Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes

Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on on...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cancer 2021-06, Vol.127 (12), p.1984-1992
Hauptverfasser: Kiong, Kimberley L., Yao, Christopher M. K. L., Lin, Fang‐Yu, Bell, Diana, Ferrarotto, Renata, Weber, Randal S., Lewis, Carol M.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1992
container_issue 12
container_start_page 1984
container_title Cancer
container_volume 127
creator Kiong, Kimberley L.
Yao, Christopher M. K. L.
Lin, Fang‐Yu
Bell, Diana
Ferrarotto, Renata
Weber, Randal S.
Lewis, Carol M.
description Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM‐free rate, and disease‐free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow‐up of 24.7 months. The 3‐year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3‐year DM‐free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3‐year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84‐13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13‐8.00) were significant independent predictors of a poorer DM‐free rate. Weight loss > 10% (HR, 5.53; 95% CI, 1.02‐30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery. A delay to surgery after neoadjuvant chemotherapy for head and neck squamous cell carcinoma results in a higher distant metastasis rate and poorer disease‐free survival.
doi_str_mv 10.1002/cncr.33471
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2494293909</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2531322680</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4591-d3a95602809b2a61a11579d7ca46a834908c8434e233316034ca20ee80a11f83</originalsourceid><addsrcrecordid>eNp90U1r3DAQBmBRWppt2kt-QBH0EgpORh_-0DFs0g8ILYQcehMTeZz1xrY2ktXif19tN-mhh57EwMPLaF7GTgScCQB57iYXzpTStXjBVgJMXYDQ8iVbAUBTlFr9OGJvYtzmsZales2OlKqUAA0rFi9pwIXPnscU7iksHLuZAp_IY7tNP3GaudvQ6OcNBdwtvJ_4hrDlOLUZuQceHxOOPkXuaBi4w-D6yY-Yczpyc-R-cn7w973jPs3OjxTfslcdDpHePb3H7PbT1e36S3H9_fPX9cV14XRpRNEqNGUFsgFzJ7ESKERZm7Z2qCtslDbQuEYrTVIpJSpQ2qEEogay7Bp1zE4PsbvgHxPF2Y593C-J-XMpWqmNlkYZMJl--IdufQpTXs7mgwklZdVAVh8PygUfY6DO7kI_YlisALtvwu6bsH-ayPj9U2S6G6n9S59Pn4E4gF_9QMt_ouz62_rmEPobzDOTGw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2531322680</pqid></control><display><type>article</type><title>Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes</title><source>MEDLINE</source><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Kiong, Kimberley L. ; Yao, Christopher M. K. L. ; Lin, Fang‐Yu ; Bell, Diana ; Ferrarotto, Renata ; Weber, Randal S. ; Lewis, Carol M.</creator><creatorcontrib>Kiong, Kimberley L. ; Yao, Christopher M. K. L. ; Lin, Fang‐Yu ; Bell, Diana ; Ferrarotto, Renata ; Weber, Randal S. ; Lewis, Carol M.</creatorcontrib><description>Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM‐free rate, and disease‐free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow‐up of 24.7 months. The 3‐year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3‐year DM‐free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3‐year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84‐13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13‐8.00) were significant independent predictors of a poorer DM‐free rate. Weight loss &gt; 10% (HR, 5.53; 95% CI, 1.02‐30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery. A delay to surgery after neoadjuvant chemotherapy for head and neck squamous cell carcinoma results in a higher distant metastasis rate and poorer disease‐free survival.</description><identifier>ISSN: 0008-543X</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/cncr.33471</identifier><identifier>PMID: 33631040</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Benchmarks ; Cancer ; Chemotherapy ; Confidence intervals ; Disease-Free Survival ; Head &amp; neck cancer ; head and neck neoplasms ; Head and Neck Neoplasms - drug therapy ; Head and Neck Neoplasms - surgery ; Humans ; Metastases ; Multivariate analysis ; Neoadjuvant Therapy ; Neoplasm Recurrence, Local - pathology ; Oncology ; Patients ; Regression analysis ; Retrospective Studies ; Squamous cell carcinoma ; Squamous Cell Carcinoma of Head and Neck - drug therapy ; Squamous Cell Carcinoma of Head and Neck - surgery ; Statistical analysis ; Surgery ; Survival ; Weight loss</subject><ispartof>Cancer, 2021-06, Vol.127 (12), p.1984-1992</ispartof><rights>2021 American Cancer Society</rights><rights>2021 American Cancer Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4591-d3a95602809b2a61a11579d7ca46a834908c8434e233316034ca20ee80a11f83</citedby><cites>FETCH-LOGICAL-c4591-d3a95602809b2a61a11579d7ca46a834908c8434e233316034ca20ee80a11f83</cites><orcidid>0000-0001-6999-4195 ; 0000-0002-3561-215X ; 0000-0002-3531-8241 ; 0000-0003-0346-716X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcncr.33471$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcncr.33471$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,1434,27926,27927,45576,45577,46411,46835</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33631040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kiong, Kimberley L.</creatorcontrib><creatorcontrib>Yao, Christopher M. K. L.</creatorcontrib><creatorcontrib>Lin, Fang‐Yu</creatorcontrib><creatorcontrib>Bell, Diana</creatorcontrib><creatorcontrib>Ferrarotto, Renata</creatorcontrib><creatorcontrib>Weber, Randal S.</creatorcontrib><creatorcontrib>Lewis, Carol M.</creatorcontrib><title>Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes</title><title>Cancer</title><addtitle>Cancer</addtitle><description>Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM‐free rate, and disease‐free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow‐up of 24.7 months. The 3‐year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3‐year DM‐free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3‐year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84‐13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13‐8.00) were significant independent predictors of a poorer DM‐free rate. Weight loss &gt; 10% (HR, 5.53; 95% CI, 1.02‐30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery. A delay to surgery after neoadjuvant chemotherapy for head and neck squamous cell carcinoma results in a higher distant metastasis rate and poorer disease‐free survival.</description><subject>Benchmarks</subject><subject>Cancer</subject><subject>Chemotherapy</subject><subject>Confidence intervals</subject><subject>Disease-Free Survival</subject><subject>Head &amp; neck cancer</subject><subject>head and neck neoplasms</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - surgery</subject><subject>Humans</subject><subject>Metastases</subject><subject>Multivariate analysis</subject><subject>Neoadjuvant Therapy</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Oncology</subject><subject>Patients</subject><subject>Regression analysis</subject><subject>Retrospective Studies</subject><subject>Squamous cell carcinoma</subject><subject>Squamous Cell Carcinoma of Head and Neck - drug therapy</subject><subject>Squamous Cell Carcinoma of Head and Neck - surgery</subject><subject>Statistical analysis</subject><subject>Surgery</subject><subject>Survival</subject><subject>Weight loss</subject><issn>0008-543X</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90U1r3DAQBmBRWppt2kt-QBH0EgpORh_-0DFs0g8ILYQcehMTeZz1xrY2ktXif19tN-mhh57EwMPLaF7GTgScCQB57iYXzpTStXjBVgJMXYDQ8iVbAUBTlFr9OGJvYtzmsZales2OlKqUAA0rFi9pwIXPnscU7iksHLuZAp_IY7tNP3GaudvQ6OcNBdwtvJ_4hrDlOLUZuQceHxOOPkXuaBi4w-D6yY-Yczpyc-R-cn7w973jPs3OjxTfslcdDpHePb3H7PbT1e36S3H9_fPX9cV14XRpRNEqNGUFsgFzJ7ESKERZm7Z2qCtslDbQuEYrTVIpJSpQ2qEEogay7Bp1zE4PsbvgHxPF2Y593C-J-XMpWqmNlkYZMJl--IdufQpTXs7mgwklZdVAVh8PygUfY6DO7kI_YlisALtvwu6bsH-ayPj9U2S6G6n9S59Pn4E4gF_9QMt_ouz62_rmEPobzDOTGw</recordid><startdate>20210615</startdate><enddate>20210615</enddate><creator>Kiong, Kimberley L.</creator><creator>Yao, Christopher M. K. L.</creator><creator>Lin, Fang‐Yu</creator><creator>Bell, Diana</creator><creator>Ferrarotto, Renata</creator><creator>Weber, Randal S.</creator><creator>Lewis, Carol M.</creator><general>Wiley Subscription Services, Inc</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>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6999-4195</orcidid><orcidid>https://orcid.org/0000-0002-3561-215X</orcidid><orcidid>https://orcid.org/0000-0002-3531-8241</orcidid><orcidid>https://orcid.org/0000-0003-0346-716X</orcidid></search><sort><creationdate>20210615</creationdate><title>Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes</title><author>Kiong, Kimberley L. ; Yao, Christopher M. K. L. ; Lin, Fang‐Yu ; Bell, Diana ; Ferrarotto, Renata ; Weber, Randal S. ; Lewis, Carol M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4591-d3a95602809b2a61a11579d7ca46a834908c8434e233316034ca20ee80a11f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Benchmarks</topic><topic>Cancer</topic><topic>Chemotherapy</topic><topic>Confidence intervals</topic><topic>Disease-Free Survival</topic><topic>Head &amp; neck cancer</topic><topic>head and neck neoplasms</topic><topic>Head and Neck Neoplasms - drug therapy</topic><topic>Head and Neck Neoplasms - surgery</topic><topic>Humans</topic><topic>Metastases</topic><topic>Multivariate analysis</topic><topic>Neoadjuvant Therapy</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Oncology</topic><topic>Patients</topic><topic>Regression analysis</topic><topic>Retrospective Studies</topic><topic>Squamous cell carcinoma</topic><topic>Squamous Cell Carcinoma of Head and Neck - drug therapy</topic><topic>Squamous Cell Carcinoma of Head and Neck - surgery</topic><topic>Statistical analysis</topic><topic>Surgery</topic><topic>Survival</topic><topic>Weight loss</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kiong, Kimberley L.</creatorcontrib><creatorcontrib>Yao, Christopher M. K. L.</creatorcontrib><creatorcontrib>Lin, Fang‐Yu</creatorcontrib><creatorcontrib>Bell, Diana</creatorcontrib><creatorcontrib>Ferrarotto, Renata</creatorcontrib><creatorcontrib>Weber, Randal S.</creatorcontrib><creatorcontrib>Lewis, Carol M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kiong, Kimberley L.</au><au>Yao, Christopher M. K. L.</au><au>Lin, Fang‐Yu</au><au>Bell, Diana</au><au>Ferrarotto, Renata</au><au>Weber, Randal S.</au><au>Lewis, Carol M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes</atitle><jtitle>Cancer</jtitle><addtitle>Cancer</addtitle><date>2021-06-15</date><risdate>2021</risdate><volume>127</volume><issue>12</issue><spage>1984</spage><epage>1992</epage><pages>1984-1992</pages><issn>0008-543X</issn><eissn>1097-0142</eissn><abstract>Background Neoadjuvant chemotherapy (NAC) is used in head and neck squamous cell carcinoma (HNSCC) for downstaging advanced disease and decreasing distant metastasis (DM). To the authors' knowledge, no study has specifically examined the impact of a delayed time to surgery (TTS) after NAC on oncologic outcomes. They thus aimed to identify a cutoff for TTS after NAC and its effect on survival indices. Methods This was a retrospective review of all patients with HNSCC receiving NAC followed by surgery with curative intent between March 2016 and March 2019 at the MD Anderson Cancer Center. Receiver operating characteristic analysis was used to identify a cutoff for TTS, and this cutoff was used to analyze the overall survival (OS), locoregional recurrence rate, DM‐free rate, and disease‐free survival (DFS). A multivariate Cox regression analysis was performed. Results One hundred one patients were analyzed with a median follow‐up of 24.7 months. The 3‐year OS and locoregional recurrence rates did not differ with a TTS ≥ 34 days. However, the 3‐year DM‐free rate was significantly worse (56% vs 90%; P = .001) in the group with a TTS ≥ 34 days, and the 3‐year DFS was significantly lower (26% vs 64%; P = .006). In a multivariate analysis, a TTS ≥ 34 days (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.84‐13.13) and extracapsular extension (HR, 3.01; 95% CI, 1.13‐8.00) were significant independent predictors of a poorer DM‐free rate. Weight loss &gt; 10% (HR, 5.53; 95% CI, 1.02‐30.24) was the only independent predictor for a TTS ≥ 34 days. Conclusions Emphasis should be placed on early definitive locoregional treatment after NAC, particularly in patients who do not respond to NAC. There is a need to validate these findings and establish new benchmarks for the interval between NAC and surgery. A delay to surgery after neoadjuvant chemotherapy for head and neck squamous cell carcinoma results in a higher distant metastasis rate and poorer disease‐free survival.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33631040</pmid><doi>10.1002/cncr.33471</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-6999-4195</orcidid><orcidid>https://orcid.org/0000-0002-3561-215X</orcidid><orcidid>https://orcid.org/0000-0002-3531-8241</orcidid><orcidid>https://orcid.org/0000-0003-0346-716X</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0008-543X
ispartof Cancer, 2021-06, Vol.127 (12), p.1984-1992
issn 0008-543X
1097-0142
language eng
recordid cdi_proquest_miscellaneous_2494293909
source MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Benchmarks
Cancer
Chemotherapy
Confidence intervals
Disease-Free Survival
Head & neck cancer
head and neck neoplasms
Head and Neck Neoplasms - drug therapy
Head and Neck Neoplasms - surgery
Humans
Metastases
Multivariate analysis
Neoadjuvant Therapy
Neoplasm Recurrence, Local - pathology
Oncology
Patients
Regression analysis
Retrospective Studies
Squamous cell carcinoma
Squamous Cell Carcinoma of Head and Neck - drug therapy
Squamous Cell Carcinoma of Head and Neck - surgery
Statistical analysis
Surgery
Survival
Weight loss
title Delay to surgery after neoadjuvant chemotherapy in head and neck squamous cell carcinoma affects oncologic outcomes
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T11%3A22%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Delay%20to%20surgery%20after%20neoadjuvant%20chemotherapy%20in%20head%20and%20neck%20squamous%20cell%20carcinoma%20affects%20oncologic%20outcomes&rft.jtitle=Cancer&rft.au=Kiong,%20Kimberley%20L.&rft.date=2021-06-15&rft.volume=127&rft.issue=12&rft.spage=1984&rft.epage=1992&rft.pages=1984-1992&rft.issn=0008-543X&rft.eissn=1097-0142&rft_id=info:doi/10.1002/cncr.33471&rft_dat=%3Cproquest_cross%3E2531322680%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2531322680&rft_id=info:pmid/33631040&rfr_iscdi=true