Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following ...spinal cord point maximum doses (Dmax) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD22) Dmax ≤70 Gy; SBRT thecal sac EQD22 Dmax ≤25 Gy, thecal sac SBRT EQD22 Dmax to cumulative EQD22 Dmax ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.
To develop consensus contouring guidelines for postoperative stereotactic body radiation therapy (SBRT) for spinal metastases.
Ten spine SBRT specialists representing 10 international centers ...independently contoured the clinical target volume (CTV), planning target volume (PTV), spinal cord, and spinal cord planning organ at risk volume (PRV) for 10 representative clinical scenarios in postoperative spine SBRT for metastatic solid tumor malignancies. Contours were imported into the Computational Environment for Radiotherapy Research. Agreement between physicians was calculated with an expectation minimization algorithm using simultaneous truth and performance level estimation with κ statistics. Target volume definition guidelines were established by finding optimized confidence level consensus contours using histogram agreement analyses.
Nine expert radiation oncologists and 1 neurosurgeon completed contours for all 10 cases. The mean sensitivity and specificity were 0.79 (range, 0.71-0.89) and 0.94 (range, 0.90-0.99) for the CTV and 0.79 (range, 0.70-0.95) and 0.92 (range, 0.87-0.99) for the PTV), respectively. Mean κ agreement, which demonstrates the probability that contours agree by chance alone, was 0.58 (range, 0.43-0.70) for CTV and 0.58 (range, 0.37-0.76) for PTV (P<.001 for all cases). Optimized consensus contours were established for all patients with 80% confidence interval. Recommendations for CTV include treatment of the entire preoperative extent of bony and epidural disease, plus immediately adjacent bony anatomic compartments at risk of microscopic disease extension. In particular, a "donut-shaped" CTV was consistently applied in cases of preoperative circumferential epidural extension, regardless of extent of residual epidural extension. Otherwise more conformal anatomic-based CTVs were determined and described. Spinal instrumentation was consistently excluded from the CTV.
We provide consensus contouring guidelines for common scenarios in postoperative SBRT for spinal metastases. These consensus guidelines are subject to clinical validation.
Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in ...which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma.
We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.
Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months 95% confidence interval (CI), 15.9-NA with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization.
Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1-5 fractions of stereotactic body ...radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM).
Spinal cord dose-volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P(max)), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/β = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy(2/2)).
The initial conventional radiotherapy nBED ranged from ~30 to 50 Gy(2/2) (median ~40 Gy(2/2)). The SBRT reirradiation thecal sac mean P(max) nBED in the no-RM group was 20.0 Gy(2/2) (95% confidence interval CI, 10.8-29.2), which was significantly lower than the corresponding 67.4 Gy(2/2) (95% CI, 51.0-83.9) in the RM group. The mean total P(max) nBED in the no-RM group was 62.3 Gy(2/2) (95% CI, 50.3-74.3), which was significantly lower than the corresponding 105.8 Gy(2/2) (95% CI, 84.3-127.4) in the RM group. The fraction of the total P(max) nBED accounted for by the SBRT P(max) nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53.
SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P(max) nBED of 20-25 Gy(2/2) appears to be safe provided the total P(max) nBED does not exceed approximately 70 Gy(2/2), and the SBRT thecal sac P(max) nBED comprises no more than approximately 50% of the total nBED.
Stereotactic radiosurgery (SRS), typically administered in a single session, is widely employed to safely, efficiently, and effectively treat small intracranial lesions. However, for large lesions or ...those in close proximity to critical structures, it can be difficult to obtain an acceptable balance of tumor control while avoiding damage to normal tissue when single-fraction SRS is utilized. Treating a lesion in 2 to 5 fractions of SRS (termed "hypofractionated SRS" HF-SRS) potentially provides the ability to treat a lesion with a total dose of radiation that provides both adequate tumor control and acceptable toxicity. Indeed, studies of HF-SRS in large brain metastases, vestibular schwannomas, meningiomas, and gliomas suggest that a superior balance of tumor control and toxicity is observed compared with single-fraction SRS. Nonetheless, a great deal of effort remains to understand radiobiologic mechanisms for HF-SRS driving the dose-volume response relationship for tumors and normal tissues and to utilize this fundamental knowledge and the results of clinic studies to optimize HF-SRS. In particular, the application of HF-SRS in the setting of immunomodulatory cancer therapies offers special challenges and opportunities.
Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This ...study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery.
Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines.
Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic disease along the circumference of the epidural space.
This report provides consensus guidelines for target volume definition for spinal metastases receiving upfront SRS in common clinical situations.
Summary 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 group's 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.
Dose-volume histogram (DVH) results for 9 cases of post spine stereotactic body radiation therapy (SBRT) radiation myelopathy (RM) are reported and compared with a cohort of 66 spine SBRT patients ...without RM.
DVH data were centrally analyzed according to the thecal sac point maximum (Pmax) volume, 0.1- to 1-cc volumes in increments of 0.1 cc, and to the 2 cc volume. 2-Gy biologically equivalent doses (nBED) were calculated using an α/β = 2 Gy (units = Gy(2/2)). For the 2 cohorts, the nBED means and distributions were compared using the t test and Mann-Whitney test, respectively. Significance (P<.05) was defined as concordance of both tests at each specified volume. A logistic regression model was developed to estimate the probability of RM using the dose distribution for a given volume.
Significant differences in both the means and distributions at the Pmax and up to the 0.8-cc volume were observed. Concordant significance was greatest for the Pmax volume. At the Pmax volume the fit of the logistic regression model, summarized by the area under the curve, was 0.87. A risk of RM of 5% or less was observed when limiting the thecal sac Pmax volume doses to 12.4 Gy in a single fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions.
We report the first logistic regression model yielding estimates for the probability of human RM specific to SBRT.
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