Military Medicine Research: Incorporation of High Risk of Irreversible Harms into a Stratified Risk Framework for Clinical Trials

2021 ◽  
pp. 253-273
Author(s):  
Alexander R. Harris ◽  
Frederic Gilbert
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Military Medicine ◽  
Medicine Research ◽  
Risk Framework

scholarly journals What Is New in the Treatment of Smoldering Multiple Myeloma?

2021 ◽  
Vol 10 (3) ◽  
pp. 421
Author(s):  
Niccolo’ Bolli ◽  
Nicola Sgherza ◽  
Paola Curci ◽  
Rita Rizzi ◽  
Vanda Strafella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Early Treatment ◽  
Individual Case ◽  
Symptomatic Disease ◽  
Plasma Cell Neoplasm ◽  
Smoldering Multiple Myeloma ◽  
Wide Range ◽  
Critical Issues

Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an “MGUS-like” behavior to “early MM” with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the “watch and wait” paradigm in SMM is abandoned in favor of early treatment.

scholarly journals Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials

2018 ◽  
Vol 199 (1) ◽  
pp. 43-52 ◽  
Author(s):  
Andrew T. Lenis ◽  
Nicholas M. Donin ◽  
David C. Johnson ◽  
Izak Faiena ◽  
Amirali Salmasi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Adjuvant Therapy ◽  
Kidney Cancer

Abstract 381: Clinical Outcomes Following Transcatheter Aortic Valve Replacement Among US Hospitals

2015 ◽  
Vol 8 (suppl_2) ◽  
Author(s):  
Fenton McCarthy ◽  
Katherine M McDermott ◽  
Vinay Kini ◽  
Dale Kobrin ◽  
Nimesh D Desai ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Aortic Valve ◽  
Aortic Valve Replacement ◽  
Clinical Outcomes ◽  
Valve Replacement ◽  
Transcatheter Aortic Valve Replacement ◽  
Mortality Rates ◽  
Transcatheter Aortic Valve ◽  
Cardiovascular Interventions

Background: Transcatheter Aortic Valve Replacement (TAVR) demonstrated excellent outcomes in clinical trials of inoperable/high-risk patients. Subsequent approval by the Food and Drug Administration and National Coverage Determination by the Centers for Medicare and Medicaid Services established unique volume requirements for institutions and physicians to perform TAVR. Diffusion of prior cardiovascular interventions has involved less stringent policies and exhibited significant institutional variation in clinical outcomes. Our objective is to compare risk-standardized procedural outcomes across US hospitals performing TAVR to identify hospitals with outlying post-procedure mortality rates. Methods: All Medicare fee-for-service beneficiaries who underwent TAVR between January 1, 2011 and November 30, 2012 were identified. Thirty-day risk-standardized mortality rates (RSMR) were calculated using the Hospital Compare statistical method, a well-validated hierarchical generalized linear model. Results: Claims were examined from 5044 patients undergoing TAVR at 199 hospitals, with a crude 30-day mortality rate of 5.97%. RSMRs modeled using patient-level predictors varied from 4.5 % to 9.0 % (Figure 1). One hospital had a RSMR statistically lower than the national mean (4.5%, P<0.05), and two hospitals had RSMRs statistically higher than the national mean (8.5% and 6.9%, P<0.05). Conclusions: Clinical outcomes among TAVR hospitals in high-risk/inoperable patients demonstrated very little variability, few outliers, and excellent outcomes comparable to pre-approval clinical trials. This may be the result of the unique policy and regulatory environment governing the CMS coverage determination for TAVR institutions. As TAVR disseminates to additional hospitals and other new cardiovascular interventions are inevitably introduced, risk-standardized outcome comparisons across hospitals may facilitate ongoing surveillance to ensure high quality outcomes at all active centers.

scholarly journals Is there a role for adjuvant therapy after surgery in “high risk for recurrence” kidney cancer? An update on current concepts

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
T. Sharma ◽  
C. Tajzler ◽  
A. Kapoor
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
High Risk ◽  
Adjuvant Therapy ◽  
Patient Population ◽  
Treatment Options ◽  
Significant Proportion ◽  
High Risk Patient ◽  
Disease Free Survival ◽  
Cochrane Reviews

BackgroundAlthough surgical resection remains the standard of care for localized kidney cancers, a significant proportion of patients experience systemic recurrence after surgery and hence might benefit from effective adjuvant therapy. So far, several treatment options have been evaluated in adjuvant clinical trials, but only a few have provided promising results. Nevertheless, with the recent development of targeted therapy and immunomodulatory therapy, a series of clinical trials are in progress to evaluate the potential of those novel agents in the adjuvant setting. In this paper, we provide a narrative review of the progress in this field, and we summarize the results from recent adjuvant trials that have been completed.MethodsA literature search was conducted. The primary search strategy at the medline, Cochrane reviews, and http://ClinicalTrials.gov/ databases included the keywords “adjuvant therapy,” “renal cell carcinoma,” and “targeted therapy or/and immunotherapy.”ConclusionsData from the s-trac study indicated that, in the “highest risk for recurrence” patient population, disease-free survival was increased with the use of adjuvant sunitinib compared with placebo. The assure trial showed no benefit for adjuvant sunitinib or sorafenib in the “intermediate- to high-risk” patient population. The ariser (adjuvant girentuximab) and protect (adjuvant pazopanib) trials indicated no survival benefit, but subgroup analyses in both trials recommended further investigation. The inconsistency in some of the current results can be attributed to a variety of factors pertaining to the lack of standardization across the trials. Nevertheless, patients in the “high risk of recurrence” category after surgery for their disease would benefit from a discussion about the potential benefits of adjuvant treatment and enrolment in ongoing adjuvant trials.

Dexamethasone in Patients with Spontaneous Intracerebral Hemorrhage: An Updated Meta-Analysis

2020 ◽  
Vol 49 (5) ◽  
pp. 495-502
Author(s):  
Stephanie Wintzer ◽  
Josef Georg Heckmann ◽  
Hagen B. Huttner ◽  
Stefan Schwab
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Intracerebral Hemorrhage ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Risk Of Bias ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Control Groups ◽  
Language Data ◽  
Negative Effect

<b><i>Background:</i></b> Spontaneous intracerebral hemorrhage (ICH) is a frequent cerebrovascular disorder and still associated with high mortality and poor clinical outcomes. The purpose of this review was to update a 15-year-old former meta-analysis on randomized clinical trials (RCTs) addressing the question of whether ICH patients treated with dexamethasone have better outcomes than controls. <b><i>Methods:</i></b> The electronic databases PubMed, SCOPUS, and Cochrane as well as web platforms on current clinical trials were searched for the years 1970–2020 without constriction on language. Data were extracted and outcomes were pooled for conventional and cumulative meta-analysis using a commercial software program (www.Meta-Analysis.com). <b><i>Results:</i></b> Finally, 7 RCTs were identified and analyzed including 248 participants in the dexamethasone groups and 242 in the control groups. Five studies showed a high risk of bias. The overall relative risk (RR) for death was 1.32 (95% confidence interval [CI] 0.99–1.76; <i>p</i> = 0.06) and did not differ significantly between the 2 groups. After exclusion of studies with high risk of bias, the RR for death was 1.37 (95% CI 0.54–3.42; <i>p</i> = 0.51). The RR for poor outcome did not differ significantly between the 2 groups analyzed for all included studies (RR = 0.69; 95% CI 0.47–1; <i>p</i> = 0.05) and after exclusion of studies with high risk of bias (RR = 0.7; 95% CI 0.45–1.08; <i>p</i> = 0.11). The RR for complications did not differ significantly including all studies (RR = 1.29; 95% CI 0.77–2.17; <i>p</i> = 0.34) and after exclusion of studies with high risk of bias (RR = 1.27; 95% CI 0.18–8.89; <i>p</i> = 0.81). The cumulative statistics delivered no other results; however, it pointed out fewer complications over time in the dexamethasone group. <b><i>Conclusion:</i></b> Clear evidence of a beneficial or negative effect of dexamethasone is still lacking. Modern RCTs or observational studies with propensity design are necessary to evaluate the efficacy and safety of treatment with dexamethasone in patients with ICH.

scholarly journals Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 374
Author(s):  
Simon Bailey ◽  
Nicolas André ◽  
Lorenza Gandola ◽  
Maura Massimino ◽  
Stefan Rutkowski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Disease Risk ◽  
Risk Groups ◽  
Randomised Clinical Trial ◽  
Paediatric Oncology ◽  
High Dose ◽  
The Status ◽  
Risk Patients

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

How I Treat High-risk Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Elena Zamagni ◽  
Simona Barbato ◽  
Michele Cavo
Keyword(s):  
Quality Of Life ◽  
Risk Factors ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Specific Drug ◽  
Improve Quality

Survival of multiple myeloma (MM) has significantly improved over the last decade; however, a composed group of patients (15-20%), named high-risk (HR) MM, still experience reduced survival. Both tumor biology and suboptimal/absent responses to therapy may underlie HR definition and a clear uniform identification of risk factors is crucial for a proper management of these patients. In biologic-HRMM, MRD negativity attainment and sustain, inside and outside BM, should be the primary goal and therapy should be adapted in patients with frailty to reduce toxicity and improve quality of life. MM treatment has traditionally been tailored on age and more recently frailty or comorbidities, but very rarely on the biology of the disease, mainly because of the lack of a clear benefit derived from a specific drug/combination, inhomogeneity in HR definition and lack of data coming from prospective, properly designed clinical trials. Some attempts have been successfully made recently in this direction. In this review, we are discussing the current different definitions of HR and the need for a consensus, the results of available trials in HR patients and the way through risk-adapted treatment strategies. For this purpose, we are proposing several clinical cases of difficult-to-treat patients throughout different treatment phases.

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