A. Magnelli

Relationship of Imaging Frequency and Planning Margin to Account for Intrafraction Prostate Motion: Analysis Based on Real-Time Monitoring Data

PURPOSE Correction for intrafraction prostate motion becomes important for hypofraction treatment of prostate cancer. The purpose of this study was to estimate an ideal planning margin to account for intrafraction prostate motion as a function of imaging and repositioning frequency in the absence of continuous prostate motion monitoring. METHODS AND MATERIALS For 31 patients receiving intensity modulated radiation therapy treatment, prostate positions sampled at 10 Hz during treatment using the Calypso system were analyzed. Using these data, we simulated multiple, less frequent imaging protocols, including intervals of every 10, 15, 20, 30, 45, 60, 90, 120, 180, and 240 seconds. For each imaging protocol, the prostate displacement at the imaging time was corrected by subtracting prostate shifts from the subsequent displacements in that fraction. Furthermore, we conducted a principal component analysis to quantify the direction of prostate motion. RESULTS Averaging histograms of every 240 and 60 seconds for all patients, vector displacements of the prostate were, respectively, within 3 and 2 mm for 95% of the treatment time. A vector margin of 1 mm achieved 91.2% coverage of the prostate with 30 second imaging. The principal component analysis for all fractions showed the largest variance in prostate position in the midsagittal plane at 54° from the anterior direction, indicating that anterosuperior to inferoposterior is the direction of greatest motion. The smallest prostate motion is in the left-right direction. CONCLUSIONS The magnitudes of intrafraction prostate motion along the superior-inferior and anterior-posterior directions are comparable, and the smallest motion is in the left-right direction. In the absence of continuous prostate motion monitoring, and under ideal circumstances, 1-, 2-, and 3-mm vector planning margins require a respective imaging frequency of every 15, 60, and 240 to account for intrafraction prostate motion while achieving adequate geometric target coverage for 95% of the time.

30 Gy or 34 Gy? Comparing 2 Single-Fraction SBRT Dose Schedules for Stage I Medically Inoperable Non-Small Cell Lung Cancer

PURPOSE To review outcomes of 2 single-fraction lung stereotactic body radiation therapy (SBRT) schedules used for medically inoperable early stage lung cancer. METHODS AND MATERIALS Patients in our institution have been treated on and off protocols using single-fraction SBRT (30 Gy and 34 Gy, respectively). All patients had node-negative lung cancer measuring ≤5 cm and lying ≥2 cm beyond the trachea-bronchial tree and were treated on a Novalis/BrainLAB system with the ExactTrac positioning system for daily image guidance. RESULTS For the interval from 2009 to 2012, 80 patients with 82 lesions were treated with single-fraction lung SBRT. Fifty-five patients (69%) and 25 patients (31%) received 30 Gy and 34 Gy, respectively. In a comparison of 30 Gy and 34 Gy cohorts, patient and tumor characteristics were balanced and median follow-up in months was 18.7 and 17.8, respectively. The average heterogeneity-corrected mean doses to the target were 33.75 Gy and 37.94 Gy for the 30-Gy and 34-Gy prescriptions, respectively. Comparing 30-Gy and 34-Gy cohorts, 92.7% and 84.0% of patients, respectively, experienced no toxicity (P was not significant), and had neither grade 3 nor higher toxicities. For the 30-Gy and 34-Gy patients, rates of 1-year local failure, overall survival, and lung cancer-specific mortality were 2.0% versus 13.8%, 75.0% versus 64.0%, and 2. 1% versus 16.0%, respectively (P values for differences were not significant). CONCLUSIONS This is the largest single-fraction lung SBRT series yet reported. and it confirms the safety, efficacy, and minimal toxicity of this schedule for inoperable early stage lung cancer.

Dose calculation differences between Monte Carlo and pencil beam depend on the tumor locations and volumes for lung stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) has been increasingly used as an efficacious treatment modality for early‐stage non‐small cell lung cancer. The accuracy of dose calculations is compromised due to the presence of inhomogeneity. For the purpose of a consistent prescription, radiation doses were calculated without heterogeneity correction in several RTOG trials. For patients participating in these trials, recalculations of the planned doses with more accurate dose methods could provide better correlations between the treatment outcomes and the planned doses. Using a Monte Carlo (MC) dose calculation algorithm as a gold standard, we compared the recalculated doses with the MC algorithm to the original pencil beam (PB) calculations for our institutional clinical lung SBRT plans. The focus of this comparison is to investigate the volume and location dependence on the differences between the two dose calculations. Thirty‐one clinical plans that followed RTOG and other protocol guidelines were retrospectively investigated in this study. Dosimetric parameters, such as D1, D95, and D99 for the PTV and D1 for organs at risk, were compared between two calculations. Correlations of mean lung dose and V20 of lungs between two calculations were investigated. Significant dependence on tumor size and location was observed from the comparisons between the two dose calculation methods. When comparing the PB calculations without heterogeneity correction to the MC calculations with heterogeneity correction, we found that in terms of D95 of PTV: (1) the two calculations resulted in similar D95 for edge tumors with volumes greater than 25.1 cc; (2) an average overestimation of 5% in PB calculations for edge tumors with volumes less than 25.1 cc; and (3) an average overestimation of 9% or underestimation of 3% in PB calculations for island tumors with volumes smaller or greater than 22.6 cc, respectively. With heterogeneity correction, the PB calculations resulted in an average reduction of 23.8% and 15.3% in the D95 for the PTV for island and edge lesions, respectively, when compared to the MC calculations. For organs at risks, very small differences were found among all the comparisons. Excellent correlations for mean dose and V20 of lungs were observed between the two calculations. This study demonstrated that using a single scaling factor may be overly simplified when accounting for the effects of heterogeneity correction. Accurate dose calculations, such as the Monte Carlo algorithms, are highly recommended to understand dose responses in lung SBRT. PACS number: 87.53.Ly

Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Spinal Sarcomas

Purpose: Despite advancements in local and systemic therapy, metastasis remains common in the natural history of sarcomas. Unfortunately, such metastases are the most significant source of morbidity and mortality in this heterogeneous disease. As a classically radioresistant histology, stereotactic radiosurgery has emerged to control spinal sarcomas and provide palliation. However, there is a lack of data regarding pain relief and relapse following stereotactic radiosurgery. Methods: We queried a retrospective institutional database of patients who underwent spine stereotactic radiosurgery for primary and metastatic sarcomas. The primary outcome was pain relief following stereotactic radiosurgery. Secondary outcomes included progression of pain, radiographic failure, and development of toxicities following treatment. Results: Forty treatment sites were eligible for inclusion; the median prescription dose was 16 Gy in a single fraction. Median time to radiographic failure was 14 months. At 6 and 12 months, radiographic control was 63% and 51%, respectively. Among patients presenting with pain, median time to pain relief was 1 month. Actuarial pain relief at 6 months was 82%. Median time to pain progression was 10 months; at 12 months, actuarial pain progression was 51%. Following multivariate analysis, presence of neurologic deficit at consult (hazard ratio: 2.48, P < .01) and presence of extraspinal bone metastases (hazard ratio: 2.83, P < .01) were associated with pain relief. Greater pain at consult (hazard ratio: 1.92, P < .01), prior radiotherapy (hazard ratio: 4.65, P = .02), and greater number of irradiated vertebral levels were associated with pain progression. Conclusions: Local treatment of spinal sarcomas has remained a challenge for decades, with poor rates of local control and limited pain relief following conventional radiotherapy. In this series, pain relief was achieved in 82% of treatments at 6 months, with half of patients experiencing pain progression by 12 months. Given minimal toxicity and suboptimal pain control at 12 months, dose escalation beyond 16 Gy is warranted.

Single-Fraction Spine Stereotactic Body Radiation Therapy for the Treatment of Chordoma.

Purpose: Chordoma is a radioresistant tumor that presents a therapeutic challenge with spine involvement, as high doses of radiation are needed for local control while limiting dose to the spinal cord. The purpose of this study is to determine the efficacy and safety of single-fraction spine stereotactic body radiation therapy for the treatment of spine chordoma. Methods: A retrospective review of our institutional database from 2006 to 2013 identified 8 patients (12 cases) with chordoma of the spine who were treated with spine stereotactic body radiation therapy. Surgical resection was performed in 7 of the 12 cases. The treatment volume was defined by the bony vertebral level of the tumor along with soft tissue extension appreciated on magnetic resonance imaging fusion. Medical records and imaging were assessed for pain relief and local control. Treatment toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results: Median age was 59 years (range, 17-91). Median target volume was 48 cm3 (1-304), and median prescription dose was 16 Gy (11-16). Median conformality index was 1.44 (1.14-3.21), and homogeneity index was 1.12 (1.05-1.19). With a median follow-up time of 9.7 months (.5-84), local control was achieved in 75% of the cases treated. One patient developed limited grade 2 spinal cord myelopathy that resolved with steroids. There were no other treatment toxicities from spine stereotactic body radiation therapy. Conclusion: Single-fraction spine stereotactic body radiation therapy can be safely delivered to treat chordoma of the spine with the potential to improve pain symptoms. Although the early data are suggestive, long-term follow-up with more patients is necessary to determine the efficacy of spine stereotactic body radiation therapy in the treatment of chordoma of the spine.

Impact of cervicothoracic region stereotactic spine radiosurgery on adjacent organs at risk

OBJECTIVE Stereotactic radiosurgery (SRS) of the spine is a conformal method of delivering a high radiation dose to a target in a single or few (usually ≤ 5) fractions with a sharp fall-off outside the target volume. Although efforts have been focused on evaluating spinal cord tolerance when treating spinal column metastases, no study has formally evaluated toxicity to the surrounding organs at risk (OAR), such as the brachial plexus or the oropharynx, when performing SRS in the cervicothoracic region. The aim of this study was to evaluate the radiation dosimetry and the acute and delayed toxicities of SRS on OAR in such patients. METHODS Fifty-six consecutive patients (60 procedures) with a cervicothoracic spine tumor involving segments within C5-T1 who were treated using single-fraction SRS between February 2006 and July 2014 were included in the study. Each patient underwent CT simulation and high-definition MRI before treatment. The clinical target volume and OAR were contoured on BrainScan and iPlan software after image fusion. Radiation toxicity was evaluated using the common toxicity criteria for adverse events and correlated to the radiation doses delivered to these regions. The incidence of vertebral body compression fracture (VCF) before and after SRS was evaluated also. RESULTS Metastatic lesions constituted the majority (n = 52 [93%]) of tumors treated with SRS. Each patient was treated with a median single prescription dose of 16 Gy to the target. The median percentage of tumor covered by SRS was 93% (maximum target dose 18.21 Gy). The brachial plexus received the highest mean maximum dose of 17 Gy, followed by the esophagus (13.8 Gy) and spinal cord (13 Gy). A total of 14 toxicities were encountered in 56 patients (25%) during the study period. Overall, 14% (n = 8) of the patients had Grade 1 toxicity, 9% (n = 5) had Grade 2 toxicity, 2% (n = 1) had Grade 3 toxicity, and none of the patients had Grade 4 or 5 toxicity. The most common (12%) toxicity was dysphagia/odynophagia, followed by axial spine pain flare or painful radiculopathy (9%). The maximum radiation dose to the brachial plexus showed a trend toward significance (p = 0.066) in patients with worsening post-SRS pain. De novo and progressive VCFs after SRS were noted in 3% (3 of 98) and 4% (4 of 98) of vertebral segments, respectively. CONCLUSIONS From the analysis, the current SRS doses used at the Cleveland Clinic seem safe and well tolerated at the cervicothoracic junction. These preliminary data provide tolerance benchmarks for OAR in this region. Because the effect of dose-escalation SRS strategies aimed at improving local tumor control needs to be balanced carefully with associated treatment-related toxicity on adjacent OAR, larger prospective studies using such approaches are needed.

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.

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

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.

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 Grays 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.

SU-F-J-29: Dosimetric Effect of Image Registration ROI Size and Focus in Automated CBCT Registration for Spine SBRT

PURPOSE Spinal stereotactic body radiotherapy (SBRT) involves highly conformal dose distributions and steep dose gradients due to the proximity of the spinal cord to the treatment volume. To achieve the planning goals while limiting the spinal cord dose, patients are setup using kV cone-beam CT (kV-CBCT) with 6 degree corrections. The kV-CBCT registration with the reference CT is dependent on a user selected region of interest (ROI). The objective of this work is to determine the dosimetric impact of ROI selection. METHODS Twenty patients were selected for this study. For each patient, the kV-CBCT was registered to the reference CT using three ROIs including: 1) the external body, 2) a large anatomic region, and 3) a small region focused in the target volume. Following each registration, the aligned CBCTs and contours were input to the treatment planning system for dose evaluation. The minimum dose, dose to 99% and 90% of the tumor volume (D99%, D90%), dose to 0.03cc and the dose to 10% of the spinal cord subvolume (V10Gy) were compared to the planned values. RESULTS The average deviations in the tumor minimum dose were 2.68%±1.7%, 4.6%±4.0%, 14.82%±9.9% for small, large and the external ROIs, respectively. The average deviations in tumor D99% were 1.15%±0.7%, 3.18%±1.7%, 10.0%±6.6%, respectively. The average deviations in tumor D90% were 1.00%±0.96%, 1.14%±1.05%, 3.19%±4.77% respectively. The average deviations in the maximum dose to the spinal cord were 2.80%±2.56%, 7.58%±8.28%, 13.35%±13.14%, respectively. The average deviation in V10Gy to the spinal cord were 1.69%±0.88%, 1.98%±2.79%, 2.71%±5.63%. CONCLUSION When using automated registration algorithms for CBCT-Reference alignment, a small target-focused ROI results in the least dosimetric deviation from the plan. It is recommended to focus narrowly on the target volume to keep the spinal cord dose below tolerance.