Stereotactic body radiotherapy is an effective treatment in reirradiating spinal metastases: current status and practical considerations for safe practice

Spinal metastases are a relatively common manifestation in advanced cancer patients. Low-dose conventional radiotherapy has long been the mainstay of treatment under the assumption that patients have a limited life expectancy in the order of 3-6 months. However, with new developments in systemic therapies, patients are surviving longer than expected. As the spinal retreatment rates, secondary to conventional radiation, can approach 20-50%, retreatments are likely to be more frequent. Rather than a second course of even lower-dose conventional radiation, spine stereotactic body radiotherapy (SBRT) has been developed predominantly to overcome the limitations of conventional reirradiation. Spine SBRT permits a second course of high-dose radiation aimed at local tumor control while sparing the spinal cord, and other surrounding normal tissues, of a toxic dose. The focus of this review is to provide an overview of reirradiation spine SBRT, and address key issues surrounding safe and effective practice.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

Impact of modafinil on spasticity reduction and quality of life in children with CP

This randomized double blind AB/BA cross-over trial evaluates the effect of oral modafinil versus placebo on spasticity, function, and quality of life in children with cerebral palsy (CP). Outcomes were measured at the start and end of both 8-week treatment periods (modafinil and placebo). The order of the treatment periods was randomly assigned. There was a 4-week wash-out period between treatments. Primary outcomes include the Modified Ashworth Score (MAS), and the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD), a disorder-specific quality of life measure. Ten children were randomized and eight children completed the study. The mean age of participants was 11 years 5 months (SD 1 y 5 mo, range 8 y 8 mo-12 y 11 mo). Five of the participants were male and three female. Seven children had a diagnosis of spastic quadriplegic CP and one child had spastic diplegia with overflow tone to the upper extremities. The Gross Motor Function Classification System ranged from Level III to V with one child at Level III, six children at Level IV, and one at Level V. The CPCHILD pre- to post-total scores showed a slight improvement in quality of life during the placebo period and a slight deterioration in the modafinil period (overall mean change of 7.1, SD 7.6). A t-test between post differences was statistically significant (t=2.65, p=0.03) in favor of the placebo period. The MAS for elbow flexors, ankle flexors, and hip adductors did not show any significant reduction post-modafinil or post-placebo (p values ranged from 0.41-0.79). This study did not find evidence that modafinil reduces spasticity or has a positive impact on quality of life in children with spastic CP.     

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.     

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.     

Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr- labeled platelets differ

Mean platelet survival and turnover were simultaneously determined with autologous 111In-labeled platelets (111In-AP) and homologous 51Cr- labeled platelets (51Cr-HP) in ten patients with chronic immune thrombocytopenic purpura (ITP). In vivo redistribution of the 111In-AP was quantitated with a scintillation camera and computer-assisted image analysis. The patients were divided into two groups: those with splenic platelet sequestration (spleen-liver 111In activity ratio greater than 1.4), and those with diffuse sequestration in the reticuloendothelial system. The latter patients had more severe ITP reflected by pronounced thrombocytopenia, decreased platelet turnover, and prominent early hepatic platelet sequestration. Mean platelet life span estimated with 51Cr-HP was consistently shorter than that of 111In-AP. Platelet turnover determined with 51Cr-HP was thus over-estimated. The difference in results with the two isotope labels was apparently due to greater in vivo elution of 51Cr. Although the limitations of the techniques should be taken into account, these findings indicate that platelet turnover is not always normal or increased in ITP, but is low in severe disease. We suggest that this may be ascribed to damage to megakaryocytes by antiplatelet antibody. The physical characteristics in 111In clearly make this radionuclide superior to 51Cr for the study of platelet kinetics in ITP.