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Background The primary goal of palliative treatment of spinal metastases is to maintain or improve health-related quality of life (HRQOL). We translated and validated a Dutch version of The Spine Oncology Study Group Outcome Questionnaire (SOSGOQ2.0), a valid and reliable 20-item questionnaire to evaluate HRQOL in patients with spinal metastases. Methods After cross-cultural translation and adaptation, the questionnaire was pre-tested in fifteen patients referred for spine surgery and/or radiotherapy. This resulted in a final questionnaire that was sent to patients for assessment of internal consistency, construct (i.e., convergent and divergent) validity, discriminative power and test-retest reliability. Results Overall, 147 patients (mean age 65.6 years, SD = 10.4) completed the questionnaire after a median time of 45.4 months (IQR = 18.9–72.9) after spine surgery and/or radiotherapy. Internal consistency was good for the Physical function, Pain, and Mental health domains (α = 0.87, 0.86, 0.72), but not for Social function (α = 0.04). Good convergent validity was demonstrated except for Social function (rs = 0.37 95%CI = 0.21–0.51). Discriminative power between patients with ECOG performance scores of 0–1 and 2–4 was found on all domains and Neurological function items. Test-retest reliability was acceptable for Physical function, Pain and Mental health (ICC = 0.89 95%CI = 0.81–0.94, ICC = 0.88 95%CI = 0.78–0.93, ICC = 0.68 95%CI = 0.48–0.81), whereas ICC = 0.45 (95%CI = 0.17–0.66) for Social function was below threshold. After removing item 20 from the Social function domain, internal consistency improved, and convergent validity and test-retest reliability were good. Conclusion The Dutch version of the SOSGOQ2.0 questionnaire is a reliable and valid tool to measure HRQOL in patients with spinal metastases. Item 20 was removed to retain psychometric properties.

This is the second part of the guidelines on the management of bone metastases. In the first part, the diagnosis and management of uncomplicated bone metastases have been addressed. Bone metastases may significantly reduce quality of life due to related symptoms and possible complications. The most common symptoms include pain and neurologic deficits. The most serious complications of bone metastases are skeletal-related events (SRE), defined as pathologic fracture, spinal cord compression, pain, or other symptoms requiring an urgent intervention such as surgery or radiotherapy. Diffuse bone metastases may lead to hypercalcaemia that can be fatal if untreated. The growing access to modern diagnostic tools allows early detection of asymptomatic bone metastases that could be successfully managed with local treatment if oligometastatic or systemic treatment for diffuse bone metastases to try to avoid the development of SRE. ispartof: RADIOTHERAPY AND ONCOLOGY vol:173 pages:240-253 ispartof: location:Ireland status: published

Purpose: Pain response after conventional external beam radiation therapy (cRT) in patients with painful bone metastases is observed in 60% to 70% of patients. The aim of the VERTICAL trial was to investigate whether stereotactic body radiation therapy (SBRT) improves pain response.Methods and Materials: This single-center, phase 2, randomized controlled trial was conducted within the PRESENT cohort, which consists of patients referred for radiation therapy of bone metastases to our tertiary center. Cohort participants with painful bone metastases who gave broad informed consent for randomization were randomly assigned to cRT or SBRT. Only patients in the intervention arm received information about the trial and were offered SBRT (1 x 18 Gy, 3 x 10 Gy, or 5 x 7 Gy), which they could accept or refuse. Patients who refused SBRT underwent standard cRT (1 x 8 Gy, 5 x 4 Gy, or 10 x 3 Gy). Patients in the control arm were not informed. Primary endpoint was pain response at 3 months after radiation therapy. Secondary outcomes were pain response at any point within 3 months, mean pain scores, and toxicity. Data were analyzed intention to treat (ITT) and per protocol (PP). This trial was registered with Clinicaltrials.gov, NCT02364115.Results: Between January 29, 2015, and March 20, 2019, 110 patients were randomized. ITT analysis included 44 patients in the cRT arm and 45 patients in the SBRT arm. In the intervention arm, 12 patients (27%) declined SBRT, and 7 patients (16%) were unable to complete the SBRT treatment. In ITT, 14 of 44 patients (32%; 95% confidence interval [CI], 18%-45%) in the control arm and 18 of 45 patients (40%; 95% CI, 26%-54%) in the SBRTarm reported a pain response at 3 months (P = .42). In PP, these proportions were 14 of 44 (32%; 95% CI, 18%-45%) and 12 of 23 patients (46%; 95% CI, 27%-66%), respectively (P = .55). In ITT, a pain response within 3 months was reported by 30 of 44 control patients (82%; 95% CI, 68%-90%) and 38 of 45 patients (84%; 95% CI, 71%-92%) in the SBR Tarm (P = .12). In PP, these proportions were 36 of 44 (82%; 95% CI, 68%-90%) and 26 of 27 patients (96%; 95% CI; 81%-100%), respectively (P = .12). No grade 3 or 4 toxicity was observed in either arm.Conclusions: SBRT did not significantly improve pain response in patients with painful bone metastases. One in 4 patients preferred to undergo cRT over SBRT, and 1 in 5 patients starting SBRT was unable to complete this treatment. Because of this selective dropout, which can be attributed to the character of the intervention, the trial was underpowered to detect the prespecified difference in pain response. (C) 2020 The Author(s). Published by Elsevier Inc.

Background and Objective: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. Methods: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). Results: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions,"10% felt reassured (6/62) and 2% scared/insecure (2/62). Conclusion: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: Painful bone metastases hamper quality of life (QoL). The aim of this prespecified secondary analysis of the PRESENT trial was to compare change in global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects after conventional radiation therapy (cRT) versus stereotactic body RT (SBRT).Methods and Materials: A total of 110 patients were enrolled in the phase 2 randomized controlled VERTICAL trial (NCT02364115) following the " trials within cohorts" design and randomized 1:1 to cRT or SBRT. Patient-reported global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects were assessed by the European Organization for Research and Treatment of Cancer QoL Questionnaire (QLQ) Core 15 Palliative Care and QLQ Bone Metastases 22 modules. Changes in QoL domains over time were compared between patients treated with cRT and SBRT using intention-to-treat (ITT) and per-protocol (PP) linear mixed model analysis adjusting for baseline scores. Proportions of patients in the cRT versus SBRT arm reporting a clinically relevant change in QoL within 3 months were compared using a x2 test.Results: QoL scores had improved over time and were comparable between groups for all domains in both the ITT and PP analyses, except for functional interference and psychological aspects in the ITT. Functional interference scores had improved more after 12 weeks in the cRT arm than in the SBRT arm (25.5 vs 14.1 points, respectively; effect size [ES] = 0.49, P =.04). Psychosocial aspects scores had improved more after 8 weeks in the cRT arm than in the SBRT arm (12.2 vs 7.3; ES = 0.56, P =.04). No clinically relevant differences between groups at 12 weeks in terms of global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects were observed.Conclusions: Palliative RT improves QoL. Both SBRT and cRT have a comparable effect on patient-reported QoL outcomes in patients with painful bone metastases. Functional interference and psychological aspects scores improved more in patients treated with cRT versus patients offered SBRT. (C) 2022 Elsevier Inc. All rights reserved.

Objectives: To evaluate patients’ experience of having served as controls without a notification at the time of randomization in the context of the trial within cohorts (TwiCs) design.Methods: Patients were asked for their opinion on having served as controls in TwiCs, before and after having been provided the trial results. Patients had provided broad consent to randomization at cohort entry and had served as controls in one of two TwiCs (an exercise program after breast cancer treatment or radiotherapy dose-escalation for rectal cancer).Results: Two to 6 years after cohort entry, 15% (n = 16) of all patients remembered having provided broad consent to randomization. Before disclosure of trial results, 47% (n = 52) of patients thought positively, 45% (n = 50) neutrally, and 2% (n = 2) negatively of having served as controls in one of the two trials. Seventeen percent (n = 18) of patients were positive, 65% (n = 71) neutral, and 11% (n = 12) negative about not having been notified when serving as controls. The survey results were comparable after disclosure of trial results.Conclusions: These results support the use of the TwiCs design with the staged-informed consent procedure. Keeping patients engaged and aware of the consents provided might further improve patients’ experience of serving as controls in TwiCs.

Background and purpose: Spine delineation is essential for high quality radiotherapy treatment planning of spinal metastases. However, manual delineation is time-consuming and prone to interobserver variability. Automatic spine delineation, especially using deep learning, has shown promising results in healthy subjects. We aimed to evaluate the clinical utility of deep learning-based vertebral body delineations for radiotherapy planning purposes. Materials and methods: A multi-scale convolutional neural network (CNN) was used for automatic segmentation and labeling. Two approaches were tested: the combined approach using one CNN for both segmentation and labeling, and the sequential approach using separate CNN’s for these tasks. Training and internal validation data included 580 vertebrae, external validation data included 202 vertebrae. For quantitative assessment, Dice similarity coefficient (DSC) and Hausdorff distance (HD) were used. Axial slices from external images were presented to radiation oncologists for subjective evaluation. Results: Both approaches performed comparably during the internal validation (DSC: 96.7%, HD: 3.6 mm), but the sequential approach proved more robust during the external validation (DSC: 94.5% vs 94.4%, p

Introduction: Clinician predicted survival (CPS) is a crucial part of palliative care but is often found to be inaccurate with most clinicians providing overestimates of survival, potential...

Background: In metastatic renal cell carcinoma (mRCC) there has been a treatment shift towards targeted therapy, which has resulted in improved overall survival. Therefore, there is a need for better local control of the tumor and its metastases. Image-guided stereotactic body radiotherapy (SBRT) in bone metastases provides improved symptom palliation and local control. With the use of SBRT there is a need for accurate target delineation. The hypothesis is that MRI allows for better visualization of the extend of bone metastases in mRCC and will optimize the accuracy of tumor delineation for stereotactic radiotherapy purposes, compared with CT only. Methods: From 2013 to 2016, patients who underwent SBRT for RCC bone metastases were included. A planning CT and MRI were performed in radiotherapy treatment position. Gross tumor volumes (GTV) in both CT and MRI were delineated. Contouring was performed by a radiation oncologist specialized in bone metastases and verified by a radiologist, based on local consensus contouring guidelines. In both CT and MRI, the GTV volumes, conformity index (CI) and distance between the centers of mass (dCOM) were compared. Results: Nine patients with 11 RCC bone metastases were included. The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT. The median GTV volume on MRI was 33.4 mL (range 0.2–247.6 mL), compared to 18.1 mL on CT (range 0.1–195.9) (P=0.013). Conclusions: Contouring of RCC bone metastases on MRI resulted in clinically relevant and statistically significant larger lesions (mean increase 41%) compared with CT. MRI seems to represent the extend of the GTV in RCC bone metastases more accurately. Contouring based on CT-only could result in an underestimation of the actual tumor volume, which may cause underdosage of the GTV in SBRT treatment plans.

Background Stereotactic radiotherapy (SBRT) might improve pain and local control in patients with bone metastases compared to conventional radiotherapy, although an overall estimate of these outcomes is currently unknown. Methods A systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pubmed, Embase, and Cochrane databases were systematically searched to identify studies reporting pain response and local control among patients with bone metastases from solid-organ tumors who underwent SBRT in 1–6 fractions. All studies prior to April 15, 2017, were included. Study quality was assessed by predefined criteria, and pain response and local control rates were extracted. Results A total of 2619 studies were screened; 57 were included (reporting outcomes for 3995 patients) of which 38 reported pain response and 45 local control rates. Local control rates were high with pain response rates above those previously reported for conventional radiotherapy. Marked heterogeneity in study populations and delivered treatments were identified such that quantitative synthesis was not appropriate. Reported toxicity was limited. Of the pain response studies, 73.7% used a retrospective cohort design and only 10.5% used the international consensus endpoint definitions of pain response. The median survival within the included studies ranged from 8 to 30.4 months, suggesting a high risk of selection bias in the included observational studies. Conclusions This review demonstrates the potential benefit of SBRT over conventional palliative radiotherapy in improving pain due to bone metastases. Given the methodological limitations of the published literature, however, large randomized trials are now urgently required to better quantify this benefit.

Purpose Stereotactic body radiation therapy (SBRT) has become a widely adopted treatment for patients with oligometastatic disease, despite limited evidence of superiority. We compared pain response and quality of life (QoL) in patients with oligometastatic disease treated with conventionally fractionated 3-dimensional radiation therapy (3DCRT) or SBRT to bone metastases. Methods and Materials We included patients with oligometastatic disease (≤5 lesions within ≤3 organs) treated within the prospective PRESENT cohort. Main outcomes were pain response, clinical local control, and QoL 2, 4, and 8 weeks and 3, 6, and 12 months after treatment. Pain response was assessed only in patients who reported pain at baseline and was defined according to international consensus criteria. Results Of 131 patients with oligometastatic disease, 66 patients were treated with 3DCRT and 65 patients with SBRT. A pain response was achieved in 81% (3DCRT) versus 84% (SBRT) with a median duration of 23 weeks (range, 1-58) and 24 weeks (range, 0-50), respectively. Reirradiation was needed in 33% versus 5% of the patients, respectively. None of the QoL subscales were significantly different between both groups. Conclusions In patients with oligometastatic disease, SBRT to bone metastases did not improve pain response or QoL compared with 3DCRT. Reirradiation was less often needed in the SBRT group.

Introduction: Volumetric and density parameters measured from computed tomography scans were investigated for evaluating treatment response of nonspine bone lesions following stereotactic body radiation therapy. Methods: Twenty-three patients treated with stereotactic body radiation therapy to nonspine bone metastases with pre- and post-treatment radiological follow-up with computed tomography imaging were identified in a retrospective review. An expert radiologist classified 26 lesions by type (lytic, sclerotic) and by response. Two independent radiation oncologists created separate contours of the bone and soft tissue lesion volumes. Density and volume were assessed relative to baseline values. Results: For bone-only lesions, all lesions designated as local control decreased in volume or remained within 20% of baseline volumes. Lytic lesions classified as progressive disease exhibited much larger volume increases. Lytic bone lesions showed indications of remineralization with some exhibiting immediate increases in density (1-6 months) and others decreasing initially then increasing back toward baseline between 7 and 12 months. The majority of sclerotic lesions, all classified as local control, decreased slightly in both volume and density. Lesions with both soft tissue and boney involvement resulted in contradictory results when employing both radiological and size parameters for assessing treatment response. Classification was dominated by changes in soft tissue volume, despite associated volume or density changes in the corresponding boney lesion. In contrast, when soft tissue volume changes were minimal (Conclusions: Volume and density changes show promise as quantitative parameters for classifying treatment responses of nonspine osseous lesions. Further work is required for clarifying how these metrics can be applied to lesions with both boney and soft tissue components.

Background: Assessment of pain is important in daily clinical practice and as an endpoint in clinical studies. Because pain perception is highly subjective, pain measurement is complex. Selfrating pain scales are currently of great importance but have limitations. They depend on many more factors than pain, which could lead to an incorrect assessment of therapies or clinical studies. Therefore, there is need for valid, reliable, safe, and low-cost methods to determine and quantify patients’ pain more objectively. Objective: To provide an overview of devices and techniques that can be used to administer a pain stimulus with similar intensity as the endogenous pain experienced by the patient, in order to quantify and subsequently follow patients’ pain more objectively. Study Design: In this systematic review, articles from PubMed, EMBASE, Cochrane library and Scopus were reviewed for eligibility. Methods: Studies that described a device or technique that could be used to induce a variable, controlled, and measurable pain stimulus were included. Studies that made correlations with established pain scales or those who compared outcomes in multiple tests were selected to assess validity and reliability. Results: A total of 1,308 manuscripts were initially retrieved. After independent screening by a team of 4 reviewers, 19 studies were eventually included describing 15 different devices or techniques. These devices could be divided into groups based on stimulus administration: electrical, external pressure (probe) and miscellaneous pain stimulators. Electrical stimulators were found to be tested extensively and proven to be both valid and reliable. Limitations: To correlate new techniques with older methods such as the Numeric Rating Scale (NRS) and Visual Analogue Scale (VAS) for which an improvement is desired, is debatable. To (partially) address this problem, the reliability is added as an additional primary outcome to assess which device works best. Further limitations include the heterogeneity of studies found in both the types of pain measured as in outcome measures presented. In addition, it is important to note that part of the devices described cannot directly be used for clinical practice due to products that have cease to exist or the description of solely techniques rather than testing ready-to-use devices. Conclusion: Several devices and techniques compared pain intensity experienced by patients with an external pain stimulus that potentially could be used as a new objective pain measurement tool. Given the results of our review, electrical stimulators that have been tested extensively with high validity, reliability, and feasibility would be recommended for use for clinical and research purposes. Moreover, normalization of pain intensity scores for current perception is important. Pain intensity normalization leads to higher correlations with established pain scales and possibly to increased inter-patient reliability. Registration number: Registered in the PROSPERO database (PROSPERO 2016:CRD42016041974) Key words: Systematic review, objective pain measurement, pain scales; devices, techniques, validity, reliability, safety, feasibility

Objective: Radiotherapy is the standard local treatment for patients with painful bone metastases, but effectiveness has primarily been evaluated in trial populations. The aim of this study was to study pain response to palliative radiotherapy in a prospective cohort of unselected patients with bone metastases. Methods: Patients with painful bone metastases referred to the UMC Utrecht for radiotherapy and enrolled in the PRESENT cohort were included in this study. For all patients, pain response to radiotherapy was assessed, and responders were defined as patients with a complete or partial pain response. Patients with stable pain scores, pain increase, or undetermined response were regarded non-responders. Pain scores obtained at baseline and after 2, 4, 6, 8, and 12 weeks following radiotherapy were obtained. Pain response rates of the total treated population, as well as response rates of the assessable patients, were calculated. To measure the percentage of the remaining time spent with pain relief, the net pain relief (NPR) was calculated by dividing the period of pain relief by the period of survival. Results: Of the 432 patients enrolled in this study, 262 patients (61%) experienced a complete or partial response. In the 390 assessable patients, this percentage was 67%. Median time to response was 4 weeks (range 1-15 weeks), and the NPR was 64%. Conclusion: Compared to randomized trial populations, palliative radiotherapy in our unselected patients with bone metastases showed similar pain response rates (61%), with a reasonable duration of this effect.

Background: Routine treatment for unstable spinal metastases consists of surgical stabilization followed by external beam radiotherapy (EBRT) or stereotactic body radiotherapy (SBRT) after a minimum of 1-2 weeks to allow for initial wound healing. Although routine treatment, there are several downsides. First, radiotherapy induced pain relief is delayed by the time interval required for wound healing. Second, EBRT often requires multiple hospital visits and only 60% of the patients experience pain relief. Third, spinal implants cause imaging artifacts hindering SBRT treatment planning and delivery. Reversing the order of surgery and radiotherapy, with dose sparing of the surgical area by SBRT, could overcome these disadvantages and by eliminating the interval between the two treatments, recovery, and palliation may occur earlier. Design: The safety of SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases was investigated. Safety was evaluated using the Common-Toxicity-Criteria-Adverse-Events-4.0, with the occurrence of wound complications within 90-days being the primary concern. Results: Between June-2015 and January-2017, 13 patients underwent SBRT followed by surgical stabilization for unstable spinal metastases. The median time between SBRT and surgery was 17-h (IQR 5-19). None of the patients experienced wound complications. Improvements in pain and quality of life were observed over time for all patients. Conclusion: SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases is safe. Palliation may be experienced earlier and with both treatments being performed in one hospital admission the treatment burden decreases.

Purpose Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in-human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT. Methods and Materials Ten patients with spinal metastases secondary to various solid tumors were treated with preoperative single-fraction SBRT (18 Gy) to the magnetic resonance imaging–defined macroscopic metastasis, followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy specimen available for a matched comparison. The samples were stained for tumor necrosis on routine hematoxylin-eosin–stained slices and, subsequently, immunohistochemical staining for T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), endothelium (CD31+), and apoptotic activity (caspase-3). Results Perioperative biopsy specimens were obtained ∼6 hours (range 4.5-7.5) or 21 hours (range 18.5-22.5) after SBRT. Necrosis was observed in 83% of the 21-hour post-SBRT samples (5 of 6) compared with 0% of pre-SBRT biopsies (0 of 6) and 6-hour post-SBRT biopsies (0 of 4). Tumor cell apoptosis had increased greatly in the 21-hour post-SBRT samples compared with before and 6 hours after SBRT. The CD31+ vessel counts decreased after SBRT, as did mitotic activity. Both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4 of 6) of the pre-SBRT samples compared with 100% (10 of 10) the post-SBRT samples. The T-cell and natural killer cell counts were relatively unaffected. Conclusions High-dose single-fraction SBRT induced tumor necrosis, desmoplasia, and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-human results imply direct vascular and DNA damage mechanisms important in the clinical efficacy specific to spinal SBRT.

Background Stable spinal metastases are effectively treated with radiotherapy, whereas unstable spinal metastases often need surgical fixation followed by radiotherapy for local control. The Spinal Instability Neoplastic Score (SINS) was developed as a tool to assess spinal neoplastic related instability with the goal of helping to guide referrals among oncology specialists. We compare the average degree of spinal instability between patients with spinal metastases referred for surgery or for radiotherapy and evaluate whether this difference changed after introduction of the SINS in clinical practice. Methods All patients with spinal metastases treated with palliative surgery or radiotherapy in the period 2009-2013 were identified in two spine centers. For all patients, the SINS was scored on pretreatment imaging. The SINS before and after introduction of the SINS in 2011 were compared within the surgical and radiotherapy group. Furthermore, the overall SINS was compared between the two groups. Results The overall SINS was significantly higher in the surgical group, with a mean SINS of 10.7 (median 11) versus 7.2 (median 8) for the radiotherapy group. The mean SINS decreased significantly for both groups after introduction of the SINS in clinical practice from 11.2 to 10.3 in the surgical group and from 8.4 to 7.2 in the radiotherapy group. Conclusion The SINS differed significantly between patients treated with surgery or radiotherapy. The introduction of SINS led to a decrease in SINS score for both groups, suggesting that using SINS in metastatic spinal disease increases awareness for instability and may subsequently result in earlier referrals for surgical intervention. Implications for practice Spinal metastases can present with varying degrees of mechanical instability. Because unstable spinal metastases may respond insufficiently to palliative radiotherapy and can lead to loss of ambulation, timely detection and appropriate referral are important. The Spinal Instability Neoplastic Score (SINS) may help physicians caring for patients with metastasized disease to identify spinal instability before the onset of neurological deficits. In this study, it was shown that the introduction of SINS in routine practice led to a decrease in spinal instability in radiotherapy and surgical cohorts. The use of SINS may increase awareness of instability and subsequently result in earlier referrals.

Background A substantial number of patients with spinal metastases experience no treatment effect from palliative radiotherapy. Mechanical spinal instability, due to metastatic disease, could be associated with failed pain control following radiotherapy. This study investigates the relationship between the degree of spinal instability, as defined by the Spinal Instability Neoplastic Score (SINS), and response to radiotherapy in patients with symptomatic spinal metastases in a multi-institutional cohort. Methods and materials The SINS of 155 patients with painful thoracic, lumbar, or lumbosacral metastases from two tertiary hospitals was calculated using images from radiotherapy planning CT scans. Patient-reported pain response, available for 124 patients, was prospectively assessed. Pain response was categorized, according to international guidelines, as complete, partial, indeterminate, or progression of pain. The association between SINS and pain response was estimated by multivariable logistic regression analysis, correcting for predetermined clinical variables. Results Of the 124 patients, 16 patients experienced a complete response and 65 patients experienced a partial response. Spinal Instability Neoplastic Score was associated with a complete pain response (adjusted odds-radio [ORadj] 0.78; 95% confidence interval [CI] 0.62-0.98), but not with an overall pain response (ORadj 0.94; 95% CI 0.81-1.10). Conclusions A lower SINS, indicating spinal stability, is associated with a complete pain response to radiotherapy. This supports the hypothesis that pain resulting from mechanical spinal instability responds less well to radiotherapy compared with pain from local tumor activity. No association could be determined between SINS and an overall pain response, which might indicate that this referral tool is not yet optimal for prediction of treatment outcome. Implications for practice Patients with stable painful spinal metastases, as indicated by a Spinal Instability Neoplastic Score (SINS) of 6 or lower, can effectively be treated with palliative external beam radiotherapy. The majority of patients with (impending) spinal instability, as indicated by a SINS score of 7 or higher, will achieve a (partial) response after palliative radiotherapy; however, some patients might require surgical intervention. Therefore, it is recommended to refer patients with a SINS score of 7 or higher to a spine surgeon to evaluate the need for surgical intervention.

Background: The aim of this article was to systematically review the efficacy and safety of various antiemetics in prophylaxis of radiation-induced nausea and vomiting (RINV). Methods: A literature search of Ovid MEDLINE, EMBASE and Cochrane CENTRAL was performed to identify randomized controlled trials (RCTs) that evaluated the efficacy of prophylaxis for RINV in patients receiving radiotherapy to abdomen/pelvis, including total body irradiation (TBI). Primary endpoints were complete control of nausea and complete control of vomiting during acute and delayed phases. Secondary endpoints included use of rescue medication, quality of life (QoL) and incidence of adverse events. Results: Seventeen RCTs were identified. Among patients receiving radiotherapy to abdomen/pelvis, our meta-analysis showed that prophylaxis with a 5-hydroxytryptamine-3 receptor antagonist (5HT3 RA) was significantly more efficacious than placebo and dopamine receptor antagonists in both complete control of vomiting [OR 0.49; 95% confidence interval (CI): 0.33–0.72 and OR 0.17; 95% CI: 0.05–0.58 respectively] and complete control of nausea (OR 0.43; 95% CI: 0.26–0.70 and OR 0.46; 95% CI: 0.24–0.88 respectively). 5HT3 RAs were also more efficacious than rescue therapy and dopamine receptor antagonists plus dexamethasone. The addition of dexamethasone to 5HT3 RA compared to 5HT3 RA alone provides a modest improvement in prophylaxis of RINV. Among patients receiving TBI, 5HT3 RA was more effective than other agents (placebo, combination of metoclopramide, dexamethasone and lorazepam). Conclusions: 5HT3 RAs are more effective than other antiemetics for prophylaxis of RINV in patients receiving radiotherapy to abdomen/pelvis and TBI. Future RCTs should investigate the efficacy of newer agents such as substance P neurokinin 1 receptor antagonists in addition to 5HT3 RAs in prophylaxis of RINV during both acute and delayed phases.

The "cohort multiple randomized controlled trial," a new design for pragmatic trials, embeds multiple trials within a cohort. The cohort multiple RCT is an attractive alternative to conventional RCTs in fields where recruitment is slow, multiple new (competing) interventions for the same condition have to be tested, new interventions are highly preferred by patients and doctors, and the risk of disappointment bias, cross-over, and contamination is considerable. To prevent these unwanted effects, the cohort multiple RCT provides information on randomization to the intervention group/arm only, and only after randomization (i.e., prerandomization). To some, especially in a clinical setting, this is not ethically acceptable. In this article, we argue that prerandomization in the cohort multiple randomized controlled trial (cmRCT) can be avoided by adopting a staged-informed consent procedure. In the first stage, at entry into the cohort, all potential participants are asked for their informed consent to participate in a cohort study and broad consent to be either randomly selected to be approached for experimental interventions or to serve as control without further notice during participation in the cohort. In a second stage, at the initiation of an RCT within the cohort, informed consent to receive the intervention is then only sought in those randomly selected for the intervention arm. At the third stage, after completion of each RCT, all cohort participants receive aggregate disclosure of trial results. This staged-informed consent procedure avoids prerandomization in cmRCT and aims to keep participants actively engaged in the research process.

Randomized controlled trials (RCTs)-the gold standard for evaluating the effects of medical interventions-are notoriously challenging in terms of logistics, planning and costs. The cohort multiple randomized controlled trial approach is designed to facilitate randomized trials for pragmatic evaluation of (new) interventions and is a promising variation from conventional pragmatic RCTs. In this paper, we evaluate methodological challenges of conducting an RCT within a cohort. We argue that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. However, whether this design is more efficient compared with conducting a pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm.

BACKGROUND: Standard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease. METHODS/DESIGN: This study follows the 'cohort multiple Randomized Controlled Trial' design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm. DISCUSSION: This study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability. TRIAL REGISTRATION: The Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115 . Date of trial registration February 1, 2015.

The purpose of this study was to investigate what pseudo-CT (pCT) strategy is sufficient for online MRI based treatment plan adaptation of a stereotactic treatment for spinal bone metastases. For this purpose, the dosimetric accuracy of five increasingly complex pCT strategies was evaluated using the planning CT data of 20 patients suffering from spinal metastases. For each pCT, a treatment plan was developed and simulated on both the pCT and the original CT data of the patient. The two resulting dose distributions were compared using gamma analysis of 2%/2 mm. In this paper, a Gamma Pass Rate (GPR) of ⩾ 95% within the Target Volume (TV) was considered clinically acceptable. We additionally demonstrated in this paper the automatic generation of each investigated pCT strategy with the use of dedicated MRI data complemented with pre-treatment CT data of a patient in treatment position. The dosimetric accuracy of a pCT increases when additional bulk densities are utilized for a pCT. However, the dosimetric accuracy of even the most complex 'bulk density' pCT strategy used in this study had an average GPR of only 78% within the TV. However, if information on the heterogeneous electron density distribution within the affected vertebral body was available, a clinically acceptable 99% mean GPR was observed. All pCTs could successfully be generated using the MRI data in combination with the CT data of a patient in treatment position. The results presented in this study show that a simple 'bulk density' pseudo-CT strategy is not feasible for online MRI based treatment plan adaptation for spinal bone metastases. However, a clinically acceptable result is generated if the information on the heterogeneous electron density (ED) distribution within the affected vertebral bone is available. Therefore, any pCT strategy for this tumor site should include a method which can estimate the heterogeneous ED of the affected vertebral bone.

Background context Although radiotherapy is effective in achieving pain relief in most patients, it is not completely understood why some patients respond well to radiotherapy and others do not. Our hypothesis was that metastatic bone pain, if predominantly caused by mechanical instability of the spine, responds less well to radiotherapy than metastatic bone pain caused by local tumor activity. Recently, the spinal instability neoplastic score (SINS) was proposed as a standardized referral tool for nonspine specialists to facilitate early diagnosis of spinal instability. Purpose To investigate the association between spinal instability as defined by the SINS and response to radiotherapy in patients with spinal metastases. Study design A retrospectively matched case-control study in an academic tertiary referral center, conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Patient sample Thirty-eight patients with spinal metastases who were retreated after initial palliative radiotherapy from January 2009 to December 2010 were matched to 76 control patients who were not retreated. Outcome measures Radiotherapy failure as defined by retreatment (radiotherapy, surgery, and conservative) after palliative radiotherapy for spinal metastases. Methods Radiotherapy planning computed tomography scans were scored by a blinded spine surgeon according to the SINS criteria. The association between SINS and radiotherapy failure was estimated by univariate and multivariate conditional logistic regression analysis. Results Median SINS was 10 (range 4–16) for cases and 7 (range 1–16) for controls. The SINS was significantly and independently associated with radiotherapy failure (adjusted odds ratio, 1.3; 95% confidence interval, 1.1–1.5; p=.01). Conclusions This study shows that a higher spinal instability score increases the risk of radiotherapy failure in patients with spinal metastases, independent of performance status, primary tumor, and symptoms. These results may support the hypothesis that metastatic spinal bone pain, predominantly caused by mechanical instability, responds less well to radiotherapy than pain mainly resulting from local tumor activity.