoint, 3-year progression-free survival (PFS), compared with a predefined historical control for intermediate-risk meningioma, and secondarily evaluating overall survival (OS), local failure, and prospectively scored adverse events (AEs). METHODS NRG Oncology RTOG 0539 was a Phase II clinical trial allocating meningioma patients to 1 of 3 prognostic groups and management strategies according to WHO grade, recurrence status, and resection extent. For the intermediate-risk group (Group 2), eligible patients had either newly diagnosed WHO Grade II meningioma that had been treated with gross-total resection (GTR; Simpson Grades I-III) or recurrent WHO Grade I meningioma with any resection extent. Pathology and imaging were centrally reviewed. Patients were treated with radiation therapy (RT), either intensity modulated (IMRT) or 3D conformal (3DCRT), 54 Gy in 30 fractions. The RT target volume was defined as the tumor bed and any nodular enhancement (e.g., in patients with recurrent WHO Grade I tumors) with a minimum 8-mm and maximum 15-mm margin, depending on tumor location and setup reproducibility of the RT method. The primary endpoint was 3-year PFS. Results were compared with historical controls (3-year PFS: 70% following GTR alone and 90% with GTR + RT). AEs were scored using NCI Common Toxicity Criteria. RESULTS Fifty-six patients enrolled in the intermediate-risk group, of whom 3 were ineligible and 1 did not receive RT. Of the 52 patients who received protocol therapy, 4 withdrew without a recurrence before 3 years leaving 48 patients evaluable for the primary endpoint, 3-year PFS, which was actuarially 93.8% (p = 0.0003). Within 3 years, 3 patients experienced events affecting PFS: 1 patient with a WHO Grade II tumor died of the disease, 1 patient with a WHO Grade II tumor had disease progression but remained alive, and 1 patient with recurrent WHO Grade I meningioma died of undetermined cause without tumor progression. The 3-year actuarial local failure rate was 4.1%, and the 3-year OS rate was 96%. After 3 years, progression occurred in 2 additional patients: 1 patient with recurrent WHO Grade I meningioma and 1 patient with WHO Grade II disease; both remain alive. Among 52 evaluable patients who received protocol treatment, 36 (69.2%) had WHO Grade II tumors and underwent GTR, and 16 (30.8%) had recurrent WHO Grade I tumors. There was no significant difference in PFS between these subgroups (p = 0.52, HR 0.56, 95% CI 0.09-3.35), validating their consolidation. Of the 52 evaluable patients, 44 (84.6%) received IMRT, and 50 (96.2%) were treated per protocol or with acceptable variation. AEs (definitely, probably, or possibly related to protocol treatment) were limited to Grade 1 or 2, with no reported Grade 3 events. CONCLUSIONS This is the first clinical outcomes report from NRG Oncology RTOG 0539. Patients with intermediate-risk meningioma treated with RT had excellent 3-year PFS, with a low rate of local failure and a low risk of AEs. These results support the use of postoperative RT for newly diagnosed gross-totally resected WHO Grade II or recurrent WHO Grade I meningioma irrespective of resection extent. They also document minimal toxicity and high rates of tumor control with IMRT. Clinical trial registration no.: NCT00895622 (clinicaltrials.gov).
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http://dx.doi.org/10.3171/2016.11.JNS161170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889346PMC
July 2018

Prophylactic Cranial Irradiation for Resectable Small-Cell Lung Cancer.

Clin Lung Cancer 2018 03 26;19(2):115-119. Epub 2017 Aug 26.

Department of Radiation Oncology, Weill Cornell Medicine, New York, NY.

After definitive chemoradiation for small-cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) has been established as standard of care in patients whose tumors respond to treatment. In the modern era, however, a subset of patients might receive upfront resection for SCLC, yet the role of PCI in these patients has not been elucidated. In this review, we examine the literature to better define the role of PCI in this subset of patients. For patients with ≥ T2 disease, incomplete resection, or those not receiving adjuvant chemotherapy, PCI is expected to offer a clinical benefit. For patients with T1 tumors treated with R0 resection, however, the rate of intracranial metastasis might be < 10%. In these patients, deferral of PCI might be appropriate because it would avoid known neurocognitive sequelae of cranial irradiation.
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http://dx.doi.org/10.1016/j.cllc.2017.08.004DOI Listing
March 2018

Use Only as Directed.

Pract Radiat Oncol 2017 Nov - Dec;7(6):448. Epub 2017 Jul 12.

New York City, New York.

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http://dx.doi.org/10.1016/j.prro.2017.07.006DOI Listing
March 2018

Accuracy evaluation of a six-degree-of-freedom couch using cone beam CT and IsoCal phantom with an in-house algorithm.

Med Phys 2017 Aug 16;44(8):3888-3898. Epub 2017 Jun 16.

Department of Radiation Medicine, Northwell Health and Hofstra Northwell School of Medicine, New York, NY, 11042, USA.

Purpose: The accuracy of a six degree of freedom (6DoF) couch was evaluated using a novel method.

Methods: Cone beam CT (CBCT) images of a 3D phantom (IsoCal) were acquired with different, known combinations of couch pitch and roll angles. Pitch and roll angles between the maximum allowable values of 357 and 3 degrees were tested in one degree increments. A total of 49 combinations were tested at 0 degrees of yaw (couch rotation angle). The 3D positions of 16 tungsten carbide ball bearings (BBs), each 4 mm in diameter and arranged in a known geometry within the IsoCal phantom, were determined in the 49 image sets with in-house software. The BB positions at different rotation angles were determined using a rotation matrix from the original BB positions at zero pitch and roll angles. A linear least squares fit method estimated the rotation angles and differences between detected and nominal rotation angles were calculated. This study was conducted for the case with and without extra weight on the couch. Couch walk shifts for the system were investigated using eight combinations of rotation, roll and pitch.

Results: A total of 49 CBCT images with voxel sizes 0.5 × 0.5 × 1.0 mm were taken for the case without extra weight on the couch. The 16 BBs were determined to evaluate the isocenter translation and rotation differences between the calculated and nominal couch values. Among all 49 calculations, the maximum rotation angle differences were 0.10 degrees for pitch, 0.15 degrees for roll and 0.09 degrees for yaw. The corresponding mean and standard deviation values were 0.028 ± 0.032, -0.043 ± 0.058, and -0.009 ± 0.033 degrees. The maximum translation differences were 0.3 mm in the left-right direction, 0.5 mm in the anterior-posterior direction and 0.4 mm in the superior-inferior direction. The mean values and corresponding standard deviations were 0.07 ± 0.12, -0.05 ± 0.25, and -0.12±0.14 mm for the planes described above. With an 80 kg phantom on the couch, the maximum translation shift was 0.69 mm. The couch walk translation shifts were less than 0.1 mm and rotation shifts were less than 0.1 degree.

Conclusions: Errors of a new 6DoF couch were tested using CBCT images of a 3D phantom. The rotation errors were less than 0.3 degree and the translation errors were less than or equal to 0.8 mm in each direction. This level of accuracy is warranted for clinical radiotherapy utilization including stereotactic radiosurgery.
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http://dx.doi.org/10.1002/mp.12342DOI Listing
August 2017

Tumor-Treating Fields-A Fundamental Change in Locoregional Management for Glioblastoma.

JAMA Oncol 2016 Jun;2(6):813-4

Department of Radiation Medicine, Northwell Health System, Lake Success, New York2Hofstra Northwell School of Medicine, Lake Success, New York.

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http://dx.doi.org/10.1001/jamaoncol.2016.0081DOI Listing
June 2016

A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases - An initial report.

J Radiosurg SBRT 2016 ;4(1):43-52

Department of Therapeutic Radiology, Yale-New Haven Hospital and Yale University School of Medicine, New Haven, CT 06520, USA.

Summary: Indications and treatment goals for SRS have changed since the publication of RTOG 90-05. We present initial retrospective outcomes from a new dose selection algorithm in use at our institution felt to be more contemporary with doses being used in the radiosurgery community today and report our local control and toxicity outcomes. This dose selection algorithm will be subject to a forthcoming prospective phase 2 trial.

Introduction: To evaluate safety and efficacy of an institutional dose selection algorithm in the treatment of brain metastases (BM) with single fraction radio-surgery (SRS).

Methods And Materials: The medical records of 65 patients with ≤10 BM treated with GK at our institution between April 2012 and October 2012 were reviewed retrospectively. The prescription doses used in this study ranged from 16-22Gy and were based upon RTOG 90-05 guideline doses subsequently modified at our institution depending on lesion number, lesion volume, institutional experience and prior history of whole brain radiation therapy (WBRT). Primary endpoint was local recurrence (LR) with additional outcomes measured including distant intracranial recurrence (DIR), death without local recurrence (DWLR) and alive and disease free (ADF). Fine Gray competing risk analysis was used to examine factors affecting local recurrence.

Results: Median follow up was 8.9 months (range 1.0-29.6months) and 12 month overall survival was 37% (95% CI 24.9-49.1%). Overall local recurrence rate was 7.7%. On competing risks regression analysis, no variable was significantly associated with local recurrence, including previous whole brain radiotherapy (WBRT), (SHR 1.21 [95%CI 0.13-11.5], p=0.87 and radioresistant versus radiosensitive histology (SHR 0.51 [95% CI 0.06-7.73], p=0.55). No patient developed grade 3 or higher neurotoxicity at 12 months following GK.

Conclusions: Initial local control and toxicity results from our institutional dose selection algorithm are reported here. Comparison of our results with RTOG 90-05 is difficult due to significant differences in the patient population and their treatments. The applicability of this algorithm merits further investigation across multiple centers for the purpose of treatment and clinical trial standardization in single fraction SRS and will be the subject of a forthcoming phase 2 prospective study within our own institution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658834PMC
January 2016

Stereotactic radiosurgery alone for limited brain metastases: are we ready for prime time?

CNS Oncol 2016 18;5(1):1-4. Epub 2015 Dec 18.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.2217/cns.15.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078153PMC
October 2016

Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study.

Anticancer Res 2015 Dec;35(12):6901-7

Tufts University School of Medicine, Tufts Medical Center, Boston, MA, U.S.A.

Aim: Pancreatic cancer remains one of the deadliest cancer diagnoses and is the fourth leading cause of cancer-related deaths in the U.S. Surgery is the mainstay of treatment for the 20% for whom the tumor is resectable, however, controversy exists over the appropriate adjuvant therapy where local recurrence rates remain strikingly high (50-85%). We aimed to evaluate the safety and efficacy of adding capecitabine (a known radiosensitizer by direct and abscopal effects) to concurrent radiation in the adjuvant setting after resection of pancreatic adenocarcinoma.

Patients And Methods: We conducted a retrospective study of 63 patients diagnosed from 2004-2013 with histopathologically-confirmed stage I/II pancreatic cancer treated with a surgical resection followed by adjuvant concurrent chemoradiation to at least 45 Gy using 3D planning and capecitabine at 1,600 mg/m(2)/day (Monday-Friday) for 6 weeks. This was combined with either 4 months of gemcitabine at 1,000 mg/m(2) weekly for 3 out of 4 weeks or capecitabine at 2,000 mg/m(2) for 14 days every 3 weeks for a total of 4 months.

Results: The majority of patients were over 65 years old (71%), male (60%), had negative surgical margins (79%), had pancreatic head or neck involvement (71%), Eastern Cooperative Oncology Group performance score of 1 (71%), and a cancer antigen 19-9 in the range of 11-100 U/ml at the time of diagnosis (51%). Of the 63 patients reviewed, 61 patients (97%) completed concurrent chemoradiotherapy. Treatment was halted in one patient due to gastritis and a second for gastrointestinal bleeding. Otherwise, adverse reactions during concurrent chemoradiotherapy were well-tolerated and the majority were Common Terminology Criteria for Adverse Events grades 1 and 2. Grade 3 toxicity was anorexia (n=2) and hand and foot syndrome (n=2) and GI bleeding (n=1). The only grade 4 toxicities were anorexia (n=1) and fatigue (n=1). The median follow-up of patients at the time of analysis was 36 months. The median survival of the entire cohort was 23.5 (range=8.5-42) months. The 1-, 2- and 3-year survival rates were 80%, 35% and 25%, respectively.

Conclusion: Concurrent chemoradiation using capecitabine as a radiosensitizer in the adjuvant setting for pancreatic cancer was completed by the vast majority of patients in this series. Treatment was relatively well-tolerated, and its efficacy seems comparable to that for historical controls. This study probably represents the largest yet reported using capecitabine in this setting. Future studies including an increased sample size are required.
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December 2015

Top 25 cited articles on Gamma Knife surgery published since 2005 in journals of the American Association of Neurological Surgeons.

J Neurosurg 2015 Dec;123 Spec Suppl:1-2

Department of Radiation Medicine, Hofstra University North Shore-LIJ School of Medicine, Hofstra University, Manhasset, New York.

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http://dx.doi.org/10.3171/2015.12.JNSLeksellIntroDOI Listing
December 2015

One and Done: A Week of Radiotherapy for Glioblastoma.

J Clin Oncol 2015 Dec 26;33(35):4129-30. Epub 2015 Oct 26.

North Shore-LIJ Health System and Hofstra University Medical School, Lake Success, NY

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http://dx.doi.org/10.1200/JCO.2015.64.0763DOI Listing
December 2015