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

Tamura, Koichi; Takenaka, Yukinori; Hosokawa, Kiyohito; Sato, Takashi; Tsuda, Takeshi; Eguchi, Hirotaka; Suzuki, Masami; Fukusumi, Takahito; Suzuki, Motoyuki; Inohara, Hidenori

doi:https://doi.org/10.1371/journal.pone.0314209

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

Tamura, Koichi; Takenaka, Yukinori; Hosokawa, Kiyohito et al.

PLoS ONE, 2024, 19(11), e0314209

Number of Access:1,546（2025-08-13 22:44 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/99700

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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
Creator	CreatorName Tamura, Koichi
	NRID 1000040598398 1000040598398 ORCID 0000-0002-3135-5635 0000-0002-3135-5635 researchmap permalink yukinoritakenaka yukinoritakenaka Scopus Author ID 7102054128 7102054128 CreatorName Takenaka, Yukinori
	NRID 1000060625896 1000060625896 researchmap permalink drink drink Scopus Author ID 55914870000 55914870000 ORCID 0000-0002-5169-1038 0000-0002-5169-1038 CreatorName Hosokawa, Kiyohito
	NRID 1000030756002 1000030756002 researchmap permalink 4501 4501 Scopus Author ID 7406982585 7406982585 CreatorName Sato, Takashi
	NRID 1000000778631 1000000778631 researchmap permalink gam92471 gam92471 CreatorName Tsuda, Takeshi
	researchmap permalink eguchi-hirotaka eguchi-hirotaka Scopus Author ID 57203344374 57203344374 CreatorName Eguchi, Hirotaka
	NRID 1000080434182 1000080434182 researchmap permalink msuzukicgi msuzukicgi Scopus Author ID 57199980789 57199980789 CreatorName Suzuki, Masami
	NRID 1000070623734 1000070623734 researchmap permalink 2933 2933 Scopus Author ID 54893429600 54893429600 ORCID 0009-0002-1857-7548 0009-0002-1857-7548 CreatorName Fukusumi, Takahito
	NRID 1000050632329 1000050632329 researchmap permalink motoyukisuzuki motoyukisuzuki Scopus Author ID 55505806400 55505806400 CreatorName Suzuki, Motoyuki
	NRID 1000000273657 1000000273657 researchmap permalink read0046473 read0046473 Scopus Author ID 7004501837 7004501837 CreatorName Inohara, Hidenori
Description	Tamura K et al. (2024) 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. PLoS ONE 19(11): e0314209 doi: 10.1371/journal.pone.0314209.
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.
Publisher	Public Library of Science
Source Title	PLoS ONE
Volume (Issue)	19(11)
Page	e0314209
Date of Issued	2024-11-25
Language	English
Handle URL	https://hdl.handle.net/11094/99700
eISSN	19326203
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1371/journal.pone.0314209
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	PLoS ONE. 2024, 19(11), p. e0314209
DC.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
DC.creator	Tamura, Koichi
	Takenaka, Yukinori
	Hosokawa, Kiyohito
	Sato, Takashi
	Tsuda, Takeshi
	Eguchi, Hirotaka
	Suzuki, Masami
	Fukusumi, Takahito
	Suzuki, Motoyuki
	Inohara, Hidenori
DC.publisher	Public Library of Science
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-11-25
DC.identifier	https://doi.org/10.1371/journal.pone.0314209
DC.description	Tamura K et al. (2024) 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. PLoS ONE 19(11): e0314209 doi: 10.1371/journal.pone.0314209.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	99700
citation_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
citation_author	Tamura, Koichi
	Takenaka, Yukinori
	Hosokawa, Kiyohito
	Sato, Takashi
	Tsuda, Takeshi
	Eguchi, Hirotaka
	Suzuki, Masami
	Fukusumi, Takahito
	Suzuki, Motoyuki
	Inohara, Hidenori
citation_publisher	Public Library of Science
citation_language	English
citation_date	2024-11-25
citation_journal_title	PLoS ONE
citation_volume	19
citation_issue	11
citation_firstpage	e0314209
citation_doi	https://doi.org/10.1371/journal.pone.0314209
citation_public_url	https://hdl.handle.net/11094/99700

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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