Using standardized workflows and quantitative data-driven management to reduce time interval from simulation to treatment initiation.

PURPOSE: External beam radiotherapy is a complex process, involving timely coordination among multiple teams. The aim of this study is to report our experience of establishing a standardized workflow and using quantitative data and metrics to manage the time-to-treatment initiation (TTI). METHODS AND MATERIALS: Starting in 2014, we established a standard process in a radiation oncology-specific electronic medical record system (RO-EMR) for patients receiving external beam radiation therapy in our department, aiming to measure the time interval from simulation to treatment initiation, defined as TTI, for radiation oncology. TTI data were stratified according to the following treatment techniques: three-dimensional (3D) conformal therapy, intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT). Statistical analysis was performed with the Mann-Whitney test for the respective metrics of aggregate data for the initial period 2012- 2015 (PI) and the later period 2016-2019 (PII). RESULT: Over 8 years, the average annual number of treatments for PI and PII were 1760 and 2357 respectively, with 3D, IMRT, and SBRT treatments accounting for 53, 29, 18% and 44, 34, 22%, respectively, of the treatment techniques. The median TTI for 3D, IMRT, and SBRT for PI and PII were 1, 6, 7, and 1, 5, 7 days, respectively, while the 90th percentile TTI for the three techniques in both periods were 5, 9, 11 and 4, 9, 10 days, respectively. From the aggregate data, the TTI was significantly reduced (p = 0.0004, p < 0.0001, p < 0.0001) from PI to PII for the three treatment techniques. CONCLUSION: Establishing a standardized workflow and frequently measuring TTI resulted in shortening the TTI during the early years (in PI) and maintaining the established TTI in the subsequent years (in PII).

Neutrophil to lymphocyte ratio (NTLR) predicts local control and overall survival after stereotactic body radiotherapy (SBRT) in metastatic sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients with local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improve lymphocyte recovery should be investigated.

The dosimetric impact of titanium implants in spinal SBRT using four commercial treatment planning algorithms.

To evaluate the dosimetric impact of titanium implants in spine SBRT using four dose calculation algorithms. Twenty patients with titanium implants in the spine treated with SBRT without density override (DO) were selected. The clinical plan for each patient was created in Pinnacle and subsequently imported into Eclipse (AAA and AcurosXB) and Raystation (CC) for dose evaluation with and without DO to the titanium implant. We renormalized all plans such that 90% of the tumor volume received the prescription dose and subsequently evaluated the following dose metrics: (1) the maximum dose to 0.03 cc (Dmax), dose to 99% (D99%) and 90% (D90%) of the tumor volume; (2) Dmax and volumetric metrics of the spinal cord. For the same algorithm, plans with and without DO had similar dose distributions. Differences in Dmax, D99% and D90% of the tumor were on average <2% with slightly larger variations up to 5.58% in Dmax using AcurosXB. Dmax of the spinal cord for plans calculated with DO increased but the differences were clinically insignificant for all algorithms (mean: 0.36% ± 0.7%). Comparing to the clinical plans, the relative differences for all algorithms had an average of 1.73% (-10.36%-13.21%) for the tumor metrics and -0.93% (-9.87%-10.95%) for Dmax of the spinal cord. A few cases with small tumor and spinal cord volumes, dose differences of >10% in both D99% and Dmax of the tumor, and Dmax of the spinal cord were observed. For all algorithms, the presence of titanium implants in the spine for most patients had minimal impact on dose distributions with and without DO. For the same plan calculated with different algorithms, larger differences in volumetric metrics of >10% could be observed, impacted by dose gradient at the plan normalization volume, tumor volumes, plan complexity, and partial voxel volume interpolation.

Neutrophil to Lymphocyte Ratio (NTLR) Predicts Local Control Failure and Overall Survival after Stereotactic Body Radiotherapy (SBRT) In Metastatic Sarcoma.

The neutrophil to lymphocyte ratio (NTLR) and absolute lymphocyte count (ALC) recovery are prognostic across many cancers. We investigated whether NLTR predicts SBRT success or survival in a metastatic sarcoma cohort treated with SBRT from 2014 and 2020 (N = 42). Wilcox Signed Rank Test and Friedman Test compare NTLR changes with local failure vs. local control (N = 138 lesions). Cox analyses identified factors associated with overall survival. If local control was successful, NLTR change was not significant (p = 0.30). However, NLTR significantly changed in patients local failure (p = 0.027). The multivariable Cox model demonstrated higher NLTR before SBRT was associated with worse overall survival (p = 0.002). The optimal NTLR cut point was 5 (Youden index: 0.418). One-year overall survival in SBRT metastatic sarcoma cohort was 47.6% (CI 34.3%-66.1%). Patients with an NTLR above 5 had a one-year overall survival of 37.7% (21.4%-66.3%); patients with an NTLR below 5 had a significantly improved overall survival of 63% (43.3%-91.6%, p = 0.014). Since NTLR at the time of SBRT was significantly associated with local control success and overall survival in metastatic sarcoma treated with SBRT, future efforts to reduce tumor inhibitory microenvironment factors and improved lymphocyte recovery should be investigated.

Implementing failure mode and effect analysis to improve the safety of volumetric modulated arc therapy for total body irradiation.

PURPOSE: Volumetric-modulated arc therapy for total body irradiation (VMAT-TBI) is a novel radiotherapy technique that has been implemented at our institution. The purpose of this work is to investigate possible failure modes (FMs) in the treatment process and to develop a quality control (QC) program for VMAT-TBI following TG-100 guidelines. METHODS: We formed a multidisciplinary team to map out the complete treatment process of VMAT-TBI following the AAPM TG-100 guidelines. This process map gives a visual representation of the VMAT-TBI workflow from the CT simulation, image processing, contouring, treatment planning, to treatment delivery. From the process map, potential FMs were identified. The occurrence (O), detectability (D), and severity of impact (S) of each FM were assigned according to scoring criteria (1-10) by the multidisciplinary team. A risk priority number (RPN) was calculated from average O, S, and D of each FM (RPN = O x S x D). High risk FMs were identified as 20% of the FMs having the highest RPN scores. After the FMEA analysis, fault-tree analysis (FTA) was performed for each major step of the treatment process to determine the effects of potential failures to the treatment outcome. Effective QC methods were identified to prevent the high risk failures and to improve the safety of the VMAT-TBI program. RESULTS: We identified a total of 55 sub-processes and 128 FMs from the VMAT-TBI workflow. The top five high-risk FMs were: (1) Prescription and/or OAR constraints changed during planning and not communicated to the planner, (2) Patient moves or breathes too heavily during the upper body CT scan (3) Patient moves during the lower body CT scan, (4) Treatment planning system not calculating total body DVH metrics correctly for TBI, (5) Improper optimization criteria used or not sufficient optimization, resulting in suboptimal dose coverage, OAR sparing or excessive hotspots during treatment planning. Two FMs have average severity scores ≥8: Incorrect PTV subdivision/isocenter placement and Prescription and/or OAR constraints changed during planning and not communicated to the planner. Quality assurance and QC interventions including staff training, standard operating procedures, and quality checklists were implemented based on the FMEA and FTA. CONCLUSION: FM and effect analysis was performed to identify high-risk FMs of our VMAT-TBI program. FMEA and FTA were effective in identifying potential FMs and determining the best quality management (QM) measures to implement in the VMAT-TBI program.

Transperineal ultrasound is a good alternative for intra-fraction motion monitoring for prostate stereotactic body radiotherapy.

PURPOSES: To report our experience in a prospective study of implementing a transperineal ultrasound system to monitor intra-fractional prostate motion for prostate stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: This IRB-approved prospective study included 23 prostate SBRT patients treated between 04/2016 and 11/2019 at our institution. The prescription doses were 36.25 Gy to the Low-Dose planning target volume (LD-PTV) and 40 Gy to the High-Dose PTV (HD-PTV) in five fractions with 3 mm planning margins. The transperineal ultrasound system was successfully used in 110 of the 115 fractions. For intra-fraction prostate motion, the real-time prostate displacements measured by ultrasound were exported for analysis. The percentage of time prostate movement exceeded a 2 mm threshold was calculated for each fraction of all patients. T-test was used for all statistical comparisons. RESULTS: Ultrasound image quality was adequate for prostate delineation and prostate motion tracking. The setup time for each fraction under ultrasound-guided prostate SBRT was 15.0 ± 4.9 min and the total treatment time per fraction was 31.8 ± 10.5 min. The presence of an ultrasound probe did not compromise the contouring of targets or critical structures. For intra-fraction motion, prostate movement exceeded 2 mm tolerance in 23 of 110 fractions for 11 of 23 patients. For all fractions, the mean percentage of time when the prostate moved more than 2 mm in any direction during each fraction was 7%, ranging from 0% to 62% of a fraction. CONCLUSION: Ultrasound-guided prostate SBRT is a good option for intra-fraction motion monitoring with clinically acceptable efficiency.

Using a daily monitoring system to reduce treatment position override rates in external beam radiation therapy.

PURPOSE/OBJECTIVES: To report our 7-year experience with a daily monitoring system to significantly reduce couch position overrides and errors in patient treatment positioning. MATERIALS AND METHODS: Treatment couch position override data were extracted from a radiation oncology-specific electronic medical record system from 2012 to 2018. During this period, we took several actions to reduce couch position overrides, including reducing the number of tolerance tables from 18 to 6, tightening tolerance limits, enforcing time outs, documenting reasons for overrides, and timely reviewing of overrides made from previous treatment day. The tolerance tables included treatment categories for head and neck (HN) (with/without cone beam CT [CBCT]), body (with/without CBCT), stereotactic body radiotherapy (SBRT), and clinical setup for electron beams. For the same time period, we also reported treatment positioning-related incidents that were recorded in our departmental incident report system. To verify our tolerance limits, we further examined couch shifts after daily kilovoltage CBCT (kV-CBCT) for the patients treated from 2018 to 2021. RESULTS: From 2012 to 2018, the override rate decreased from 11.2% to 1.6%/year, whereas the number of fractions treated in the department increased by 23%. The annual patient positioning error rate was also reduced from 0.019% in 2012, to 0.004% in 2017 and 0% in 2018. For patients treated under daily kV-CBCT guidance from 2018 to 2021, the applied couch shifts after imaging registration that exceeded the tolerance limits were low, <1% for HN, <1.2% for body, and <2.6% for SBRT. CONCLUSIONS: The daily monitoring system, which enables a timely review of overrides, significantly reduced the number of treatment couch position overrides and ultimately resulted in a decrease in treatment positioning errors. For patients treated with daily kV-CBCT guidance, couch position shifts after CBCT image guidance demonstrated a low rate of exceeding the set tolerance.

Association between biologically effective dose and local control after stereotactic body radiotherapy for metastatic sarcoma.

Introduction: Stereotactic body radiation therapy (SBRT) is increasingly utilized for patients with recurrent and metastatic sarcoma. SBRT affords the potential to overcome the relative radioresistance of sarcomas through delivery of a focused high biological effective dose (BED) as an alternative to invasive surgery. We report local control outcomes after metastatic sarcoma SBRT based on radiation dose and histology. Methods: From our IRB-approved single-institution registry, all patients treated with SBRT for metastatic sarcoma between 2014 and 2020 were identified. Kaplan-Meier analysis was used to estimate local control and overall survival at 1 and 2 years. A receiver operating characteristic (ROC) curve was generated to determine optimal BED using an α/ß ratio of 3. Local control was compared by SBRT dose using the BED cut point and evaluated by histology. Results: Forty-two patients with a total of 138 lesions met inclusion criteria. Median imaging follow up was 7.73 months (range 0.5-35.0). Patients were heavily pre-treated with systemic therapy. Median SBRT prescription was 116.70 Gy BED (range 66.70-419.30). Desmoplastic small round cell tumor, Ewing sarcoma, rhabdomyosarcoma, and small round blue cell sarcomas were classified as radiosensitive (n = 63), and all other histologies were classified as radioresistant (n = 75). Local control for all lesions was 66.7% (95% CI, 56.6-78.5) at 1 year and 50.2% (95% CI, 38.2-66.1) at 2 years. Stratifying by histology, 1- and 2-year local control rates were 65.3% and 55.0%, respectively, for radiosensitive, and 68.6% and 44.5%, respectively, for radioresistant histologies (p = 0.49). The ROC cut point for BED was 95 Gy. Local control rates at 1- and 2-years were 75% and 61.6%, respectively, for lesions receiving >95 Gy BED, and 46.2% and 0%, respectively, for lesions receiving <95 Gy BED (p = 0.01). On subgroup analysis, local control by BED > 95 Gy was significant for radiosensitive histologies (p = 0.013), and trended toward significance for radioresistant histologies (p = 0.25). Conclusion: There is a significant local control benefit for sarcoma SBRT when a BED > 95 Gy is used. Further investigation into the dose-response relationship is warranted to maximize the therapeutic index.

Image-guided volumetric-modulated arc therapy of total body irradiation: An efficient workflow from simulation to delivery.

INTRODUCTION: Using multi-isocenter volumetric-modulated arc therapy (VMAT) for total body irradiation (TBI) may improve dose uniformity and vulnerable tissue protection compared with classical whole-body field technique. Two drawbacks limit its application: (1) VMAT-TBI planning is time consuming; (2) VMAT-TBI plans are sensitive to patient positioning uncertainties due to beam matching. This study presents a robust planning technique with image-guided delivery to improve dose delivery accuracy. In addition, a streamlined sim-to-treat workflow with automatic scripts is proposed to reduce planning time. MATERIALS: Twenty-five patients were included in this study. Patients were scanned in supine head-first and feet-first directions. An automatic workflow was used to (1) create a whole-body CT by registering two CT scans, (2) contour lungs, kidneys, and planning target volume (PTV), (3) divide PTV into multiple sub-targets for planning, and (4) place isocenters. Treatment planning included feathered AP/PA beams for legs/feet and VMAT for the body. VMAT-TBI was evaluated for plan quality, planning/delivery time, and setup accuracy using image guidance. RESULTS: VMAT-TBI planning time can be reduced to a day with automatic scripts. Treatment time took around an hour per fraction. VMAT-TBI improved dose coverage (PTV V100 increased from 76.8 ± 10.5 to 88.5 ± 2.6; p < 0.001) and reduced lung dose (lung mean dose reduced from 10.8 ± 0.7 Gy to 9.4 ± 0.8 Gy, p < 0.001) compared with classic AP/PA technique. CONCLUSION: A VMAT-TBI sim-to-treat workflow with robust planning and image-guided delivery was proposed. VMAT-TBI improved the plan quality compared with classical whole-body field techniques.

A Volumetric Dosimetry Analysis of Vertebral Body Fracture Risk After Single Fraction Spine Stereotactic Body Radiation Therapy.

PURPOSE: Vertebral compression fractures (VCF) are a common and severe complication of spine stereotactic body radiation therapy (SBRT). We sought to analyze how volumetric dosimetry and clinical factors were associated with the risk of VCF. METHODS AND MATERIALS: We evaluated 173 spinal segments that underwent single fraction SBRT in 85 patients from a retrospective database. Vertebral bodies were contoured and dosimetric values were calculated. Competing risk models were used to evaluate the effect of clinical and dosimetry variables on the risk of VCF. RESULTS: Our primary endpoint was development of a post-SBRT VCF. New or progressive fractures were noted in 21/173 vertebrae (12.1%); the median time to fracture was 322 days. Median follow-up time was 426 days. Upon multivariable analysis, the percentages of vertebral body volume receiving >20 Gy and >24 Gy were significantly associated with increased risk of VCF (hazard ratio, 1.036, 1.104; P = .029, .044, respectively). No other patient or treatment factors were found to be significant on multivariable analysis. Sensitivity analysis revealed that the percentages of vertebral body volume receiving >20 Gy and >24 Gy required to obtain 90% sensitivity for predicting vertebral body fracture were 24% and 0%, respectively. CONCLUSIONS: VCF is a common complication after SBRT, with a crude incidence of 12.1%. Treatment plans that permit higher volumes receiving doses >20 Gy and >24 Gy to the vertebral body are associated with increased risk of VCF. To achieve 90% sensitivity for predicting VCF post-SBRT, the percentage of vertebral volume receiving >20 Gy should be <24% and maximum point dose should be <24 Gy. These results may help guide clinicians when evaluating spine SBRT treatment plans to minimize the risk of developing posttreatment VCF.

Stereotactic body radiotherapy for the treatment of oligometastatic gynecological malignancy in the abdomen and pelvis: A single-institution experience.

PURPOSE/OBJECTIVES: Metastasis-directed therapy with stereotactic body radiotherapy (SBRT) in the setting of oligometastatic disease is a rapidly evolving paradigm given ongoing improvements in systemic therapies and diagnostic modalities. However, SBRT to targets in the abdomen and pelvis is historically associated with concerns about toxicity. The purpose of this study was to evaluate the safety and efficacy of SBRT to the abdomen and pelvis for women with oligometastases from primary gynecological tumors. MATERIALS/METHODS: From our IRB-approved registry, all patients who were treated with SBRT between 2014 and 2020 were identified. Oligometastatic disease was defined as 1 to 5 discrete foci of clinical metastasis radiographically diagnosed by positron emission tomography (PET) and/or computerized tomography (CT) imaging. The primary endpoint was local control at 12 months. Local and distant control rates were estimated using the Kaplan-Meier method. Time intervals for development of local progression and distant progression were calculated based on follow up visits with re-staging imaging. Acute and late toxicity outcomes were determined based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: We identified 34 women with 43 treated lesions. Median age was 68 years (range 32-82), and median follow up time was 12 months (range 0.2-54.0). Most common primary tumor sites were ovarian (n=12), uterine (n=11), and cervical (n=7). Median number of previous lines of systemic therapy agents at time of SBRT was 2 (range 0-10). Overall, SBRT was delivered to 1 focus of oligometastasis in 29 cases, 2 foci in 2 cases, 3 foci in 2 cases, and 4 foci in 1 case. All patients were treated comprehensively with SBRT to all sites of oligometastasis. Median prescription dose was 24 Gy (range 18-54 Gy) in 3 fractions (range 3-6) to a median prescription isodose line of 83.5% (range 52-95). Local control by lesion at 12 and 24 months was 92.5% for both time points. Local failure was observed in three treated sites among two patients, two of which were at 11 months in one patient, and the other at 30 months. Systemic control rate was 60.2% at 12 months. Overall survival at 12 and 24 months was 85% and 70.2%, respectively. Acute grade 2 toxicities included nausea (n=3), and there were no grade > 3 acute toxicities. Late grade 1 toxicities included diarrhea (n=1) and fatigue (n=1), and there were no grade > 2 toxicities. CONCLUSION: SBRT to oligometastatic gynecologic malignancies in the abdomen and pelvis is feasible with encouraging preliminary safety and local control outcomes. This approach is associated with excellent local control and low rates of toxicity during our follow-up interval. Further investigations into technique, dose-escalation and utilization are warranted.

Combining automatic plan integrity check (APIC) with standard plan document and checklist method to reduce errors in treatment planning.

PURPOSE/OBJECTIVES: To report our experience of combining three approaches of an automatic plan integrity check (APIC), a standard plan documentation, and checklist methods to minimize errors in the treatment planning process. MATERIALS/METHODS: We developed APIC program and standardized plan documentation via scripting in the treatment planning system, with an enforce function of APIC usage. We used a checklist method to check for communication errors in patient charts (referred to as chart errors). Any errors in the plans and charts (referred to as the planning errors) discovered during the initial chart check by the therapists were reported to our institutional Workflow Enhancement (WE) system. Clinical Implementation of these three methods is a progressive process while the APIC was the major progress among the three methods. Thus, we chose to compared the total number of planning errors before (including data from 2013 to 2014) and after (including data from 2015 to 2018) APIC implementation. We assigned the severity of these errors into five categories: serious (S), near miss with safety net (NM), clinical interruption (CLI), minor impediment (MI), and bookkeeping (BK). The Mann-Whitney U test was used for statistical analysis. RESULTS: A total of 253 planning error forms, containing 272 errors, were submitted during the study period, representing an error rate of 3.8%, 3.1%, 2.1%, 0.8%, 1.9% and 1.3% of total number of plans in these years respectively. A marked reduction of planning error rate in the S and NM categories was statistically significant (P < 0.01): from 0.6% before APIC to 0.1% after APIC. The error rate for all categories was also significantly reduced (P < 0.01), from 3.4% before APIC and 1.5% per plan after APIC. CONCLUSION: With three combined methods, we reduced both the number and the severity of errors significantly in the process of treatment planning.

Heterogenous Dose-escalated Prostate Stereotactic Body Radiation Therapy for All Risk Prostate Cancer: Quality of Life and Clinical Outcomes of an Institutional Pilot Study.

OBJECTIVES: Previous prostate stereotactic body radiation therapy studies delivered uniform doses of 35 to 40 Gy/5 fx. Attempts at uniform dose escalation to 50 Gy caused high rates of gastrointestinal (GI) toxicity. We hypothesize that heterogeneous dose escalation to regions nonadjacent to sensitive structures (urethra, rectum, and bladder) is safe and efficacious. MATERIALS AND METHODS: Patients were enrolled on a prospective pilot study. The primary endpoint was treatment-related GI and genitourinary (GU) toxicity. The secondary endpoints included quality of life (QOL) assessed by the EPIC-26 questionnaire and biochemical control. The target volume received 36.25 Gy/5 fx. The target >3 mm from sensitive was dose escalated to 50 Gy/5 fx. RESULTS: Thirty-five patients were enrolled. Three patients had low, 14 intermediate, and 18 high-risk disease. The mean initial prostate specific antigen was 15.1 ng/mL. Androgen deprivation therapy was given to 19 patients. Median follow-up was 46 months. Urinary irritation/obstructive and urinary bother scores declined by minimal clinically important difference threshold from baseline at 6 weeks, but subsequently recovered by 4 months. No differences in QOL scores were observed for urinary incontinence, bowel domain, bloody stools, or sexual domain. One patient developed acute grade 4 GU toxicity and acute grade 4 GI toxicity. The incidence of late high grade toxicity was 1/35 for GU toxicity and 2/35 for GI toxicity. Freedom from biochemical failure at 3 years was 88.0%. CONCLUSIONS: Heterogeneous dose-escalated prostate stereotactic body radiation therapy is feasible with low rates of acute and late toxicities and favorable QOL outcomes in patients with predominantly intermediate-risk and high-risk prostate cancer.

Use of a Linear Accelerator for Conducting In Vitro Radiobiology Experiments.

Radiation therapy remains one of the cornerstones of cancer management. For most cancers, it is the most effective, nonsurgical therapy to debulk tumors. Here, we describe a method to irradiate cancer cells with a linear accelerator. The advancement of linear accelerator technology has improved the precision and efficiency of radiation therapy. The biological effects of a wide range of radiation doses and dose rates continue to be an intense area of investigation. Use of linear accelerators can facilitate these studies using clinically relevant doses and dose rates.

The effects of extra high dose rate irradiation on glioma stem-like cells.

Radiation therapy is an integral part of treatment for patients with glioblastoma. New technological advances in linear accelerators have made extra-high dose rate irradiation possible. This shortens patient treatment time significantly compared to standard dose rate irradiation, but the biologic effects of extra high dose rate irradiation are poorly understood. Glioma stem-like cells (GSCs) are resistant to standard radiation and contribute to tumor progression. Here, we assess the therapeutic effect of extra high dose rate vs. standard dose rate irradiation on GSCs. GSCs were exposed to 2, 4 and 6 Gy X-irradiation at dose rates of 4.2 Gy/min or 21.2 Gy/min (400 monitoring units (MU)/min or 2100 MU/min). We analyzed cell survival with cell growth assays, tumorsphere formation assays and colony formation assays. Cell kill and self-renewal were dependent on the total dose of radiation delivered. However, there was no difference in survival of GSCs or DNA damage repair in GSCs irradiated at different dose rates. GSCs exhibited significant G1 and G2/M phase arrest and increased apoptosis with higher doses of radiation but there was no difference between the two dose rates at each given dose. In a GSC-derived preclinical model of glioblastoma, radiation extended animal survival, but there was no difference in survival in mice receiving different dose rates of radiation. We conclude that GSCs respond to larger fractions of radiation, but extra high dose rate irradiation has no significant biologic advantage in comparison with standard dose rate irradiation.

Pain flare after stereotactic radiosurgery for spine metastases.

PURPOSE: Understanding of pain flare (PF) following spine stereotactic radiosurgery (sSRS) is lacking. This study sought to determine the incidence and risk factors associated with PF following single fraction sSRS. MATERIALS/METHODS: An IRB-approved database was compiled to include patients who underwent sSRS. Patient and disease characteristics as well as treatment and dosimetric details were collected retrospectively. Pain relief post-sSRS was prospectively collected using the Brief Pain Inventory (BPI). These factors were correlated to the development of PF (defined as an increase in pain within 7 days of treatment which resolved with steroids). Survival was calculated using Kaplan-Meier analysis and logistic regression was utilized to evaluate the association between the clinical and treatment factors and occurrence of PF. RESULTS: A total of 348 patients with 507 treatments were included. Median age and prescription dose were 59 years and 15 Gy (range: 7-18), respectively, and 62% of patients were male. Renal cell carcinoma (24%), lung cancer (14%), and breast cancer (11%) were the most common histologies, and 74% had epidural disease and 43% had thecal sac compression. The most common location of metastases was in the cervical/thoracic spine (59%), followed by lumbar spine (32%), and sacral spine (9%). Most common reason for treatment was pain (73%), followed by pain and neurological deficit (13%), asymptomatic disease (10%), and neurologic deficit only (3%). Median time to pain relief was 1.8 months. Median overall survival, time to radiographic failure, and time to pain progression were 13.6 months, 26.5 months, and 56.6 months, respectively. Only 14.4% of treatments resulted in the development of PF. Univariate analysis showed that higher Karnofsky performance score (KPS) (OR=1.03, p=0.03), female gender (OR=1.80, p=0.02), higher prescription dose (OR=1.30, p=0.008), and tumor location of cervical/thoracic spine vs lumbar spine (OR=1.81, p=0.047) were predictors for the development of PF. On multivariate analysis, higher consult KPS (OR=1.03, p=0.04), female gender (OR=1.93, p=0.01), higher prescription dose (OR=1.27, p=0.02), and tumor location of cervical/thoracic spine vs lumbar spine (OR=1.81, p=0.05) remained predictors of PF. No other dosimetric parameters were associated with the development of PF. CONCLUSION: PF is an infrequent complication of sSRS. Predictors for the development of PF include higher consult KPS, female gender, higher prescription dose, and cervical/thoracic tumor location. Dose to the spinal cord was not a predictor of PF. Since a minority (14.4%) of treatments result in PF, we do not routinely utilize prophylactic steroid treatment; however, prophylactic steroids may be considered in female patients with cervical/thoracic metastases receiving higher dose sSRS.

Dosimetric differences between local failure and local controlled non-small cell lung cancer patients treated with stereotactic body radiotherapy: A matched-pair study.

INTRODUCTION: Concerns were raised about the accuracy of pencil beam (PB) calculation and potential underdosing of medically inoperable non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). From our institutional series, we designed a matched-pair study where each local failure and controlled patient was matched based upon several clinical factors, to investigate the dose difference between the matched-pair. METHODS: Eighteen pairs of NSCLC patients, treated with 50 Gy in five fractions, were selected. These patients were matched based on treatment intent, tumour size, histology and clinical follow-up. All PB calculated clinical plans were retrospectively recalculated with a MC algorithm. The D99 and DMean of the gross tumour volume (GTV) and D95 and DMean of the planning tumour volume (PTV) from PB and Monte Carlo (MC) calculation were compared between local failures and controls using the Mann-Whitney test. RESULTS: The mean PB calculated D95 of PTV was 50.4 Gy for both failures and controls (P = 0.85), indicating no planning differences between the groups. From MC calculations, the mean (±SD) of GTV D99 , GTV DMean , PTV D95 , PTV DMean were 47.6 ± 2.6/46.3 ± 2.4, 50.4 ± 2.1/49.8 ± 1.6, 44.4 ± 2.7/43.6 ± 3.1, 48.7 ± 2.4/48.2 ± 2.4 Gy for failure/controlled groups, respectively, and there was no significant difference between two groups (all P > 0.1). The dose differences between MC and PB calculations were in agreement with other literatures and there was no significant difference between two groups. CONCLUSIONS: While PB algorithms may overestimate tumour doses relative to MC algorithms, our matched-pair study did not find dose differences between local failure and local controlled cases.

Tumor Control and Toxicity for Common Stereotactic Body Radiation Therapy Dose-Fractionation Regimens in Stage I Non-Small Cell Lung Cancer.

PURPOSE: To examine the impact of stereotactic body radiation therapy (SBRT) dose on outcomes in early-stage non-small cell lung cancer in a large single-institution series. METHODS AND MATERIALS: We reviewed 600 patients treated from 2003 to 2012 for early-stage non-small cell lung cancer. The SBRT dose was at physician discretion on the basis of tumor size and location. Peripheral tumors were treated to 60 Gy in 3 fractions (homogeneous planning), 48-50 Gy in 4-5 fractions, or 30-34 Gy in 1 fraction. Central tumors were treated to 50 Gy in 5 fractions, 60 Gy in 8 fractions, or 50 Gy in 10 fractions. Patient, tumor, and treatment factors were assessed for their impact on patterns of failure, toxicity, and survival. RESULTS: An SBRT dose of 54-60 Gy in 3 fractions was associated with a statistically significant lower rate of local failure (LF) (4.3% at 2 years) compared with 30-34 Gy in 1 fraction (21%), 48-50 Gy in 4-5 fractions (15.5%), and 50-60 Gy in 8-10 fractions (13.3%). Lower pre-SBRT hemoglobin and higher positron emission tomography standardized uptake value were also associated with LF. Nodal failure, distant failure, and overall survival were similar between fractionation groups. Pulmonary toxicity (crude rate, any grade) was slightly higher for 3 fractions (5.0%) compared with 1 (3.2%) or 4-5 fractions (3.8%). Chest wall toxicity was also higher for 3 (23.7%) compared with 1 (8.6%) or 4-5 (7.7%) fraction regimens. CONCLUSIONS: Although higher biologically equivalent dose SBRT (150-180 Gy10) may be associated with slightly lower LF, it was also associated with mildly increased toxicity and no difference in other patterns of failure or overall survival.

Recursive partitioning analysis is predictive of overall survival for patients undergoing spine stereotactic radiosurgery.

Spine stereotactic radiosurgery (SRS) offers excellent radiographic and pain control for patients with spine metastases. We created a prognostic index using recursive partitioning analysis (RPA) to allow better patient selection for spine SRS. Patients who underwent single-fraction spine SRS for spine metastases were included. Primary histologies were divided into favorable (breast/prostate), radioresistant (renal cell/sarcoma/melanoma) and other. Cox proportional hazards regression was done to identify factors associated with overall survival (OS). RPA was performed to identify factors to classify patients into distinct risk groups with respect to OS. A total of 444 patients were eligible. Median dose was 16 Gy (range 8-18) in 1 fraction and median follow-up was 11.7 months. At time of analysis, 103 (23.1%) patients were alive. Median OS was 12.9 months. RPA identified three distinct classes. Class 1 was defined as KPS > 70 with controlled systemic disease (n = 142); class 3 was defined as KPS ≤ 70 and age < 54 years or KPS ≤ 70 age ≥ 54 years and presence of visceral metastases (n = 95); all remaining patients comprise class 2 (n = 207). Median overall survival was 26.7 months for class 1, 13.4 months for class 2, and 4.5 months for class 3 (p < 0.01). Our analysis demonstrates that there is considerably variability in survival among patients undergoing spine SRS. We created an objective risk stratification via RPA for spine SRS. Given the safety and efficacy of spine SRS and good survival in class 1 and 2 patients, this RPA can help clinicians identify patients who may benefit from upfront spine SRS.

The impact of decompression with instrumentation on local failure following spine stereotactic radiosurgery.

OBJECTIVE Spine stereotactic radiosurgery (SRS) is a safe and effective treatment for spinal metastases. However, it is unknown whether this highly conformal radiation technique is suitable at instrumented sites given the potential for microscopic disease seeding. The authors hypothesized that spinal decompression with instrumentation is not associated with increased local failure (LF) following SRS. METHODS A 2:1 propensity-matched retrospective cohort study of patients undergoing SRS for spinal metastasis was conducted. Patients with less than 1 month of radiographic follow-up were excluded. Each SRS treatment with spinal decompression and instrumentation was propensity matched to 2 controls without decompression or instrumentation on the basis of demographic, disease-related, dosimetric, and treatment-site characteristics. Standardized differences were used to assess for balance between matched cohorts. The primary outcome was the 12-month cumulative incidence of LF, with death as a competing risk. Lesions demonstrating any in-field progression were considered LFs. Secondary outcomes of interest were post-SRS pain flare, vertebral compression fracture, instrumentation failure, and any Grade ≥ 3 toxicity. Cumulative incidences analysis was used to estimate LF in each cohort, which were compared via Gray's test. Multivariate competing-risks regression was then used to adjust for prespecified covariates. RESULTS Of 650 candidates for the control group, 166 were propensity matched to 83 patients with instrumentation. Baseline characteristics were well balanced. The median prescription dose was 16 Gy in each cohort. The 12-month cumulative incidence of LF was not statistically significantly different between cohorts (22.8% [instrumentation] vs 15.8% [control], p = 0.25). After adjusting for the prespecified covariates in a multivariate competing-risks model, decompression with instrumentation did not contribute to a greater risk of LF (HR 1.21, 95% CI 0.74-1.98, p = 0.45). The incidences of post-SRS pain flare (11% vs 14%, p = 0.55), vertebral compression fracture (12% vs 22%, p = 0.04), and Grade ≥ 3 toxicity (1% vs 1%, p = 1.00) were not increased at instrumented sites. No instrumentation failures were observed. CONCLUSIONS In this propensity-matched analysis, LF and toxicity were similar among cohorts, suggesting that decompression with instrumentation does not significantly impact the efficacy or safety of spine SRS. Accordingly, spinal instrumentation may not be a contraindication to SRS. Future studies comparing SRS to conventional radiotherapy at instrumented sites in matched populations are warranted.