scholarly journals VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS

2014 ◽  
Vol 30 (3) ◽  
pp. 312-324 ◽  
Author(s):  
Oriana Ciani ◽  
Sarah Davis ◽  
Paul Tappenden ◽  
Ruth Garside ◽  
Ken Stein ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Statistical Methods ◽  
Surrogate Endpoint ◽  
Cytotoxic Agents ◽  
Surrogate Endpoints ◽  
Treatment Level ◽  
Cancer Type ◽  
Policy Makers ◽  
New Therapies ◽  
Advanced Tumor

Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

scholarly journals Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies

2021 ◽  
pp. 0272989X2199455
Author(s):  
Oriana Ciani ◽  
Bogdan Grigore ◽  
Hedwig Blommestein ◽  
Saskia de Groot ◽  
Meilin Möllenkamp ◽  
...  
Keyword(s):  
Health Technology Assessment ◽  
Technology Assessment ◽  
International Health ◽  
Surrogate Endpoint ◽  
Health Technology ◽  
Surrogate Endpoints ◽  
Patient Centered ◽  
Statistical Validation ◽  
Level Of Evidence ◽  
The Impact

Background Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA). Objectives 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies. Methods We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency’s acceptability of the surrogate endpoint and their coverage recommendation. Results Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports ( k-coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60–13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23–2.20; P = 0.55). Conclusions Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.

scholarly journals Cancer-Specific Immune Prognostic Signature in Solid Tumors and Its Relation to Immune Checkpoint Therapies

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2476 ◽  
Author(s):  
Shaoli Das ◽  
Kevin Camphausen ◽  
Uma Shankavaram
Keyword(s):  
Immune Function ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Data Sets ◽  
Cancer Type ◽  
Rna Seq ◽  
Prognostic Signature ◽  
Cell Functions ◽  
Cancer Types ◽  
Disease Free

To elucidate the role of immune cell infiltration as a prognostic signature in solid tumors, we analyzed immune-function-related genes from four publicly available single-cell RNA-Seq data sets and twenty bulk tumor RNA-Seq data sets from The Cancer Genome Atlas (TCGA). Unsupervised clustering of pan-cancer transcriptomic signature showed two major immune function types: one related to NK-, T-, and B-cell functions and the other related to monocyte, macrophage, dendritic cell, and Toll-like receptor functions. Kaplan–Meier analysis showed differential prognosis of these two groups, dependent on the cancer type. Our analysis of TCGA solid tumors with an elastic net model identified 155 genes associated with disease-free survival in different tumor types with varied influence across different cancer types. With this gene set, we computed cancer-specific prognostic immune score models for individual cancer types that predicted disease-free and overall survival. Validation of our model on available published data of immune checkpoint blockade therapies on melanoma, kidney renal cell carcinoma, non-small cell lung cancer, gastric cancer and bladder cancer confirmed that cancer-specific higher immune scores are associated with response to immunotherapy. Our analysis provides a comprehensive map of cancer-specific immune-related prognostic gene sets that are associated with immunotherapy response.

Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2606-2606
Author(s):  
Yanling Niu ◽  
Tonghui Ma ◽  
Yanling Niu ◽  
Tao Li
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Center ◽  
Cancer Type ◽  
Cancer Dataset ◽  
Predictive Values ◽  
Esophagogastric Cancer ◽  
Cancer Types

2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.

scholarly journals Epidemiology of Microsatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Maria Lorenzi ◽  
Mayur Amonkar ◽  
Jacky Zhang ◽  
Shivani Mehta ◽  
Kai-Li Liaw
Keyword(s):  
Literature Review ◽  
Solid Tumors ◽  
English Language ◽  
Meta Analysis ◽  
Evidence Base ◽  
Published Data ◽  
Cancer Type ◽  
Pooled Prevalence ◽  
Tumor Types ◽  
Structured Literature Review

Background. Given limited data on the epidemiology of MSI-H and dMMR across solid tumors (except colorectal cancer (CRC)), the current study was designed to estimate their prevalence. Materials and Methods. A structured literature review identified English language publications that used immunohistochemistry (IHC) or polymerase chain replication (PCR) techniques. Publications were selected for all tumors except CRC using MEDLINE, EMBASE, and Cochrane databases and key congresses; CRC and pan-tumor genomic publications were selected through a targeted review. Meta-analysis was performed to estimate pooled prevalence of MSI-H/dMMR across all solid tumors and for selected tumor types. Where possible, prevalence within tumor types was estimated by disease stages. Results. Of 1,176 citations retrieved, 103 and 48 publications reported prevalence of MSI-H and dMMR, respectively. Five pan-tumor genomic studies supplemented the evidence base. Tumor types with at least 5 publications included gastric (n = 39), ovarian (n = 23), colorectal (n = 20), endometrial (n = 53), esophageal (n = 6), and renal cancer (n = 8). Overall MSI-H prevalence (with 95% CI) across 25 tumors was based on 90 papers (28,213 patients) and estimated at 14% (10%–19%). MSI-H prevalence among Stage 1/2 cancers was estimated at 15% (8%–23%); Stages 3 and 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), respectively. Overall, dMMR prevalence across 13 tumor types (based on 54 papers and 20,383 patients) was estimated at 16% (11%–22%). Endometrial cancer had the highest pooled MSI-H and dMMR prevalence (26% and 25% all stages, respectively). Conclusions. This is the first comprehensive attempt to report pooled prevalence estimates of MSI-H/dMMR across solid tumors based on published data. Prevalence determined by IHC and PCR was generally comparable, with some variations by cancer type. Late-stage prevalence was lower than that in earlier stages.

scholarly journals Cognitive impairment after cytotoxic chemotherapy

2019 ◽  
Vol 7 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Petra Huehnchen ◽  
Antonia van Kampen ◽  
Wolfgang Boehmerle ◽  
Matthias Endres
Keyword(s):  
Breast Cancer ◽  
Colon Cancer ◽  
Cognitive Impairment ◽  
Cancer Patients ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Drugs ◽  
Cytotoxic Agents ◽  
Cancer Type ◽  
Breast Cancer Patients ◽  
The Impact

Abstract Background Neurotoxicity is a frequent side effect of cytotoxic chemotherapy and affects a large number of patients. Despite the high medical need, few research efforts have addressed the impact of cytotoxic agents on cognition (ie, postchemotherapy cognitive impairment; PCCI). One unsolved question is whether individual cytotoxic drugs have differential effects on cognition. We thus examine the current state of research regarding PCCI. Neurological symptoms after targeted therapies and immunotherapies are not part of this review. Methods A literature search was conducted in the PubMed database, and 1215 articles were reviewed for predefined inclusion and exclusion criteria. Thirty articles were included in the systematic review. Results Twenty-five of the included studies report significant cognitive impairment. Of these, 21 studies investigated patients with breast cancer. Patients mainly received combinations of 5-fluorouracil, epirubicin, cyclophosphamide, doxorubicin, and taxanes (FEC/FEC-T). Five studies found no significant cognitive impairment in chemotherapy patients. Of these, 2 studies investigated patients with colon cancer receiving 5-fluorouracil and oxaliplatin (FOLFOX). Independent risk factors for PCCI were patient age, mood alterations, cognitive reserve, and the presence of apolipoprotein E e4 alleles. Conclusions There is evidence that certain chemotherapy regimens cause PCCI more frequently than others as evidenced by 21 out of 23 studies in breast cancer patients (mainly FEC-T), whereas 2 out of 3 studies with colon cancer patients (FOLFOX) did not observe significant changes. Further studies are needed defining patient cohorts by treatment protocol in addition to cancer type to elucidate the effects of individual cytotoxic drugs on cognitive functions.

scholarly journals Severe Oral Mucositis in Pediatric Cancer Patients: Survival Analysis and Predictive Factors

2020 ◽  
Vol 17 (4) ◽  
pp. 1235
Author(s):  
Lecidamia Cristina Leite Damascena ◽  
Nyellisonn Nando Nóbrega de Lucena ◽  
Isabella Lima Arrais Ribeiro ◽  
Tarciana Liberal Pereira ◽  
Luiz Medeiros Araújo Lima-Filho ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Solid Tumors ◽  
Oral Mucositis ◽  
Associated Factors ◽  
Pediatric Patients ◽  
Hematologic Malignancies ◽  
Chemotherapeutic Agents ◽  
Cancer Type ◽  
Pediatric Cancer Patients ◽  
Severe Oral Mucositis

This paper investigates the occurrence of severe oral mucositis and associated factors in blood and solid cancer pediatric patients subjected to cancer treatment, using a survival analysis. A longitudinal, descriptive, observational and inductive study of 142 pediatric patients aged from 0 to 19 years was conducted from 2013 to 2017. Data were collected using a form to record the sociodemographic characteristics and health-related aspects of patients and the modified Oral Assessment Guide (OAG). Survival analysis was performed using the Kaplan–Meier method and Cox semiparametric model. The median times to occurrence of severe oral mucositis were 35.3 and 77.1 days for patients with hematologic malignancies and solid tumors, respectively. The Cox model showed that white cell changes and platelet counts as well as the use of natural chemotherapeutic agents are risk factors for the occurrence of oral mucositis among patients with hematologic malignancies. Nonetheless, among patients with solid tumors, the occurrence of oral mucositis was associated with female sex, mixed ethnicity, the presence of metastasis, abnormal creatinine levels, a combination of chemotherapy, radiotherapy, and surgery, and the administration of chemotherapeutic agents included in the miscellaneous group. The time to occurrence of severe oral mucositis and its associated factors varied according to cancer type.

Study on the Application of Data Mining Based on Campus Card Platform

2013 ◽  
Vol 846-847 ◽  
pp. 977-980 ◽  
Author(s):  
Yuan Qian ◽  
Quan Shi
Keyword(s):  
College Students ◽  
Data Mining ◽  
Time Series ◽  
Statistical Methods ◽  
Business Intelligence ◽  
Sql Server ◽  
Policy Makers ◽  
University Policy ◽  
Development Tools ◽  
Intelligence Development

The thesis uses data in the database of campus card platform as the analysis object, combined with statistical methods and data mining technology to analyze the students consumption and the situation of the canteens. We use the Microsoft .NET and SQL Server 2008 business intelligence development tools to mine and analyze these data; know canteens consumption and learn about the business status and the popular shops of the canteen by using the K-means algorithm; analyze and predict students behavior and the situation of the canteen by using time series algorithm. It is convenient to manage the college students, and provide data support for university policy makers and shoppers to make plans.

scholarly journals Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

2020 ◽  
Vol 21 (15) ◽  
pp. 5484 ◽  
Author(s):  
Tae Jin Kim ◽  
Kyo Chul Koo
Keyword(s):  
Prostate Cancer ◽  
Solid Tumors ◽  
Treatment Modality ◽  
Cytotoxic Agents ◽  
Therapeutic Modality ◽  
Current Status ◽  
Molecular Diagnostic ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against cancer cells shows potential as a therapeutic modality for various solid tumors and hematologic malignancies. With technological advances over the last decade, immunotherapy has become an integral treatment modality for advanced solid tumors. The feasibility of immunotherapy has shown promise for patients with PCa, and with advances in molecular diagnostic platforms and our understanding of immune mechanisms, immunotherapy is reemerging as a potential treatment modality for PCa. Various combinations of individualized immunotherapy and immune checkpoint blockers with androgen receptor-targeted therapies and conventional cytotoxic agents show promise. This article will review the current status of immunotherapy, including new discoveries and precision approaches to PCa, and discuss future directions in the continuously evolving landscape of immunotherapy.

Assessing the validity of surrogate endpoints in the context of a controversy about the measurement of effectiveness of hepatitis C virus treatment

2018 ◽  
Vol 23 (2) ◽  
pp. 50-53 ◽  
Author(s):  
Claudia C Dobler ◽  
Rebecca L Morgan ◽  
Yngve Falck-Ytter ◽  
Victor M Montori ◽  
M Hassan Murad
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Low Density Lipoprotein ◽  
Sustained Viral Response ◽  
Density Lipoprotein ◽  
Surrogate Endpoint ◽  
Glycated Haemoglobin ◽  
Surrogate Endpoints ◽  
Indirect Measures ◽  
Based Medicine

Surrogate endpoints are often used in clinical trials, as they allow for indirect measures of outcomes (eg, shorter trials with less participants). Improvements in surrogate endpoints (eg, reduction in low density lipoprotein cholesterol, normalisation of glycated haemoglobin) achieved with an intervention are, however, not always associated with improvements in patient-important outcomes. The common tendency in evidence-based medicine is to view results based on surrogate endpoints as less certain than results based on long term, final patient-important outcomes and rate them as ‘lower quality evidence’. However, careful appraisal of the validity of a surrogate endpoint as a measure of the final, patient-important outcome is more useful than an automatic judgement. In this guide, we use a contemporary and currently highly debated example of the surrogate endpoint ‘sustained viral response’ (ie, viral eradication considered to represent successful treatment) in patients treated for chronic hepatitis C virus. We demonstrate how the validity of a surrogate endpoint can be critically appraised to assess the quality of the evidence (ie, the certainty in estimates) and the implications for decision-making.

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