Dosimetric evaluation of a spinal cord dose-limiting 3D-CRT technique for radiotherapy of spinal metastases.

BACKGROUND: To evaluate the possible advantages of a simple spinal cord (SC) dose-limiting three-dimensional conformal radiotherapy (3D-CRT) technique in comparison to conventional two-dimensional (2D) techniques and other 3D-CRT techniques for spinal bone irradiation. METHODS: For 41 spinal target volumes, seven different techniques were evaluated, using a standard schedule of 30 Gy in 10 fractions. The SC dose-limiting 3D-CRT technique 1F2S-18MV using a single posterior field (F) supplemented by two anterior segment fields (S) and 18-MV photon beams was compared to two conventional 2D techniques (a single posterior field, PA, and two opposed anterior-posterior fields, APPA), three other 3D-CRT techniques (a single posterior field supplemented by four segment fields, 1F4S; two wedged fields, WD, and the SC dose-limiting variant using 6 MV, 1F2S-6MV) along with the original clinically applied plans. RESULTS: 1F2S-18MV demonstrated notably better results for all target volume parameters compared to the conventional 2D techniques (p < 0.001). Limitation of the SC dose was significantly superior with 1F2S-18MV in comparison to PA and APPA (SC Dmean: 28.9 ± 0.4  vs. 30.1 ± 0.6 Gy and 30.1 ± 0.4 Gy; SC Dmax: 30.9 ± 0.7  vs. 32.5 ± 1.0 Gy and 31.8 ± 0.7 Gy; SC D1cm3 : 30.1 ± 0.6  vs. 31.7 ± 0.9 Gy and 31.1 ± 0.6 Gy; p < 0.001). Likewise, lower mean SC doses with 1F2S-18MV were observed in comparison to the more treatment time-consuming 3D-CRT techniques (1F4S, WD) and the original plans without relevant compromises on the dose homogeneity in the target volume and the dose exposure to the other OARs. CONCLUSION: In treatment planning of spinal metastases, simple variants of 3D-CRT-techniques like 1F2S-18MV can offer a significant dose limitation to the SC while providing a sufficient dose coverage of the target volume. Especially in patients with favorable life expectancy and potential need for re-irradiation, such SC dose-limiting 3D-CRT techniques may be a reasonable approach.

Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma.

BACKGROUND: Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. METHODS: Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. RESULTS: Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). CONCLUSIONS: Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.

Chemoradiotherapy by intensity-modulated radiation therapy with simultaneous integrated boost in locally advanced or oligometastatic non-small-cell lung cancer-a two center experience.

PURPOSE: Integrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer. METHODS: From 2010-2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used. RESULTS: A total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2-29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6-86.9) and 16.0 months (range 0.2-86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5-36.4) and 12.1 months (95% CI 8.2-16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients. CONCLUSIONS: Chemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.

Comparison of treatment plans for hypofractionated high-dose prostate cancer radiotherapy using the Varian Halcyon and the Elekta Synergy platforms.

PURPOSE: To compare radiotherapy plans between an O-ring and a conventional C-arm linac for hypofractionated high-dose prostate radiotherapy in terms of plan quality, dose distribution, and quality assurance in a multi-vendor environment. METHODS: Twenty prostate cancer treatment plans were irradiated on the O-ring Varian Halcyon linac and were re-optimized for the C-arm Elekta Synergy Agility linac. Dose-volume histogram metrics for target coverage and organ at risk dose, quality assurance, and monitor units were retrospectively compared. Patient-specific quality assurance with ion chamber measurements, gamma index analysis, and portal dosimetry was performed using the Varian Portal Dosimetry system and the ArcCHECK® phantom (Sun Nuclear Corporation). Prostate-only radiotherapy was delivered with simultaneous integrated boost (SIB) volumetric modulated arc therapy (VMAT) in 20 fractions of 2.5/3.0 Gy each. RESULTS: For both linacs, target coverage was excellent and plan quality comparable. Homogeneity in PTVBoost was high for Synergy as well as Halcyon with a mean homogeneity index of 0.07 ± 0.01 and 0.05 ± 0.01, respectively. Mean dose for the organs at risk rectum and bladder differed not significantly between the linacs but were higher for the femoral heads and penile bulb for Halcyon. Quality assurance showed no significant differences in terms of ArcCHECK gamma pass rates. Median pass rate for 3%/2 mm was 99.3% (96.7 to 99.8%) for Synergy and 99.8% (95.6 to 100%) for Halcyon. Agreement between calculated and measured dose was high with a median deviation of -0.6% (-1.7 to 0.8%) for Synergy and 0.2% (-0.6 to 2.3%) for Halcyon. Monitor units were higher for the Halcyon by approximately 20% (p < 0.001). CONCLUSION: Hypofractionated high-dose prostate cancer SIB VMAT on the Halcyon system is feasible with comparable plan quality in reference to a standard C-arm Elekta Synergy linac.

Dose-intensified hypofractionated stereotactic body radiation therapy for painful spinal metastases: Results of a phase 2 study.

BACKGROUND: The objective of this study was to prospectively evaluate dose-intensified hypofractionated stereotactic body radiation therapy (SBRT) in patients with painful spinal metastases in a multicenter, single-arm, phase 2 study. METHODS: Patients with 2 or fewer distinct, noncontiguous, painful, mechanically stable, unirradiated spinal metastases from a solid tumor with a Karnofsky performance status ≥ 60 were eligible. Patients with a long (Mizumoto score ≤ 4) or intermediate overall survival expectancy (Mizumoto score = 5-9) received 48.5 Gy in 10 fractions or 35 Gy in 5 fractions, respectively, with SBRT. The primary outcome was the overall (complete and partial) pain response as measured with international consensus guidelines 3 months after SBRT. RESULTS: There were 57 patients enrolled between 2012 and 2015, and 54 of these patients with 60 painful vertebral metastases were analyzed. The 3-month pain response was evaluated in 42 patients (47 lesions). An overall pain response was observed in 41 lesions (87%), and the pain response remained stable for at least 12 months. The mean maximum pain scores on a visual analogue scale significantly improved from the baseline of 6.1 (standard deviation, 2.5) to 2.0 (standard deviation, 2.3) 3 months after treatment (P < .001). The 5-level EuroQol 5-Dimension Questionnaire quality-of-life (QOL) dimensions (self-reported mobility, usual activities, and pain/discomfort) significantly improved from the baseline to 3 months after treatment. The 12-month overall survival and local control rates were 61.4% (95% confidence interval [CI], 48%-74.8%) and 85.9% (95% CI, 76.7%-95%), respectively. Grade 3 toxicity was limited to acute pain in 1 patient (2%). No patient experienced radiation-induced myelopathy. Six patients (11%) developed progressive vertebral compression fractures (VCFs), and 8 patients (15%) developed new VCFs. CONCLUSIONS: Dose-intensified SBRT achieved durable local metastasis control and resulted in pronounced and long-term pain responses and improved QOL. Cancer 2018;124:2001-9. © 2018 American Cancer Society.

Long-term safety and efficacy of fractionated stereotactic body radiation therapy for spinal metastases.

PURPOSE: Patients with long life expectancy despite metastatic status might benefit from long-term local control of spinal metastases. Dose-intensified radiotherapy (RT) is believed to control tumor growth better and thus offers longer pain relief. This single-institution study reports on fractionated stereotactic body radiation therapy (SBRT) for spinal metastases in patients with good life expectancy based on performance status, extent of metastases, histology, and time to metastasis. METHODS: Between 2004 and 2010, 36 treatment sites in 32 patients (median age 55 years; male 61%; median Karnofsky performance score 85) were treated with fractionated SBRT. The median treatment dose was 60 Gy (range, 48.5-65 Gy) given in a median of 20 fractions (range, 17-33); the median maximum dose to the planning risk volume for the spinal cord (PRV-SC) was 46.6 Gy. RESULTS: All patients suffering from pain prior to RT reported pain relief after treatment; after a median follow-up of 20.3 months, 61% of treatment sites were pain-free, another 25% associated with mild pain. In 86% of treatments, patients were free from neurological symptoms at the time of the last clinical follow-up. Acute grade 1 toxicities (CTCAE 3.0) were observed in 11 patients. Myelopathy did not occur in any patient. Radiologically controlled freedom from local progression was 92 and 84% after 12 and 24 months, respectively. Median overall survival (OS) was 19.6 months. CONCLUSION: Patient selection resulted in long OS despite metastatic disease, and dose-intensified fractionated SBRT for spinal metastases was safe and achieved long-term local tumor control and palliation of pain.

Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center.

In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher Dmean values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0-1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: Dmean bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5-V45 (p < 0.01), Dmean anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and Dmean femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.

Long-Term Results of Dose-Intensified Fractionated Stereotactic Body Radiation Therapy (SBRT) for Painful Spinal Metastases.

PURPOSE: To report long-term outcome of fractionated stereotactic body radiation therapy (SBRT) for painful spinal metastases. METHODS AND MATERIALS: This prospective, single-arm, multicenter phase 2 clinical trial enrolled 57 patients with 63 painful, unirradiated spinal metastases between March 2012 and July 2015. Patients were treated with 48.5 Gy in 10 SBRT fractions (long life expectancy [Mizumoto score ≤4]) or 35 Gy in 5 SBRT fractions (intermediate life expectancy [Mizumoto score 5-9]). Pain response was defined as pain improvement of a minimum of 2 points on a visual analog scale, and net pain relief was defined as the sum of time with pain response (complete and partial) divided by the overall follow-up time. RESULTS: All 57 patients received treatment per protocol; 32 and 25 patients were treated with 10- and 5-fraction SBRT, respectively. The median follow-up of living patients was 60 months (range, 33-74 months). Of evaluable patients, 82% had complete or partial pain response (responders) at 3 months' follow-up (primary endpoint), and pain response remained stable over 5 years. Net pain relief was 74% (95% CI, 65%-80%). Overall survival rates of 1, 3, and 5 years were 59.6% (95% CI, 47%-72%), 33.3% (95% CI, 21%-46%), and 21% (95% CI, 10%-32%), respectively. Freedom from local spinal-metastasis progression was 82% at the last imaging follow-up. Late grade-3 toxicity was limited to pain in 2 patients (nonresponders). There were no cases of myelopathy. SBRT resulted in long-term improvements of all dimensions of the 5-level EuroQol 5-Dimension Questionnaire except anxiety/depression. CONCLUSIONS: Fractionated SBRT achieved durable pain response and improved quality of life at minimum late toxicity.

In-field stereotactic body radiotherapy (SBRT) reirradiation for pulmonary malignancies as a multicentre analysis of the German Society of Radiation Oncology (DEGRO).

Data of thoracic in-field reirradiation with two courses of stereotactic body radiotherapy (SBRT) is scarce. Aim of this study is to investigate feasibility and safety of this approach. Patients with a second course of thoracic SBRT and planning target volume (PTV) overlap were analyzed in this retrospective, multicenter study. All plans and clinical data were centrally collected. 27 patients from 8 centers have been amenable for evaluation: 12 with non-small-cell lung cancer, 16 with metastases, treated from 2009 (oldest first course) to 2020 (latest second course). A median dose of 38.5 Gy to the 65%-isodose over a median of 5 fractions was prescribed in the first course and 40 Gy in 5 fractions for the second SBRT-course. Median PTV of the second SBRT was 29.5 cm3, median PTV overlap 22 cm3. With a median interval of 20.2 months between the two SBRT-courses, 1-year OS, and -LCR were 78.3% and 70.3% respectively. 3 patients developed grade 1 and one grade 2 pneumonitis. No grade > 2 toxicity was observed. Peripheral location and dose were the only factors correlating with tumor control. A second SBRT-course with PTV overlap appears safe and achieves reasonable local control.

Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells.

Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 degrees C for 1h) and X-ray (5 or 10Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

Combination of ionising irradiation and hyperthermia activates programmed apoptotic and necrotic cell death pathways in human colorectal carcinoma cells.

PURPOSE: The malignancy of tumor cells can be attenuated by interfering with cell death pathways. Since hyperthermia (HT) is a very potent radiosensitizer, the influence of HT (41.5 °C for 1 hour) alone and in combination with ionising irradiation (X-ray; 5 Gy or 10 Gy) on the form of cell death as well as on the expression of proteins known to be major components in tumor cells' apoptotic and necrotic pathways were examined in colorectal tumor cells. MATERIAL AND METHODS: The expression of proteins was analysed by western blot and the relative activity of caspases-3/7 by fluorescence- based assay. Colony formation was analysed using the clonogenic assay and cell death was determined with annexin V-FITC/propidium iodide staining. RESULTS: Combining X-ray with HT led to similar activation of caspase-3/7 and p53 expression in comparison to irradiation only while the amount of the pro-apoptotic proteins PUMA and Bax was increased in HCT15 and SW480 cells. HT alone or combinations with X-ray further resulted in a temporarily increased level of the anti-apoptotic protein Bcl-2. Irradiation plus HT further led to an up-regulation of IRF-5. The levels of RIP-1, a marker for programmed necrosis, increased in tumor cells which were treated with HT and/or X-ray. Combining 5 Gy irradiation with HT compared to irradiation resulted in a significantly increased number of necrotic tumor cells and in decreased colony formation. CONCLUSION: The combined treatment of colorectal tumor cells with X-ray and HT activates distinct tumor cell pathways and fosters the early appearance of a necrotic tumor cell phenotype.

Evaluation of intrafraction prostate motion tracking using the Clarity Autoscan system for safety margin validation.

BACKGROUND: The purpose of the study was to monitor intrafraction prostate motion in real-time using transperineal 4D ultrasound (TPUS) and analyze trajectories to validate clinical safety margins. METHODS: 401 trajectories of US monitoring sessions were retrospectively evaluated for 14 patients treated for prostate cancer. The Elekta Clarity Autoscan system was used for intrafraction monitoring along the 3 directions: superior-inferior (SI), left-right (LR) and anterior-posterior (AP). RESULTS: The intrafraction monitoring resulted in a mean prostate displacement of (-0.06 ± 0.49) mm, (-0.09 ± 0.61) mm and (-0.01 ± 0.78) mm in the SI, LR and AP directions, respectively. Even though large deviations up to 8 mm were detected, the frequency of occurrence was less than 0.1%. The prostate moved within ±2 mm in 99%, 98.1%, and 96.6% of the treatment time in the SI, LR and AP directions, respectively. During 100 s of monitoring, the median displacement increased from 0.2 mm to 0.8 mm and the maximum displacements increased from 5.2 mm to 7.8 mm. The majority of displacement values (99%) were within the clinical safety margins which ensures a good target coverage. CONCLUSIONS: The largest variation of intrafraction prostate displacement was observed along the AP direction. Throughout most of the treatment time, the prostate moved within a few millimeters. The extent of prostate displacement increased for longer monitoring times. During most of the tracking time, the prostate position was within the clinically safety margins.

Stereotactic Image Guided Lung Radiation Therapy for Clinical Early Stage Non-Small Cell Lung Cancer: A Long-Term Report From a Multi-Institutional Database of Patients Treated With or Without a Pathologic Diagnosis.

PURPOSE: Early stage lung cancer is treated with stereotactic body radiation therapy (SBRT) in patients who are unable or unwilling to undergo surgical resection. Some patients' comorbidities are so severe that they are unable to even undergo a biopsy. A clinical diagnosis without biopsy before SBRT has been used, but there are limited data on its efficacy. METHODS AND MATERIALS: Data on patients treated with SBRT for non-small cell lung cancer, with and without tissue confirmation, were collected from multiple institutions across Europe, Canada, and the United States. Patients with a minimum of 2 years of comprehensive follow up were selected for analysis. Treatment and patient characteristics were compared. Overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and rates of local recurrence (LR), regional recurrence (RR), and distant metastasis (DM) were calculated and analyzed. RESULTS: A total of 701 patients were identified, of which 67% had tissue confirmation of their tumors. The 3- and 5-year outcomes for OS, CSS, and DFS were 83.8%, 93.1%, 69%, and 60.6%, 86.7%, 45.5%, respectively. The rates for LR, RR, and DM at 3 and 5 years were 6.4%, 9.3%, 14.3%, and 10.5%, 14.3%, 19.7%, respectively. There were no statistically significant differences in survival outcomes or recurrences between the biopsy and no-biopsy cohorts. CONCLUSIONS: SBRT for clinically diagnosed lung cancers is efficacious in appropriately selected patients, with similar outcomes as those with a pathologic diagnosis. Thorough clinical and radiographic evaluations in a multidisciplinary setting are critical to the management of these patients.

Correlating Dose Variables with Local Tumor Control in Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Modeling Study on 1500 Individual Treatments.

BACKGROUND: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription. METHODS AND MATERIALS: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BEDmin); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BEDmax); and (3) the average between near-minimum and near-maximum doses (yielding BEDave). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion. RESULTS: There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BEDave was the best predictor of risk of local recurrence, and a model based on BEDmin had substantially less evidential support. In univariable logistic regression, the model based on BEDave also performed best. Multivariable classification using fast and frugal trees revealed BEDmax to be the most important predictor, followed by BEDave. CONCLUSIONS: BEDave was generally better correlated with tumor control probability than either BEDmax or BEDmin. Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation.

Risk factors for vertebral compression fracture after spine stereotactic body radiation therapy: Long-term results of a prospective phase 2 study.

PURPOSE: To identify frequency, clinical relevance and risk factors for vertebral compression fracture (VCF) after spine stereotactic body radiation therapy (SBRT) with long-term follow up (FU). METHODS: From 2012 to 2015, 61 lesions (56 patients) were treated within a prospective multicenter phase 2 study (NCT01594892) of SBRT for painful vertebral metastases. Post-SBRT VCF were identified. Anatomical segments, normal and tumor tissue of treated vertebrae were segmented for volumetric analyses. Predictive factors for VCF were identified by logistic regression. RESULTS: Median clinical and radiological FU for all patients was 16.2 months (range, 0-68.2) and 7.8 months (range, 0-66.9), respectively. Local metastasis control was observed in 82% of lesions at last imaging FU. Post-SBRT VCF occurred in 21 lesions (34.4%): 16.4% showed a progressive VCF, while a new VCF occurred in 18.0%. 3/56 (5.4%) patients developed painful VCF defined as pain increase by ≥2 on the visual analogue scale (VAS) and 2 (3.6%) patients required surgical stabilization. Pre-SBRT VCF, localization in the thoracic spine, Bilsky score >0, SINS score, pre-SBRT osteolytic volume and metastatic vertebral body (VB) involvement were predictive factors for VCF on univariate analysis. Relative VB involvement, osteolytic volume and pre-SBRT VCF remained in the multivariate logistic regression model that had AUC = 0.930, 83.3% sensitivity and 96.6% specificity. CONCLUSION: Spine SBRT resulted in favorable long-term pain and local metastasis control. Despite post-SBRT VCF being observed after one third of treatments, this was symptomatic in only 5% of patients. Predictive factors for developing VCF were identified which could contribute to better selection of patients for spine SBRT.

Modeling radiation pneumonitis of pulmonary stereotactic body radiotherapy: The impact of a local dose-effect relationship for lung perfusion loss.

PURPOSE: To investigate if a local dose-effect (LDE) relationship for perfusion loss improves the NTCP model fit for SBRT induced radiation pneumonitis (RP) compared to conventional LDEs. METHODS AND MATERIALS: Multi-institutional data of 1015 patients treated with SBRT were analyzed. Dose distributions were converted to NTD with α/ß = 3 Gy. The Lyman-Kutcher-Burman NTCP model was fitted to the incidence grade ≥2 RP by maximum likelihood estimation with mean lung dose (MLD), equivalent uniform doses (EUD) using three LDE functions (power-law (EUDpower), logistic with 2 free parameters (EUDlog-free) and logistic with fixed parameters describing local perfusion loss (EUDPerfusion)) and volume above a threshold dose (Vx). Models were compared with the Akaike weights (Aw) derived from the Akaike information criteria (AIC). RESULTS: The median time to grade ≥2 RP was 4.2 months and plateaued after 17 months at 5.4%. A strong dose-effect relationship for RP incidence was observed. The EUDPerfusion based NTCP model had the lowest AIC. The Aw were 0.53, 0.19, 0.11, 0.11, 0.05 for the EUDPerfusion, Vx, MLD, EUDlog-free and EUDpower LDEs respectively. CONCLUSION: A LDE for perfusion loss provided modest improvement in NTCP model fit for SBRT induced radiation pneumonitis.

Subgroup Survival Analysis in Stage I-II NSCLC Patients With a Central Tumor Partly Treated With Risk-Adapted SBRT.

PURPOSE: Stereotactic body radiation therapy has been associated with increased toxicity when delivered to patients with early-stage non-small cell lung cancer with a tumor within 2 cm of the proximal bronchial tree (PBT). We investigated noncancer deaths for these patients as related to gross tumor volume (GTV) proximity to the PBT, compared with peripheral tumors. METHODS AND MATERIALS: We included 765 patients with early-stage non-small cell lung cancer who were treated with stereotactic body radiation therapy to a median of 3 × 18 Gy. Central tumors were treated with a risk-adapted (less-intense) schedule (mostly 8 fractions) in 55% of the patients in the first-centimeter group and 27% of the patients in the second-centimeter group. An average anatomy with contouring of PBT and organs at risk (OARs) was deformed onto each patient to obtain the distance of the GTV to the PBT and doses to OARs. Log-rank, 1-way analysis of variance, and Cox regressions were performed to assess differences in the first-centimeter, second centimeter, and peripheral groups and associations with noncancer deaths. RESULTS: The median overall survival was 42.7 months, the median noncancer death occurred in 57.3 months, and the median follow-up was 34.8 months. Noncancer death in the first-centimeter group (31 patients) was significantly different from noncancer death in the other groups, with a hazard ratio of 3.175 (P < .001). Noncancer death in the second-centimeter group (71 patients) was not different from noncancer death in the peripheral group (P = .53). Doses to OARs were higher in the first- and second-centimeter groups than in the peripheral group for all OARs. High dose to the PBT was associated with noncancer death (D1%; hazard ratio, 1.006 Gy-1; P = .003). CONCLUSIONS: Patients with a GTV in the first centimeter surrounding the PBT died more often from causes other than cancer compared with other patients. Noncancer death in patients with a GTV in the second centimeter, who partly received a risk-adapted schedule, was comparable to that in patients with a peripheral tumor.

Histopathological Findings After Reirradiation Compared to First Irradiation of Spinal Bone Metastases With Stereotactic Body Radiotherapy: A Cohort Study.

BACKGROUND: Stereotactic body radiotherapy (SBRT) of the spine provides superior tumor control, but vertebral compression fractures are increased and the pathophysiological process underneath is not well understood. Data on histopathological changes, particularly after salvage SBRT (sSBRT) following conventional irradiation, are scarce. OBJECTIVE: To investigate surgical specimens after sSBRT and primary SBRT (pSBRT) regarding histopathological changes. METHODS: We assessed 704 patients treated with spine SBRT 2006 to 2012. Thirty patients underwent salvage surgery; 23 histopathological reports were available. Clinical and histopathological findings were analyzed for sSBRT (69.6%) and pSBRT (30.4%). RESULTS: Mean time to surgery after sSBRT/pSBRT was 8.3/10.3 mo (P = .64). Reason for surgery included pain (sSBRT/pSBRT: 12.5%/71.4%, P = .25), fractures (sSBRT/pSBRT: 37.5%/28.6%, P = .68), and neurological symptoms (sSBRT/pSBRT: 68.8%/42.9%, P = .24). Radiological tumor progression after sSBRT/pSBRT was seen in 71.4%/42.9% (P = .2). Most specimens displayed viable/proliferative tumor (sSBRT/pSBRT: 62.5%/71.4%, P = .68 and 56.3%/57.1%, P = .97). Few specimens showed soft tissue necrosis (sSBRT/pSBRT: 20%/28.6%, P = .66), osteonecrosis (sSBRT/pSBRT: 14.3%/16.7%, P = .89), or bone marrow fibrosis (sSBRT/pSBRT: 42.9%/33.3%, P = .69). Tumor bed necrosis was more common after sSBRT (81.3%/42.9%, P = .066). Radiological tumor progression correlated with viable/proliferative tumor (P = .03/P = .006) and tumor bed necrosis (P = .03). Fractures were increased with bone marrow fibrosis (P = .07), but not with osteonecrosis (P = .53) or soft tissue necrosis (P = .19). Neurological symptoms were common with radiological tumor progression (P = .07), but not with fractures (P = .18). CONCLUSION: For both, sSBRT and pSBRT, histopathological changes were similar. Neurological symptoms were attributable to tumor progression and pathological fractures were not associated with osteonecrosis or tumor progression.

Predictors and Patterns of Regional Recurrence Following Lung SBRT: A Report From the Elekta Lung Research Group.

INTRODUCTION: The objective of this study was to determine the predictors and patterns of regional recurrence (RR) following stereotactic body radiotherapy (SBRT) for primary lung cancers. MATERIAL AND METHODS: Details of patient factors, treatment, and outcome factors were extracted from a multi-institutional (5) database. All events were calculated from the end of radiotherapy. Estimates of local recurrence, RR, and distant metastases (DM) were calculated using the competing risk method. Cause-specific and overall survival were calculated using the Kaplan-Meier method. Details of locations and number of simultaneous RRs were categorized by lymph node anatomic station. RESULTS: A total of 734 patients were analyzed. The median follow-up was 3.0 years in surviving patients. Four hundred seventy-six (65%) patients had pathologic proof of disease. There were 64 patients with RR. The 2-year local recurrence, RR, and distant metastases rates were 5.6%, 9.0%, and 14.6% respectively. The 2-year cause-specific and overall survival were 89.9% and 63.7%, respectively. There were 136 simultaneous sites of RR. There were 21 recurrences in stations 4R (15.4%), 9 (6.6%) in 4L, 30 (22%) in 7, 19 (13.9%) in 10R, and 14 (10.3%) in 10L. The most common stations for isolated recurrence (n = 19) were station 7 (n = 5; 26.3%) and station 10R (n = 6; 31.6%). The most common RR levels were stations 4 and 7 for right and left upper lobe, stations 5, 7, and 10 for left lower lobe tumors, and stations 7 and 10 for right lower lobe tumors. CONCLUSION: Stations 4, 7, and 10 were the most common stations for RR. These patterns of recurrence may guide nodal staging procedures prior to SBRT.

Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.

BACKGROUND AND PURPOSE: To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively. RESULTS: Median follow-up was 34.8months. Two year Kaplan-Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009-197, HR=1.005, p-value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003-70, HR=1.025, p-value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death. CONCLUSIONS: Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied.