Browsing by Author "Watson, Gordon"
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Item Efficacy of pre-operative stereotactic radiosurgery followed by surgical resection and correlative radiobiological analysis for patients with 1-4 brain metastases: study protocol for a phase II trial(Biomed Central, 2018-12-20) Huff, Wei X.; Agrawal, Namita; Shapiro, Scott; Miller, James; Kulwin, Charles; Shah, Mitesh; Savage, Jesse J.; Payner, Troy; Vortmeyer, Alexander; Watson, Gordon; Dey, Mahua; Neurological Surgery, School of MedicineBACKGROUND: Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases. METHODS: This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure. DISCUSSION: Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival.Item GammaTile for Gliomas: A Single-Center Case Series(Springer Nature, 2021-11) Budnick, Hailey C.; Richardson, Angela M.; Shiue, Kevin; Watson, Gordon; Ng, Sook K.; Le, Yi; Shah, Mitesh V.; Radiation Oncology, School of MedicineGammaTile® (GT Medical Technologies, Tempe, Arizona) is a surgically targeted radiation source, approved by FDA for brachytherapy in primary and secondary brain neoplasms. Each GammaTile is composed of a collagen sponge with four seeds of cesium 131 and is particularly useful in recurrent tumors. We report our early experience in seven patients with recurrent gliomas to assess this type of brachytherapy with particular attention to ease of use, complication, and surgical planning. This study represents a retrospective chart review of surgical use and early clinical outcomes of GammaTile in recurrent gliomas. The number of tiles was planned using pre-operative imaging and dosimetry was planned based on post-operative imaging. Patients were followed during their hospital stay and were followed up after discharge. Parameters such as case length, resection extent, complication, ICU length of stay (LOS), hospital LOS, pre-operative Glasgow Coma Scale (GCS), immediate post-operative GCS, post-operative imaging findings, recurrence at follow-up, length of follow-up, and dosimetry were collected in a retrospective manner. Seven patients were identified that met the inclusion criteria. Two patients were diagnosed with recurrent glioblastoma multiforme (GBM), one lower-grade glioma that recurred as a GBM, one GBM that recurred as a gliosarcoma, and two recurrent oligodendrogliomas. We found that operation time, ICU LOS, hospital LOS, pre- and post-operative GCS, and post-operative complications were within the expected ranges for tumor resection patients. Further, dosimetry data suggests that six out of seven patients received adequate radiation coverage, with the seventh having implantation limitations due to nearby organs at risk. We report no postoperative complications that can be attributed to the GammaTiles themselves. In our cohort, we report seven cases where GammaTiles were implanted in recurrent gliomas. No implant-related post-operative complications were identified. This early data suggests that GammaTile can be a safe form of brachytherapy in recurrent gliomas.Item Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure(Elsevier, 2024-03-27) Shireman, Jack M.; White, Quinn; Ni, Zijian; Mohanty, Chitrasen; Cai, Yujia; Zhao, Lei; Agrawal, Namita; Gonugunta, Nikita; Wang, Xiaohu; Mccarthy, Liam; Kasulabada, Varshitha; Pattnaik, Akshita; Ahmed, Atique U.; Miller, James; Kulwin, Charles; Cohen-Gadol, Aaron; Payner, Troy; Lin, Chih-Ta; Savage, Jesse J.; Lane, Brandon; Shiue, Kevin; Kamer, Aaron; Shah, Mitesh; Iyer, Gopal; Watson, Gordon; Kendziorski, Christina; Dey, Mahua; Radiation Oncology, School of MedicineStereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.Item Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge(medRxiv, 2023-04-24) Shireman, Jack M.; White, Quinn; Agrawal, Namita; Ni, Zijian; Chen, Grace; Zhao, Lei; Gonugunta, Nikita; Wang, Xiaohu; Mccarthy, Liam; Kasulabada, Varshitha; Pattnaik, Akshita; Ahmed, Atique U.; Miller, James; Kulwin, Charles; Cohen-Gadol, Aaron; Payner, Troy; Lin, Chih-Ta; Savage, Jesse J.; Lane, Brandon; Shiue, Kevin; Kamer, Aaron; Shah, Mitesh; Iyer, Gopal; Watson, Gordon; Kendziorski, Christina; Dey, Mahua; Radiation Oncology, School of MedicineStereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.Item Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy(Elsevier, 2018) Shiue, Kevin; Cerra-Franco, Alberto; Shapiro, Ronald; Estabrook, Neil; Mannina, Edward M.; Deig, Christopher R.; Althouse, Sandra; Liu, Sheng; Wan, Jun; Zang, Yong; Agrawal, Namita; Ioannides, Pericles; Liu, Yongmei; Zhang, Chen; DesRosiers, Colleen; Bartlett, Greg; Ewing, Marvene; Langer, Mark P.; Watson, Gordon; Zellars, Richard; Kong, Feng-Ming; Lautenschlaeger, Tim; Radiation Oncology, School of MedicineIntroduction It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. Results At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.Item OMRT-9. Effect of Pre-Operative Stereotactic Radiosurgery on Brain Metastasis: Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694(Oxford University Press, 2021-07) Shireman, Jack; Huff, Wei; Monaco, Gina; Agrawal, Namita; Watson, Gordon; Dey, Mahua; Neurological Surgery, School of MedicineBackground: With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. Methods: Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing. Conclusions: Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p <.001, p<.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.Item Radt-42. Adjuvant Radiation Therapy for Subtotally Resected Cerebellar Liponeurocytoma(Oxford University Press, 2020-11) McClelland, Shearwood, III.; Gardner, Ulysses; Shah, Mitesh; Watson, Gordon; Shiue, Kevin; Radiation Oncology, School of MedicineIntroduction: Classified as a benign glioneural tumor, cerebellar liponeurocytoma is a rare disease (fewer than 80 reported cases) and was upgraded from WHO grade I to grade II in 2007 due to its high recurrence rate. The authors report a case of definitive radiation therapy for recurrent subtotally resected cerebellar liponeurocytoma. Methods: An 80-year-old man having undergone seven resections for his left cerebellar liponeurocytoma without adjuvant therapy over the previous decade at outside institutions was referred for radiation therapy two months following his eighth resection, where gross total resection was limited by the lesion proximity to his brainstem resulting in a 2 cm residual left cerebellar lesion. Pathology revealed tumor cells strongly positive for synaptophysin and a Ki-67 labeling index < 1%. Due to the propensity of this disease to recur following resection, his entire resection cavity was treated with external beam radiation therapy (EBRT) to 46 Gy, followed by a 10 Gy boost to his residual disease yielding a total of 56 Gy to the residual disease. Results: Reimaging following the initial 46 Gy revealed the residual disease remained amenable (< 3 cm) to stereotactic radiosurgery (SRS), which was delivered via linear accelerator (10 Gy to the 80% isodose line) in a single fraction. Following EBRT + SRS, the patient responded well. At last follow-up, he has demonstrated no evidence of disease progression, brainstem-related morbidity or surgical incision-related morbidity. Conclusions: The first reported case of SRS treatment of cerebellar liponeurocytoma as the culmination of a coordinated definitive plan beginning with EBRT supports the applicability and feasibility of this treatment strategy following subtotal resection. This case indicates that a radiation treatment plan similar to that for central neurocytoma may be an optimal strategy, and suggests that adjuvant radiation therapy following operative resection of this rare disease may be underutilized.Item RTHP-06. IMPACT OF THE AMERICAN TAX PAYER RELIEF ACT ON STEREOTACTIC RADIOSURGERY UTILIZATION IN THE UNITED STATES(Oxford Academic, 2019-11) McClelland III, Shearwood; Degnin, Catherine; Chen, Yiyi; Watson, Gordon; Jaboin, Jerry; Radiation Oncology, School of MedicineINTRODUCTION For brain metastases, single-fraction stereotactic radiosurgery (SRS) spares appropriately chosen patients from the invasiveness of operative intervention and the permanent cognitive morbidity of whole brain radiation. SRS is delivered predominantly via two modalities: Gamma Knife, and linear accelerator (LINAC). The implementation of the American Tax Payer Relief Act (ATRA) in 2013 represented the first time limitations specifically targeting SRS reimbursement were introduced into federal law. The subsequent impact of the ATRA on SRS utilization in the United States (US) has yet to be examined. METHODS The National Cancer Data Base (NCDB) from 2010–2016 identified brain metastases patients from non-small cell lung cancer (NSCLC) throughout the US having undergone SRS. Utilization between GKRS and LINAC was assessed before (2010–2012) versus after (2013–2016) ATRA implementation. Utilization was adjusted for several variables, including patient demographics and healthcare system characteristics. RESULTS From 2012 to 2013, there was a substantial decrease of LINAC SRS in favor of GKRS overall (37% to 28%) and individually in both academic and non-academic centers. Over the three-year span immediately preceding ATRA implementation, 65.8% received GKRS and the remaining 34.2% receiving LINAC. In the four years immediately following ATRA implementation 68.0% received GKRS compared with 32% receiving LINAC; these differences were not statistically significant. CONCLUSIONS ATRA implementation in 2013 caused an initial spike in Gamma Knife SRS utilization, followed by a steady decline, similar to rates prior to implementation. These findings are indicative that the ATRA provision mandating Medicare reduction of outpatient payment rates for Gamma Knife to be equivalent with those of LINAC SRS had a significant short-term impact on the radiosurgical treatment of metastatic brain disease throughout the US. Such findings should serve as a reminder of the importance and impact of public policy on treatment modality utilization by physicians and hospitals.Item RTHP-12. NATIONWIDE DISTRIBUTION OF LINEAR ACCELERATOR VERSUS GAMMA KNIFE STEREOTACTIC RADIOSURGERY UTILIZATION FOR METASTATIC BRAIN DISEASE IN ACADEMIC VERSUS COMMUNITY HOSPITALS(Oxford Academic, 2019-11) McClelland III, Shearwood; Degnin, Catherine; Chen, Yiyi; Watson, Gordon; Jaboin, Jerry; Radiation Oncology, School of MedicineINTRODUCTION Single-fraction stereotactic radiosurgery (SRS) is often the preferred treatment modality for metastatic brain disease, particularly when patients have a small enough volume of disease to preclude whole brain radiation therapy and its associated permanent cognitive morbidity. The two predominant SRS treatment modalities are Gamma Knife and linear accelerator (LINAC). The recent impact of SRS modality in academic versus community hospital settings in the United States (US) since the 2013 implementation of the American Tax Payer Relief Act (ATRA) has yet to be examined. METHODS Brain metastases patients from non-small cell lung cancer (NSCLC) throughout the United States having undergone SRS were identified using the 2010–2016 National Cancer Data Base (NCDB). SRS utilization in academic versus community (non-academic) hospitals was identified and assessed. RESULTS Of the 4,012 SRS patients examined, the majority (64%) were treated at academic hospitals. Beginning in 2014, LINAC SRS rapidly increased in popularity compared to GKRS, reversing an annual decline in utilization originating from 2011. The 63% LINAC composition of SRS cases at non-academic centers in 2016 was an all-time high, a 12% increase from a year earlier. This was markedly different than SRS utilization at academic hospitals, where despite a steady increase in LINAC SRS since 2013, GKRS remained the predominant SRS modality, comprising 73% of cases in 2016. CONCLUSIONS The implementation of LINAC over Gamma Knife SRS in the non-academic hospital setting has markedly increased in the timespan since ATRA implementation, comprising more than 60% of SRS cases compared to only 27% of academic hospital SRS cases in 2016. These findings indicate that without the substantially increased Medicare reimbursement advantage formerly associated with Gamma Knife compared to LINAC prior to ATRA, the non-academic setting may be more sensitive than academic centers to conditions optimizing reimbursement.Item Toxicity of Radiosurgery for Brainstem Metastases(Elsevier, 2018) Patel, Ajay; Dong, Tuo; Ansari, Shaheryar; Cohen-Gadol, Aaron; Watson, Gordon; de Moraes, Fabio Ynoe; Nakamura, Masaki; Murovic, Judith; Chang, Steven D.; Hatiboglu, Mustafa Aziz; Chung, Caroline; Miller, James; Lautenschlaeger, Tim; Radiation Oncology, School of MedicineBackground Although stereotactic radiosurgery (SRS) is an effective modality in the treatment of brainstem metastases (BSM), radiation-induced toxicity remains a critical concern. To better understand how severe or life-threatening toxicity is affected by the location of lesions treated in the brainstem, a review of all available studies reporting SRS treatment for BSM was performed. Methods Twenty-nine retrospective studies investigating SRS for BSM were reviewed. Results The rates of grade 3 or greater toxicity, based on the Common Terminology Criteria for Adverse Events, varied from 0 to 9.5% (mean 3.4 ± 2.9%). Overall, the median time to toxicity after SRS was 3 months, with 90% of toxicities occurring before 9 months. A total of 1243 cases had toxicity and location data available. Toxicity rates for lesions located in the medulla were 0.8% (1/131), compared with midbrain and pons, respectively, 2.8% (8/288) and 3.0% (24/811). Conclusions Current data suggest that brainstem substructure location does not predict for toxicity and lesion volume within this cohort with median tumor volumes 0.04–2.8 cc does not predict for toxicity.