Joanne M. van der Velden

Spinal instability as defined by the spinal instability neoplastic score is associated with radiotherapy failure in metastatic spinal disease

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.

Brief Report : Staged-informed Consent in the Cohort Multiple Randomized Controlled Trial Design

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.

The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials?

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.

The Effect of Introducing the Spinal Instability Neoplastic Score in Routine Clinical Practice for Patients With Spinal Metastases

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.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases : study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design

BackgroundStandard 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/designThis 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.DiscussionThis 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 registrationThe Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115. Date of trial registration February 1, 2015.

The ethics of ‘Trials within Cohorts’ (TwiCs): 2nd international symposium

On 7-8 November 2016, 60 people with an interest in the ‘Trials within Cohorts’ (TwiCs) approach for randomised controlled trial design met in London. The purpose of this 2 TwiCs international symposium was to share perspectives and experiences on ethical aspects of the TwiCs design, discuss how TwiCs relate to the current ethical framework, provide a forum in which to discuss and debate ethical issues and identify future directions for conceptual and empirical research. The symposium was supported by the Wellcome Trust and the NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton and attended by people from the UK, the Netherlands, Norway, Canada and USA. The two-day symposium enabled an international group to meet and share experiences of the TwiCs design (also known as the ‘cohort multiple RCT design’), and to discuss plans for future research. Over the two days, invited plenary talks were interspersed by discussions, posters and mini presentations from bioethicists, triallists and health research regulators. Key findings of the symposium were: (1) It is possible to make a compelling case to ethics committees that TwiCs designs are appropriate and ethical; (2) The importance of wider considerations around the ethics of inefficient trial designs; and (3) some questions about the ethical requirements for content and timing of informed consent for a study using the TwiCs design need to be decided on a case-by-case basis. Main report On 7-8 November 2016, 60 people with an interest in the ‘Trials within Cohorts’ (TwiCs) design met in London for the 2 TwiCs international symposium. The symposium was supported by the Wellcome Trust and NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton. As well as UK participants, people came from the Netherlands, Norway, Canada and USA. Over the two days, the invited plenary talks were interspersed by discussions, posters and mini presentations from bioethicists, triallists and health research regulators.

Prospective Evaluation of the Relationship Between Mechanical Stability and Response to Palliative Radiotherapy for Symptomatic Spinal Metastases

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.

Prophylaxis of radiation-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials

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.

Superior target delineation for stereotactic body radiotherapy of bone metastases from renal cell carcinoma on MRI compared to CT

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.

Predicting survival of patients treated with palliative radiotherapy: a systematic review

ABSTRACT 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, potentially leading to suboptimal care. The present paper reviews the literature on CPS in patients receiving palliative radiotherapy and assesses the accuracy of clinician generated survival estimates. Method: A search of Cochrane Central Register of Controlled Trials, Embase, and Ovid MEDLINE was conducted on 2 February 2018 to identify English articles analyzing the accuracy of CPS in cancer patients receiving palliative radiotherapy. Results: Seven studies were included in this review. Survival was overestimated on average, with overestimates ranging from +22.8 to +167.3 days. One study reported average underestimates of survival. No significant differences in accuracy were seen between disciplines. There was no correlation between years of experience and accuracy of CPS. Expert commentary: The incorporation of accurate CPS into treatment and family-related decisions can improve quality of life of palliative radiotherapy patients. Research is needed on survival estimates informed by prognostic tools, validation of prognostic tools specific to palliative settings, and the effects of CPS on dose fractionation and other treatment decisions.