I. Thibault

Vertebral Compression Fracture After Spine Stereotactic Body Radiotherapy: A Multi-Institutional Analysis With a Focus on Radiation Dose and the Spinal Instability Neoplastic Score

PURPOSE Vertebral compression fracture (VCF) is increasingly recognized as an adverse event after spine stereotactic body radiotherapy (SBRT). We report a multi-institutional study aimed at clarifying the risk and predictive factors associated with VCF. PATIENTS AND METHODS A total of 252 patients with 410 spinal segments treated with SBRT were included. The primary outcome was the development of VCF (a new VCF or progression of a baseline VCF). In addition to various patient-, treatment-, and tumor-specific factors, the Spinal Instability Neoplastic Scoring (SINS) system was applied to determine predictive value. RESULTS The median follow-up was 11.5 months (range, 0.03 to 113 months). The median and mean overall survival rates were 16 and 26 months, respectively. We observed 57 fractures (57 of 410, 14%), with 47% (27 of 57) new fractures and 53% (30 of 57) fracture progression. The median time to VCF was 2.46 months (range, 0.03 to 43.01 months), and 65% occurred within the first 4 months. The 1- and 2-year cumulative incidences of fracture were 12.35% and 13.49%, respectively. Multivariable analysis identified dose per fraction (greatest risk for ≥ 24 Gy v 20 to 23 Gy v ≤ 19 Gy), in addition to three of the six original SINS criteria: baseline VCF, lytic tumor, and spinal deformity, as significant predictors of VCF. CONCLUSION Caution must be observed when treating with ≥ 20 Gy/fraction, in particular, for patients with lytic tumor, spinal misalignment, and a baseline VCF. Frequent short-term follow-up is required, as nearly two thirds of all VCF occurred within the first 4 months. We also conclude that SINS may have utility in predicting patients at high risk of SBRT-induced VCF.

Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture

OBJECT The aim of this study was to evaluate local control (LC) and the risk of vertebral compression fracture (VCF) after stereotactic body radiotherapy (SBRT) in patients with renal cell cancer spinal metastases. METHODS Prospectively collected data on 71 spinal segments treated with SBRT in 37 patients were reviewed. The median follow-up was 12.3 months (range 1.2-55.4 months). The LC rate was assessed based on each spinal segment treated and overall survival (OS) according to each patient treated. Sixty of 71 segments (85%) were radiation naive, 11 of 71 (15%) were previously irradiated, and 10 of 71 (14%) were treated with postoperative SBRT. The median SBRT total dose and number of fractions were 24 Gy and 2, respectively. The VCF analysis also included evaluation of the Spinal Instability Neoplastic Score criteria. RESULTS The 1-year OS and LC rates were 64% and 83%, respectively. Multivariate analysis identified oligometastatic disease (13 of 37 patients) as a positive prognostic factor (p = 0.018) for OS. Of 61 non-postoperative spinal segments treated, 10 (16%) developed VCFs; 3 of 10 were de novo VCFs and 7 of 10 occurred as progression of an existing VCF. The 1-year VCF-free probability rate was 82%. Multivariate analysis identified single-fraction SBRT and baseline VCF as significant predictors of SBRT-induced VCF (p = 0.028 and p = 0.012, respectively). CONCLUSIONS Spine SBRT yields high rates of local tumor control in patients with renal cell cancer. Baseline VCF and 18-24 Gy delivered in a single fraction were predictive of further collapse. Patients with oligometastatic disease may benefit most from such aggressive local therapy, given the prolonged survival observed.

Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy.

BACKGROUND Spine stereotactic body radiotherapy (SBRT) is increasingly being applied to the postoperative spine metastases patient. Our aim was to identify clinical and dosimetric predictors of local control (LC) and survival. METHODS Eighty patients treated between October 2008 and February 2012 with postoperative SBRT were identified from our prospective database and retrospectively reviewed. RESULTS The median follow-up was 8.3 months. Thirty-five patients (44%) were treated with 18-26 Gy in 1 or 2 fractions, and 45 patients (56%) with 18-40 Gy in 3-5 fractions. Twenty-one local failures (26%) were observed, and the 1-year LC and overall survival (OS) rates were 84% and 64%, respectively. The most common site of failure was within the epidural space (15/21, 71%). Multivariate proportional hazards analysis identified systemic therapy post-SBRT as the only significant predictor of OS (P = .02) and treatment with 18-26 Gy/1 or 2 fractions (P = .02) and a postoperative epidural disease grade of 0 or 1 (0, no epidural disease; 1, epidural disease that compresses dura only, P = .003) as significant predictors of LC. Subset analysis for only those patients (n = 48/80) with high-grade preoperative epidural disease (cord deformed) indicated significantly greater LC rates when surgically downgraded to 0/1 vs 2 (P = .0009). CONCLUSIONS Postoperative SBRT with high total doses ranging from 18 to 26 Gy delivered in 1-2 fractions predicted superior LC, as did postoperative epidural grade.

Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.

The SPine response assessment In Neuro-Oncology (SPINO) group is a committee of the Response Assessment in Neuro-Oncology working group and comprises a panel of international experts in spine stereotactic body radiotherapy (SBRT). Here, we present the groups first report on the challenges in standardising imaging-based assessment of local control and pain for spinal metastases. We review current imaging modalities used in SBRT treatment planning and tumour assessment and review the criteria for pain and local control in registered clinical trials specific to spine SBRT. We summarise the results of an international survey of the panel to establish the range of current practices in assessing tumour response to spine SBRT. The ultimate goal of the SPINO group is to report consensus criteria for tumour imaging, clinical assessment, and symptom-based response criteria to help standardise future clinical trials.

Inverse-planned gynecologic high-dose-rate interstitial brachytherapy: Clinical outcomes and dose–volume histogram analysis

PURPOSE To present clinical outcomes and dose-volume histogram parameters of three-dimensional image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with primary or recurrent gynecologic cancer unsuitable for intracavitary brachytherapy (ICB). METHODS AND MATERIALS Records of 43 women treated between 2001 and 2009 with iridium-192 gynecologic HDR-ISBT boost, using a Syed-Neblett template and inverse planning simulated annealing dose optimization, were reviewed. Median HDR-ISBT dose was 30Gy, delivered in 4-6Gy/fraction. Dose-volume histogram parameters recommended by the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology for image-based ICB were analyzed. Total doses were normalized to 2Gy fractions (biologically equivalent dose in 2Gy fractions). Local control (LC) and survival were calculated using Kaplan-Meier method. Toxicities were defined according to Common Terminology Criteria for Adverse Events v3.0. RESULTS There were 34 primary malignancies (cervix=12, vagina=15, Bartholins gland=5, and vulva=2) and 9 recurrences. International Federation of Gynecology and Obstetrics stage distribution for primary cancers was I=2, II=13, III=15, and IV=4. Median followup was 19.3 months (range, 0-92.2). Two-year LC was 87% for primary cancers, and 45% for recurrent cancers, respectively (p=0.0175). Median V(100), D(90), and D(100) for clinical target volume were 97.6%, 90.2, and 68.7Gy(10), respectively. Median bladder and rectal D(2)(cc) were 76.6 and 79.5Gy(3), respectively. Median urethral D(10) was 80.6Gy(3). Twelve patients experienced Grades 3 and 4 late morbidity, but toxicities were transient. Only 2 patients had persistent severe toxicities. A trend toward increased risk for vaginal necrosis was observed with a clinical target volume >84cc. CONCLUSIONS HDR-ISBT may achieve good LC in gynecologic cancer unsuitable for ICB, especially in primary malignancies with a 2-year LC rate higher than 85%. Delivery of such high doses has potential advantages but may predispose to adverse effects, reversible in most cases.

Salvage Stereotactic Body Radiotherapy (SBRT) Following In-Field Failure of Initial SBRT for Spinal Metastases

PURPOSE We report our experience in salvaging spinal metastases initially irradiated with stereotactic body radiation therapy (SBRT), who subsequently progressed with imaging-confirmed local tumor progression, and were re-irradiated with a salvage second SBRT course to the same level. METHODS AND MATERIALS From a prospective database, 56 metastatic spinal segments in 40 patients were identified as having been irradiated with a salvage second SBRT course to the same level. In addition, 24 of 56 (42.9%) segments had initially been irradiated with conventional external beam radiation therapy before the first course of SBRT. Local control (LC) was defined as no progression on magnetic resonance imaging at the treated segment, and calculated according to the competing risk model. Overall survival (OS) was evaluated for each patient treated by use of the Kaplan-Meier method. RESULTS The median salvage second SBRT total dose and number of fractions was 30 Gy in 4 fractions (range, 20-35 Gy in 2-5 fractions), and for the first course of SBRT was 24 Gy in 2 fractions (range, 20-35 Gy in 1-5 fractions). The median follow-up time after salvage second SBRT was 6.8 months (range, 0.9-39 months), the median OS was 10.0 months, and the 1-year OS rate was 48%. A longer time interval between the first and second SBRT courses predicted for better OS (P=.02). The crude LC was 77% (43/56), the 1-year LC rate was 81%, and the median time to local failure was 3.0 months (range, 2.7-16.7 months). Of the 13 local failures, 85% (11/13) and 46% (6/13) showed progression within the epidural space and paraspinal soft tissues, respectively. Absence of baseline paraspinal disease predicted for better LC (P<.01). No radiation-induced vertebral compression fractures or cases of myelopathy were observed. CONCLUSION A second course of spine SBRT, most often with 30 Gy in 4 fractions, for spinal metastases that failed initial SBRT is a feasible and efficacious salvage treatment option.

Predictors of Chest Wall Toxicity after Lung Stereotactic Ablative Radiotherapy

AIMS To determine the incidence and predictive factors of rib fracture and chest wall pain after lung stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS Patients were treated with lung SABR of 48-60 Gy in four to five fractions. The treatment plan and follow-up computed tomography scans of 289 tumours in 239 patients were reviewed. Dose-volume histogram (DVH) metrics and clinical factors were evaluated as potential predictors of chest wall toxicity. RESULTS The median follow-up was 21.0 months (range 6.2-52.1). Seventeen per cent (50/289) developed a rib fracture, 44% (22/50) were symptomatic; the median time to fracture was 16.4 months. On univariate analysis, female gender, osteoporosis, tumours adjacent (within 5 mm) to the chest wall and all of the chest wall DVH metrics predicted for rib fracture, but only tumour location adjacent to the chest wall remained significant on the multivariate model (P < 0.01). The 2 year fracture-free probability for those adjacent to the chest wall was 65.6%. Among those tumours adjacent to the chest wall, only osteoporosis (P = 0.02) predicted for fracture, whereas none of the chest wall DVH metrics were predictive. Eight per cent (24/289) experienced chest wall pain without fracture. CONCLUSIONS None of the chest wall DVH metrics independently predicted for SABR-induced rib fracture when tumour location is taken into account. Patients with tumours adjacent (within 5 mm) to the chest wall are at greater risk of rib fracture after lung SABR, and among these, an additional risk was observed in osteoporotic patients.

Sensitivity of myofibroblasts to H2O2-mediated apoptosis and their antioxidant cell network.

During wound healing, the transition from granulation to scar tissue shows a decrease in myofibroblast cellularity. Previous results have correlated the disappearance of these cells with the induction of apoptotic cell death by some unknown stimuli. In contrast, hypertrophic scar appearance after wound healing is thought to be linked to a disorder of apoptotic function which induces myofibroblast persistence in granulation tissue. Oxidative stress being an important mediator of apoptosis, we have evaluated the apoptotic response of normal and pathological wound myofibroblasts (WMyo and HMyo respectively) in their interaction with two oxidative stress inducers: hydrogen peroxide, using a high concentration as a single dose, and sodium ascorbate which induced a continuous release of H2O2 at a low concentration. Our results showed that, according to the H2O2 treatment type, HMyo were more sensitive (after ascorbate treatment) or less sensitive (after H2O2 treatment) when compared to WMyo and Fb. We next assessed the presence of several molecules known to be involved in the antioxidant network protecting cells against H2O2 injury and found HMyo to have a higher level of activity of glutathione peroxidase and a lower level of activity of catalase than WMyo. These results can help explain the contradictory responses of myofibroblasts according to the oxidative stress treatment. This is the first study linking refractory oxidative stress mediated cell death to cellular phenotype in hypertrophic myofibroblasts, and indicates a pivotal role for the antioxidant enzyme system in this type of resistance.

The emerging roles of stereotactic ablative radiotherapy for metastatic renal cell carcinoma.

Purpose of reviewTo discuss the emerging roles of stereotactic ablative radiotherapy (SABR) in patients with metastatic renal cell carcinoma (RCC). Recent findingsRCC tumours are not as radio-resistant as previously thought, as local control rates of tumours treated with SABR are high. Therefore, SABR is an attractive treatment option for RCC tumours in which effective long-term palliation of symptoms or local control is desired. Like surgical resection of metastatic tumours, SABR can also be used as a method of eradicating oligometastases to potentially ‘cure’ or offer prolonged disease-free survival in patients with low-volume metastatic disease. In patients who develop progression of a solitary or few tumours (termed oligoprogression), SABR to the progressing ‘rogue’ tumours may delay the need to start or change systemic therapy. Finally, there is the potential for SABR to improve the efficacy of immunotherapy for metastatic RCC, given the known immune-modulated abscopal effect of radiotherapy. SummarySABR is increasingly being used in metastatic RCC patients, given the great potential to improve various outcomes. More prospective clinical trials are needed to identify and quantify the clinical benefits.

A comparison between accelerated hypofractionation and stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC): Results of a propensity score-matched analysis

BACKGROUND AND PURPOSE Stereotactic ablative radiotherapy (SABR) has become standard for inoperable early-stage non-small cell lung cancer (NSCLC). However, there is no randomized evidence demonstrating benefit over more fractionated radiotherapy. We compared accelerated hypofractionation (AH) and SABR using a propensity score-matched analysis. MATERIALS AND METHODS From 1997-2007, 119 patients (T1-3N0M0 NSCLC) were treated with AH (48-60 Gy, 12-15 fractions). Prior to SABR, this represented our institutional standard. From 2008-2012, 192 patients (T1-3N0M0 NSCLC) were treated with SABR (48-52 Gy, 4-5 fractions). A total of 114 patients (57 per cohort) were matched (1:1 ratio, caliper: 0.10) using propensity scores. RESULTS Median follow-up (range) for the AH cohort was 36.3 (2.5-109.1) months, while that for the SABR group was 32.5 (0.3-62.6)months. Three-year overall survival (OS) and local control (LC) rates were 49.5% vs. 72.4% [p=0.024; hazard ratio (HR): 2.33 (1.28, 4.23), p=0.006] and 71.9% vs. 89.3% [p=0.077; HR: 5.56 (1.53, 20.2), p=0.009], respectively. On multivariable analysis, tumour diameter and PET staging were predictive for OS, while the only predictive factor for LC was treatment cohort. CONCLUSIONS OS and LC were improved with SABR, although OS is more closely related to non-treatment factors. This represents one of the few studies comparing AH to SABR for early-stage lung cancer.