Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma
Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately...
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| description | Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. In the landmark analysis, the 1-year PFS rates were 47.6% and 27.2% for irAE+ and irAE- patients, respectively (p = 0.049), and the 1-year OS rates were 85.7% and 66.5%, respectively (p = 0.006). Regarding PFS, the adjusted HRs for irAEs were 0.49 (95% confidence interval (CI) 0.28-0.85) in the PH analysis and 0.75 (95% CI 0.40-1.40) in the EC analysis. As for OS, the adjusted HRs for irAEs were 0.36 (95% CI 0.19-0.66) in the PH analysis and 0.51 (95% CI 0.27-0.95) in the EC analysis. IrAEs were an independent prognostic factor for OS but not PFS. Without considering the immortal time bias, the association between irAEs and oncologic outcomes in patients with HNSCC treated with ICIs was overestimated. Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings. |
| doi_str_mv | 10.1371/journal.pone.0314209 |
| format | Article |
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Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. In the landmark analysis, the 1-year PFS rates were 47.6% and 27.2% for irAE+ and irAE- patients, respectively (p = 0.049), and the 1-year OS rates were 85.7% and 66.5%, respectively (p = 0.006). Regarding PFS, the adjusted HRs for irAEs were 0.49 (95% confidence interval (CI) 0.28-0.85) in the PH analysis and 0.75 (95% CI 0.40-1.40) in the EC analysis. As for OS, the adjusted HRs for irAEs were 0.36 (95% CI 0.19-0.66) in the PH analysis and 0.51 (95% CI 0.27-0.95) in the EC analysis. IrAEs were an independent prognostic factor for OS but not PFS. Without considering the immortal time bias, the association between irAEs and oncologic outcomes in patients with HNSCC treated with ICIs was overestimated. Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0314209</identifier><identifier>PMID: 39585818</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Adverse events ; Aged ; Aged, 80 and over ; Analysis ; Bias ; Biology and life sciences ; Cancer ; Care and treatment ; Cell-mediated cytotoxicity ; Chemotherapy ; Cytotoxicity ; Development and progression ; Disease control ; Female ; Head & neck cancer ; Head and neck cancer ; Head and neck carcinoma ; Head and Neck Neoplasms - drug therapy ; Head and Neck Neoplasms - immunology ; Health aspects ; Hormone replacement therapy ; Human papillomavirus ; Humans ; Immune checkpoint inhibitors ; Immune Checkpoint Inhibitors - adverse effects ; Immune Checkpoint Inhibitors - therapeutic use ; Inhibitors ; Kaplan-Meier Estimate ; Male ; Medical prognosis ; Medicine and Health Sciences ; Metastases ; Middle Aged ; Oncology, Experimental ; Otolaryngology ; People and Places ; Prognosis ; Progression-Free Survival ; Proportional Hazards Models ; Regression analysis ; Research and Analysis Methods ; Retrospective Studies ; Risk factors ; Squamous cell carcinoma ; Squamous Cell Carcinoma of Head and Neck - drug therapy ; Squamous Cell Carcinoma of Head and Neck - immunology ; Statistical analysis ; Survival ; Thyroid gland ; Treatment Outcome</subject><ispartof>PloS one, 2024-11, Vol.19 (11), p.e0314209</ispartof><rights>Copyright: © 2024 Tamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2024 Public Library of Science</rights><rights>2024 Tamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 Tamura et al 2024 Tamura et al</rights><rights>2024 Tamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c616t-2f39df854406f4904e7fe4399808decb41c064ff729faa302f6aebd42a5e5c4f3</cites><orcidid>0000-0002-3135-5635</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11588234/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11588234/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39585818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tamura, Koichi</creatorcontrib><creatorcontrib>Takenaka, Yukinori</creatorcontrib><creatorcontrib>Hosokawa, Kiyohito</creatorcontrib><creatorcontrib>Sato, Takashi</creatorcontrib><creatorcontrib>Tsuda, Takeshi</creatorcontrib><creatorcontrib>Eguchi, Hirotaka</creatorcontrib><creatorcontrib>Suzuki, Masami</creatorcontrib><creatorcontrib>Fukusumi, Takahito</creatorcontrib><creatorcontrib>Suzuki, Motoyuki</creatorcontrib><creatorcontrib>Inohara, Hidenori</creatorcontrib><title>Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. 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Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings.</description><subject>Adult</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Analysis</subject><subject>Bias</subject><subject>Biology and life sciences</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell-mediated cytotoxicity</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Development and progression</subject><subject>Disease control</subject><subject>Female</subject><subject>Head & neck cancer</subject><subject>Head and neck cancer</subject><subject>Head and neck carcinoma</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - immunology</subject><subject>Health aspects</subject><subject>Hormone replacement therapy</subject><subject>Human 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Head and Neck - immunology</subject><subject>Statistical analysis</subject><subject>Survival</subject><subject>Thyroid gland</subject><subject>Treatment 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Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tamura, Koichi</au><au>Takenaka, Yukinori</au><au>Hosokawa, Kiyohito</au><au>Sato, Takashi</au><au>Tsuda, Takeshi</au><au>Eguchi, Hirotaka</au><au>Suzuki, Masami</au><au>Fukusumi, Takahito</au><au>Suzuki, Motoyuki</au><au>Inohara, Hidenori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2024-11-25</date><risdate>2024</risdate><volume>19</volume><issue>11</issue><spage>e0314209</spage><pages>e0314209-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. In the landmark analysis, the 1-year PFS rates were 47.6% and 27.2% for irAE+ and irAE- patients, respectively (p = 0.049), and the 1-year OS rates were 85.7% and 66.5%, respectively (p = 0.006). Regarding PFS, the adjusted HRs for irAEs were 0.49 (95% confidence interval (CI) 0.28-0.85) in the PH analysis and 0.75 (95% CI 0.40-1.40) in the EC analysis. As for OS, the adjusted HRs for irAEs were 0.36 (95% CI 0.19-0.66) in the PH analysis and 0.51 (95% CI 0.27-0.95) in the EC analysis. IrAEs were an independent prognostic factor for OS but not PFS. Without considering the immortal time bias, the association between irAEs and oncologic outcomes in patients with HNSCC treated with ICIs was overestimated. Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>39585818</pmid><doi>10.1371/journal.pone.0314209</doi><tpages>e0314209</tpages><orcidid>https://orcid.org/0000-0002-3135-5635</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2024-11, Vol.19 (11), p.e0314209 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_3132776072 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adult Adverse events Aged Aged, 80 and over Analysis Bias Biology and life sciences Cancer Care and treatment Cell-mediated cytotoxicity Chemotherapy Cytotoxicity Development and progression Disease control Female Head & neck cancer Head and neck cancer Head and neck carcinoma Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - immunology Health aspects Hormone replacement therapy Human papillomavirus Humans Immune checkpoint inhibitors Immune Checkpoint Inhibitors - adverse effects Immune Checkpoint Inhibitors - therapeutic use Inhibitors Kaplan-Meier Estimate Male Medical prognosis Medicine and Health Sciences Metastases Middle Aged Oncology, Experimental Otolaryngology People and Places Prognosis Progression-Free Survival Proportional Hazards Models Regression analysis Research and Analysis Methods Retrospective Studies Risk factors Squamous cell carcinoma Squamous Cell Carcinoma of Head and Neck - drug therapy Squamous Cell Carcinoma of Head and Neck - immunology Statistical analysis Survival Thyroid gland Treatment Outcome |
| title | Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma |
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