Efficacy and safety of SBRT for spine metastases: A systematic review and meta-analysis for preparation of an ESTRO practice guideline.

BACKGROUND AND PURPOSE: Advances in characterizing cancer biology and the growing availability of novel targeted agents and immune therapeutics have significantly changed the prognosis of many patients with metastatic disease. Palliative radiotherapy needs to adapt to these developments. In this study, we summarize the available evidence for stereotactic body radiotherapy (SBRT) in the treatment of spinal metastases. MATERIALS AND METHODS: A systematic review and meta-analysis was performed using PRISMA methodology, including publications from January 2005 to September 2021, with the exception of the randomized phase III trial RTOG-0631 which was added in April 2023. Re-irradiation was excluded. For meta-analysis, a random-effects model was used to pool the data. Heterogeneity was assessed with the I2-test, assuming substantial and considerable as I2 > 50 % and I2 > 75 %, respectively. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 69 studies assessing the outcomes of 7236 metastases in 5736 patients were analyzed. SBRT for spine metastases showed high efficacy, with a pooled overall pain response rate of 83 % (95 % confidence interval [CI] 68 %-94 %), pooled complete pain response of 36 % (95 % CI: 20 %-53 %), and 1-year local control rate of 94 % (95 % CI: 86 %-99 %), although with high levels of heterogeneity among studies (I2 = 93 %, I2 = 86 %, and 86 %, respectively). Furthermore, SBRT was safe, with a pooled vertebral fracture rate of 9 % (95 % CI: 4 %-16 %), pooled radiation induced myelopathy rate of 0 % (95 % CI 0-2 %), and pooled pain flare rate of 6 % (95 % CI: 3 %-17 %), although with mixed levels of heterogeneity among the studies (I2 = 92 %, I2 = 0 %, and 95 %, respectively). Only 1.7 % of vertebral fractures required surgical stabilization. CONCLUSION: Spine SBRT is characterized by a favorable efficacy and safety profile, providing durable results for pain control and disease control, which is particularly relevant for oligometastatic patients.

ESTRO clinical practice guideline: Stereotactic body radiotherapy for spine metastases.

BACKGROUND AND PURPOSE: Recent progress in diagnostics and treatment of metastatic cancer patients have improved survival substantially. These developments also affect local therapies, with treatment aims shifting from short-term palliation to long-term symptom or disease control. There is consequently a need to better define the value of stereotactic body radiotherapy (SBRT) for the treatment of spinal metastases. METHODS: This ESTRO clinical practice guideline is based on a systematic literature review conducted according to PRISMA standards, which formed the basis for answering four key questions about the indication and practice of SBRT for spine metastases. RESULTS: The analysis of the key questions based on current evidence yielded 22 recommendations and 5 statements with varying levels of endorsement, all achieving a consensus among experts of at least 75%. In the majority, the level of evidence supporting the recommendations and statements was moderate or expert opinion, only, indicating that spine SBRT is still an evolving field of clinical research. Recommendations were established concerning the selection of appropriate patients with painful spine metastases and oligometastatic disease. Recommendations about the practice of spinal SBRT covered technical planning aspects including dose and fractionation, patient positioning, immobilization and image-guided SBRT delivery. Finally, recommendations were developed regarding quality assurance protocols, including description of potential SBRT-related toxicity and risk mitigation strategies. CONCLUSIONS: This ESTRO clinical practice guideline provides evidence-based recommendations and statements regarding the selection of patients with spinal metastases for SBRT and its safe implementation and practice. Enrollment of patients into well-designed prospective clinical trials addressing clinically relevant questions is considered important.

Influence of volumetric modulated arc therapy and FET-PET scanning on treatment outcomes for glioblastoma patients.

BACKGROUND: We sought to assess the influence of the clinical introduction of new radiotherapy technologies on glioblastoma patients' outcomes. METHODS: Newly diagnosed glioblastoma patients treated with 60 Gy and temozolomide (2005-2014) were analyzed. The patients' GTV and CTV were defined based on MR (n = 521) or FET-PET/MR (n = 190), and were treated using conformal radiotherapy (CRT, n = 159) or image-guided volumetric modulated arc therapy with hippocampal sparing (IG-VMAT, n = 362). Progression-free survival (PFS) was assessed using the McDonald criteria. Associations between clinical data, dosimetry data, treatment technology, for PFS and overall survival (OS) were explored. RESULTS: The PFS (7 months) and OS (15 months) were unaffected by CRT, IG-VMAT and FET-PET technology. Mean brain dose was correlated with tumor volume, and was lower for IG-VMAT vs. CRT (p < 0.001). Larger mean brain dose was associated with inferior PFS (univariate/multivariate Cox models, p < 0.001) and OS (univariate, p < 0.001). Multivariate Cox models revealed association of larger mean brainstem dose (p < 0.001), BTV (p = 0.045), steroid use at baseline (p = 0.003), age (p = 0.019) and MGMT status (p = 0.022) with lower OS. CONCLUSIONS: Introduction of hippocampal-sparing IG-VMAT technology appeared to be safe, and may have reduced toxicity and cognitive impairment. Larger mean brain dose was strongly associated with inferior PFS and OS.

Injectable silver nanosensors: in vivo dosimetry for external beam radiotherapy using positron emission tomography.

Development of safe and efficient radiotherapy routines requires quantification of the delivered absorbed dose to the cancer tissue in individual patients. In vivo dosimetry can provide accurate information about the absorbed dose delivered during treatment. In the current study, a novel silver-nanosensor formulation based on poly(vinylpyrrolidinone)-coated silver nanoparticles formulated in a gelation matrix composed of sucrose acetate isobutyrate has been developed for use as an in vivo dosimeter for external beam radiotherapy. In situ photonuclear reactions trigger the formation of radioactive (106)Ag, which enables post treatment verification of the delivered dose using positron emission tomography imaging. The silver-nanosensor was investigated in a tissue equivalent thorax phantom using clinical settings and workflow for both standard fractionated radiotherapy (2 Gy) and stereotactic radiotherapy (10- and 22 Gy) in a high-energy beam setting (18 MV). The developed silver-nanosensor provided high radiopacity on the planning CT-scans sufficient for patient positioning in image-guided radiotherapy and provided dosimetric information about the absorbed dose with a 10% and 8% standard deviation for the stereotactic regimens, 10 and 22 Gy, respectively.

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy.

OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT.

Doses to head and neck normal tissues for early stage Hodgkin lymphoma after involved node radiotherapy.

PURPOSE: To evaluate dose plans for head and neck organs at risk (OARs) for classical Hodgkin lymphoma (HL) patients using involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), and intensity modulated proton therapy (PT), in comparison to the past mantle field (MF). MATERIALS AND METHODS: Data from 37 patients with cervical lymph node involvement were used. All patients originally received chemotherapy followed by 3DCRT-INRT (30.6 Gy). A VMAT-INRT, PT-INRT (both 30.6 Gy), and a MF plan (36 Gy) were simulated. Doses to head and neck OARs were compared with cumulative DVHs and repeated measures ANOVA. RESULTS: The estimated median mean doses were 15.3, 19.3, 15.4, and 37.3 Gy (thyroid), 10.9, 12.0, 7.9, and 34.5 Gy (neck muscles), 2.3, 11.1, 1.8, and 37.1 Gy (larynx), 1.7, 5.1, 1.3, and 23.8 Gy (pharynx), 0.5, 0.8, 0.01, and 32.3 Gy (ipsilateral parotid), and 2.4, 3.8, 0.7, and 34.7 Gy (ipsilateral submandibular) with 3DCRT, VMAT, PT, and MF (all p<0.0001), respectively. CONCLUSION: The use of INRT significantly lowered the estimated radiation dose to the head and neck OARs. VMAT appeared suboptimal compared to 3DCRT and PT, and for some patients, PT offered an additional gain.

Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). PATIENTS AND METHODS: For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. RESULTS: 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. CONCLUSIONS: In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.

Interobserver delineation variation in lung tumour stereotactic body radiotherapy.

OBJECTIVES: In radiotherapy, delineation uncertainties are important as they contribute to systematic errors and can lead to geographical miss of the target. For margin computation, standard deviations (SDs) of all uncertainties must be included as SDs. The aim of this study was to quantify the interobserver delineation variation for stereotactic body radiotherapy (SBRT) of peripheral lung tumours using a cross-sectional study design. METHODS: 22 consecutive patients with 26 tumours were included. Positron emission tomography/CT scans were acquired for planning of SBRT. Three oncologists and three radiologists independently delineated the gross tumour volume. The interobserver variation was calculated as a mean of multiple SDs of distances to a reference contour, and calculated for the transversal plane (SD(trans)) and craniocaudal (CC) direction (SD(cc)) separately. Concordance indexes and volume deviations were also calculated. RESULTS: Median tumour volume was 13.0 cm(3), ranging from 0.3 to 60.4 cm(3). The mean SD(trans) was 0.15 cm (SD 0.08 cm) and the overall mean SD(cc) was 0.26 cm (SD 0.15 cm). Tumours with pleural contact had a significantly larger SD(trans) than tumours surrounded by lung tissue. CONCLUSIONS: The interobserver delineation variation was very small in this systematic cross-sectional analysis, although significantly larger in the CC direction than in the transversal plane, stressing that anisotropic margins should be applied. This study is the first to make a systematic cross-sectional analysis of delineation variation for peripheral lung tumours referred for SBRT, establishing the evidence that interobserver variation is very small for these tumours.

An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

Reference dosimetry at the neutron capture therapy facility at Studsvik.

The purpose of this publication was to present and evaluate the methods for reference dosimetry in the epithermal neutron beam at the neutron capture therapy facility at Studsvik. Measurements were performed in a PMMA phantom and in air using ionization chambers and activation probes in order to calibrate the epithermal neutron beam. Appropriate beam-dependant calibration factors were determined using Monte Carlo methods for the detectors used in the present publication. Using the presented methodology, the photon, neutron and total absorbed dose to PMMA was determined with an estimated uncertainty of +/- 5.0%, +/- 25%, and +/- 5.5% (2 SD), respectively. The uncertainty of the determination of the photon absorbed dose was comparable to the case in conventional radiotherapy, while the uncertainty of the neutron absorbed dose is much higher using the present methods. The thermal neutron group fluence, i.e., the neutron fluence in the energy interval 0-0.414 eV, was determined with an estimated uncertainty of +/- 2.8% (2 SD), which is acceptable for dosimetry in epithermal neutron beams.

Photon quality correction factors for ionization chambers in an epithermal neutron beam.

Photon quality correction factors (kQy) for ionization chamber photon dosimetry in an epithermal neutron beam were determined according to a modified absorbed dose to water formalism which was extended to mixed radiation fields. We have studied two commercially available ionization chambers in the epithermal neutron beam optimized for BNCT at the facility at Studsvik, Sweden. One of the chambers is nominally neutron insensitive; a magnesium-walled detector flushed with pure argon gas (denoted by Mg/Ar). The second chamber has approximately the same sensitivity for neutrons and photons; it is considered a 'tissue equivalent' detector, with A-150 walls flushed with methane-based tissue-equivalent gas (denoted by TE/TE). The kQy-factors in epithermal neutron beams have previously been assumed to be equal to unity or estimated from measurements in clinical accelerator produced photon beams. In this work the kQy-factors have been determined from absorbed dose calculations using cavity theory together with Monte Carlo derived electron fluences obtained with the MCNP4c system for water and PMMA phantoms. The calculated quality correction factors differ substantially from unity, being in the order of 10% for the Mg/Ar detector at shallow phantom depths, and between 2 and 4% for other depths and for the TE/TE chamber.

Toward clinical application of prompt gamma spectroscopy for in vivo monitoring of boron uptake in boron neutron capture therapy.

In boron neutron capture therapy (BNCT) the absorbed dose to the tumor cells and healthy tissues depends critically on the boron uptake. Pronounced individual variations in the uptake patterns have been observed for two boron compounds currently used in clinical trials. This implies a high uncertainty in the determination of the boron dose component. In the present work a technique known as prompt gamma spectroscopy (PGS) is studied that potentially can be used for in vivo and noninvasive boron concentration determination at the time of the treatment. The technique is based upon measurement of gamma rays promptly emitted in the 10B(n,alpha)7Li and 1H(n,gamma)2D reactions. The aim of this work is to prepare the present setup for clinical application as a monitor of boron uptake in BNCT patients. Therefore, a full calibration and a set of phantom experiments were performed in a clinical setting. Specifically, a nonuniform boron distribution was studied; a skin/ dura, a larger blood vessel, and tumor within a head phantom was simulated. The results show that it is possible to determine a homogeneous boron concentration of 5 microg/g within +/-3% (1 standard deviation). In the nonuniform case, this work shows that the boron concentration can be determined through a multistep measurement procedure, however, with a somewhat higher uncertainty (approximately 10%). The present work forms the basis for a subsequent clinical application of the PGS setup aimed at in vivo monitoring of boron uptake.