Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254
Summary Background Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, l...
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| creator | Thanarajasingam, Gita, Dr Atherton, Pamela J, MS Novotny, Paul J, MS Loprinzi, Charles L, Prof Sloan, Jeff A, Prof Grothey, Axel, Prof |
| description | Summary Background Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. Methods We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 ( NCT00003594 ), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. Findings In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p |
| doi_str_mv | 10.1016/S1470-2045(16)00038-3 |
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Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. Methods We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 ( NCT00003594 ), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. Findings In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). Interpretation The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. Funding National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(16)00038-3</identifier><identifier>PMID: 27083333</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; Adverse Drug Reaction Reporting Systems ; Aged ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Camptothecin - adverse effects ; Camptothecin - analogs & derivatives ; Cancer therapies ; Clinical trials ; Clinical Trials as Topic ; Colorectal cancer ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - pathology ; Data analysis ; Data collection ; Female ; Fluorouracil - adverse effects ; Grants ; Hematology, Oncology and Palliative Medicine ; Humans ; Leucovorin - adverse effects ; Long Term Adverse Effects - classification ; Long Term Adverse Effects - pathology ; Male ; Metastasis ; Methods ; Middle Aged ; Oncology ; Organoplatinum Compounds - adverse effects ; Quality of life ; Regulatory approval ; Toxicity ; Writing</subject><ispartof>The lancet oncology, 2016-05, Vol.17 (5), p.663-670</ispartof><rights>Elsevier Ltd</rights><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited May 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c561t-73e60d81a994a7d7a65d80cbb48b1080c5ccde4df38f3f586cdd1b1c4be0093b3</citedby><cites>FETCH-LOGICAL-c561t-73e60d81a994a7d7a65d80cbb48b1080c5ccde4df38f3f586cdd1b1c4be0093b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1786786805?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000,64390,64392,64394,72474</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27083333$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thanarajasingam, Gita, Dr</creatorcontrib><creatorcontrib>Atherton, Pamela J, MS</creatorcontrib><creatorcontrib>Novotny, Paul J, MS</creatorcontrib><creatorcontrib>Loprinzi, Charles L, Prof</creatorcontrib><creatorcontrib>Sloan, Jeff A, Prof</creatorcontrib><creatorcontrib>Grothey, Axel, Prof</creatorcontrib><title>Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Summary Background Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. Methods We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 ( NCT00003594 ), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. Findings In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). Interpretation The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. Funding National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.</description><subject>Adult</subject><subject>Adverse Drug Reaction Reporting Systems</subject><subject>Aged</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Camptothecin - adverse effects</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Clinical Trials as Topic</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Data analysis</subject><subject>Data collection</subject><subject>Female</subject><subject>Fluorouracil - adverse effects</subject><subject>Grants</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Leucovorin - adverse effects</subject><subject>Long Term Adverse Effects - classification</subject><subject>Long Term Adverse Effects - pathology</subject><subject>Male</subject><subject>Metastasis</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Organoplatinum Compounds - adverse effects</subject><subject>Quality of life</subject><subject>Regulatory approval</subject><subject>Toxicity</subject><subject>Writing</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkcFu1DAQhiMEoqXwCCBLXLaHgB3bscMBVK2gIK3KgXC2HHtSXJK4tZMVeQ5eGGezBakXLEsej7_5rZk_y14S_IZgUr79RpjAeYEZ35DyHGNMZU4fZacpzXLOpHx8iFfkJHsW4w3GRBDMn2YnhcCSpnWa_d754dqNk3WD7pC2ewgREOxhGJGOEWLsl9ANyA_Gd_56RqZzgzOJHoPTXXyHxh-Aav_LGTfOyCcFVLse0Cbl6nOkk_AcXUS-RRdd5_Rg4FiKrrbb-hJdVYKRxFlUiarg7Hn2pE2v8OJ4nmXfP32st5_z3dfLL9uLXW54ScZcUCixlURXFdPCCl1yK7FpGiYbglPEjbHAbEtlS1suS2MtaYhhDWBc0YaeZZtV9zb4uwniqHoXDXSdHsBPURFRCc5wWYiEvn6A3vgppM4WSpZpS8wTxVfKBB9jgFbdBtfrMCuC1eKaOrimFktUuh1cUzTVvTqqT00P9m_VvU0J-LACkMaxdxBUNA7SIK0LYEZlvfvvF-8fKNzb-BNmiP-6UbFQeBVZNEh5UKD0Dw0_urI</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Thanarajasingam, Gita, Dr</creator><creator>Atherton, Pamela J, MS</creator><creator>Novotny, Paul J, MS</creator><creator>Loprinzi, Charles L, Prof</creator><creator>Sloan, Jeff A, Prof</creator><creator>Grothey, Axel, Prof</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20160501</creationdate><title>Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254</title><author>Thanarajasingam, Gita, Dr ; Atherton, Pamela J, MS ; Novotny, Paul J, MS ; Loprinzi, Charles L, Prof ; Sloan, Jeff A, Prof ; Grothey, Axel, Prof</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c561t-73e60d81a994a7d7a65d80cbb48b1080c5ccde4df38f3f586cdd1b1c4be0093b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Adverse Drug Reaction Reporting Systems</topic><topic>Aged</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - pathology</topic><topic>Camptothecin - adverse effects</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Cancer therapies</topic><topic>Clinical trials</topic><topic>Clinical Trials as Topic</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Data analysis</topic><topic>Data collection</topic><topic>Female</topic><topic>Fluorouracil - adverse effects</topic><topic>Grants</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Leucovorin - adverse effects</topic><topic>Long Term Adverse Effects - classification</topic><topic>Long Term Adverse Effects - pathology</topic><topic>Male</topic><topic>Metastasis</topic><topic>Methods</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Organoplatinum Compounds - adverse effects</topic><topic>Quality of life</topic><topic>Regulatory approval</topic><topic>Toxicity</topic><topic>Writing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thanarajasingam, Gita, Dr</creatorcontrib><creatorcontrib>Atherton, Pamela J, MS</creatorcontrib><creatorcontrib>Novotny, Paul J, MS</creatorcontrib><creatorcontrib>Loprinzi, Charles L, Prof</creatorcontrib><creatorcontrib>Sloan, Jeff A, Prof</creatorcontrib><creatorcontrib>Grothey, Axel, Prof</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thanarajasingam, Gita, Dr</au><au>Atherton, Pamela J, MS</au><au>Novotny, Paul J, MS</au><au>Loprinzi, Charles L, Prof</au><au>Sloan, Jeff A, Prof</au><au>Grothey, Axel, Prof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>17</volume><issue>5</issue><spage>663</spage><epage>670</epage><pages>663-670</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><coden>LANCAO</coden><abstract>Summary Background Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. Methods We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 ( NCT00003594 ), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. Findings In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). Interpretation The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. Funding National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27083333</pmid><doi>10.1016/S1470-2045(16)00038-3</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Adverse Drug Reaction Reporting Systems Aged Antineoplastic Combined Chemotherapy Protocols - adverse effects Breast Neoplasms - drug therapy Breast Neoplasms - pathology Camptothecin - adverse effects Camptothecin - analogs & derivatives Cancer therapies Clinical trials Clinical Trials as Topic Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - pathology Data analysis Data collection Female Fluorouracil - adverse effects Grants Hematology, Oncology and Palliative Medicine Humans Leucovorin - adverse effects Long Term Adverse Effects - classification Long Term Adverse Effects - pathology Male Metastasis Methods Middle Aged Oncology Organoplatinum Compounds - adverse effects Quality of life Regulatory approval Toxicity Writing |
| title | Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254 |
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