Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients
Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We...
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| creator | Khuri, Fadlo R. Lee, J. Jack Lippman, Scott M. Kim, Edward S. Cooper, Jay S. Benner, Steven E. Winn, Rodger Pajak, Thomas F. Williams, Brendell Shenouda, George Hodson, Ian Fu, Karen Shin, Dong M. Vokes, Everett E. Feng, Lei Goepfert, Helmuth Hong, Waun Ki |
| description | Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC. |
| doi_str_mv | 10.1093/jnci/djj091 |
| format | Article |
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Jack ; Lippman, Scott M. ; Kim, Edward S. ; Cooper, Jay S. ; Benner, Steven E. ; Winn, Rodger ; Pajak, Thomas F. ; Williams, Brendell ; Shenouda, George ; Hodson, Ian ; Fu, Karen ; Shin, Dong M. ; Vokes, Everett E. ; Feng, Lei ; Goepfert, Helmuth ; Hong, Waun Ki</creator><creatorcontrib>Khuri, Fadlo R. ; Lee, J. Jack ; Lippman, Scott M. ; Kim, Edward S. ; Cooper, Jay S. ; Benner, Steven E. ; Winn, Rodger ; Pajak, Thomas F. ; Williams, Brendell ; Shenouda, George ; Hodson, Ian ; Fu, Karen ; Shin, Dong M. ; Vokes, Everett E. ; Feng, Lei ; Goepfert, Helmuth ; Hong, Waun Ki</creatorcontrib><description>Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.</description><identifier>ISSN: 0027-8874</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djj091</identifier><identifier>PMID: 16595780</identifier><identifier>CODEN: JNCIEQ</identifier><language>eng</language><publisher>Cary, NC: Oxford University Press</publisher><subject><![CDATA[Aged ; Anticarcinogenic Agents - administration & dosage ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Biological and medical sciences ; Carcinoma, Squamous Cell - prevention & control ; Carcinoma, Squamous Cell - secondary ; Chemotherapy ; Clinical trials ; Disease-Free Survival ; Drug Administration Schedule ; Drugs ; Female ; Head & neck cancer ; Head and Neck Neoplasms - pathology ; Humans ; Isotretinoin - administration & dosage ; Male ; Medical sciences ; Multivariate Analysis ; Neoplasm Staging ; Neoplasms, Second Primary - etiology ; Neoplasms, Second Primary - prevention & control ; Odds Ratio ; Oncology ; Patient Selection ; Pharmacology. Drug treatments ; Proportional Hazards Models ; Risk Factors ; Smoking - adverse effects ; Survival Analysis ; Treatment Failure ; Tumors]]></subject><ispartof>JNCI : Journal of the National Cancer Institute, 2006-04, Vol.98 (7), p.441-450</ispartof><rights>2006 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Apr 5, 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c448t-4a18756f8b129d89b481f24eccc60c428992f53e66a48b66bf200fd1090e9f83</citedby><cites>FETCH-LOGICAL-c448t-4a18756f8b129d89b481f24eccc60c428992f53e66a48b66bf200fd1090e9f83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17691614$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16595780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Khuri, Fadlo R.</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>Lippman, Scott M.</creatorcontrib><creatorcontrib>Kim, Edward S.</creatorcontrib><creatorcontrib>Cooper, Jay S.</creatorcontrib><creatorcontrib>Benner, Steven E.</creatorcontrib><creatorcontrib>Winn, Rodger</creatorcontrib><creatorcontrib>Pajak, Thomas F.</creatorcontrib><creatorcontrib>Williams, Brendell</creatorcontrib><creatorcontrib>Shenouda, George</creatorcontrib><creatorcontrib>Hodson, Ian</creatorcontrib><creatorcontrib>Fu, Karen</creatorcontrib><creatorcontrib>Shin, Dong M.</creatorcontrib><creatorcontrib>Vokes, Everett E.</creatorcontrib><creatorcontrib>Feng, Lei</creatorcontrib><creatorcontrib>Goepfert, Helmuth</creatorcontrib><creatorcontrib>Hong, Waun Ki</creatorcontrib><title>Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>JNCI J Natl Cancer Inst</addtitle><description>Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.</description><subject>Aged</subject><subject>Anticarcinogenic Agents - administration & dosage</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Squamous Cell - prevention & control</subject><subject>Carcinoma, Squamous Cell - secondary</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Disease-Free Survival</subject><subject>Drug Administration Schedule</subject><subject>Drugs</subject><subject>Female</subject><subject>Head & neck cancer</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Humans</subject><subject>Isotretinoin - administration & dosage</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Multivariate Analysis</subject><subject>Neoplasm Staging</subject><subject>Neoplasms, Second Primary - etiology</subject><subject>Neoplasms, Second Primary - prevention & control</subject><subject>Odds Ratio</subject><subject>Oncology</subject><subject>Patient Selection</subject><subject>Pharmacology. Drug treatments</subject><subject>Proportional Hazards Models</subject><subject>Risk Factors</subject><subject>Smoking - adverse effects</subject><subject>Survival Analysis</subject><subject>Treatment Failure</subject><subject>Tumors</subject><issn>0027-8874</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkV-P1CAUxYnRuOPqk--GmLgvpi5QSuHRTJydSSbr6s6D8YVQCkq3hRXa9c9X8EtL7cRN5AVy749zb84B4DlGbzAS5XnntTtvuw4J_ACsMGWoIBhVD8EKIVIXnNf0BDxJqUP5CEIfgxPMKlHVHK3A74_Kt2Fwv0wLr76qZOBut4OH6FQPg4X78L1ow1xNYYxmdD44D22I8CqaO-NHF_zMXRsdfFaIblDxJzxMQ4gJZvR6VF_yb5inZGW4Nar9-740-gauldcmS6nRZan0FDyyqk_m2fE-BYfNu8N6W-zfX-zWb_eFppSPBVWY1xWzvMFEtFw0lGNLqNFaM6Qp4UIQW5WGMUV5w1hjCUK2zV4hIywvT8HZInsbw7fJpFEOLmnT98qbMCXJal4SxusMvvwP7MIUfV5NkuwwqRClGXq9QDqGlKKx8nYxQWIk53zknI9c8sn0i6Pk1AymvWePgWTg1RFQSavexmyRS_dczQRmeB5bLJxLo_nxr6_iTd6_rCu5_fRZXqIPF_UGbyQr_wCUL6dX</recordid><startdate>20060405</startdate><enddate>20060405</enddate><creator>Khuri, Fadlo R.</creator><creator>Lee, J. Jack</creator><creator>Lippman, Scott M.</creator><creator>Kim, Edward S.</creator><creator>Cooper, Jay S.</creator><creator>Benner, Steven E.</creator><creator>Winn, Rodger</creator><creator>Pajak, Thomas F.</creator><creator>Williams, Brendell</creator><creator>Shenouda, George</creator><creator>Hodson, Ian</creator><creator>Fu, Karen</creator><creator>Shin, Dong M.</creator><creator>Vokes, Everett E.</creator><creator>Feng, Lei</creator><creator>Goepfert, Helmuth</creator><creator>Hong, Waun Ki</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><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>7U9</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20060405</creationdate><title>Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients</title><author>Khuri, Fadlo R. ; Lee, J. Jack ; Lippman, Scott M. ; Kim, Edward S. ; Cooper, Jay S. ; Benner, Steven E. ; Winn, Rodger ; Pajak, Thomas F. ; Williams, Brendell ; Shenouda, George ; Hodson, Ian ; Fu, Karen ; Shin, Dong M. ; Vokes, Everett E. ; Feng, Lei ; Goepfert, Helmuth ; Hong, Waun Ki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-4a18756f8b129d89b481f24eccc60c428992f53e66a48b66bf200fd1090e9f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Aged</topic><topic>Anticarcinogenic Agents - administration & dosage</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Squamous Cell - prevention & control</topic><topic>Carcinoma, Squamous Cell - secondary</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Disease-Free Survival</topic><topic>Drug Administration Schedule</topic><topic>Drugs</topic><topic>Female</topic><topic>Head & neck cancer</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Humans</topic><topic>Isotretinoin - administration & dosage</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Multivariate Analysis</topic><topic>Neoplasm Staging</topic><topic>Neoplasms, Second Primary - etiology</topic><topic>Neoplasms, Second Primary - prevention & control</topic><topic>Odds Ratio</topic><topic>Oncology</topic><topic>Patient Selection</topic><topic>Pharmacology. Drug treatments</topic><topic>Proportional Hazards Models</topic><topic>Risk Factors</topic><topic>Smoking - adverse effects</topic><topic>Survival Analysis</topic><topic>Treatment Failure</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Khuri, Fadlo R.</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>Lippman, Scott M.</creatorcontrib><creatorcontrib>Kim, Edward S.</creatorcontrib><creatorcontrib>Cooper, Jay S.</creatorcontrib><creatorcontrib>Benner, Steven E.</creatorcontrib><creatorcontrib>Winn, Rodger</creatorcontrib><creatorcontrib>Pajak, Thomas F.</creatorcontrib><creatorcontrib>Williams, Brendell</creatorcontrib><creatorcontrib>Shenouda, George</creatorcontrib><creatorcontrib>Hodson, Ian</creatorcontrib><creatorcontrib>Fu, Karen</creatorcontrib><creatorcontrib>Shin, Dong M.</creatorcontrib><creatorcontrib>Vokes, Everett E.</creatorcontrib><creatorcontrib>Feng, Lei</creatorcontrib><creatorcontrib>Goepfert, Helmuth</creatorcontrib><creatorcontrib>Hong, Waun Ki</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><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>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Khuri, Fadlo R.</au><au>Lee, J. Jack</au><au>Lippman, Scott M.</au><au>Kim, Edward S.</au><au>Cooper, Jay S.</au><au>Benner, Steven E.</au><au>Winn, Rodger</au><au>Pajak, Thomas F.</au><au>Williams, Brendell</au><au>Shenouda, George</au><au>Hodson, Ian</au><au>Fu, Karen</au><au>Shin, Dong M.</au><au>Vokes, Everett E.</au><au>Feng, Lei</au><au>Goepfert, Helmuth</au><au>Hong, Waun Ki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>JNCI J Natl Cancer Inst</addtitle><date>2006-04-05</date><risdate>2006</risdate><volume>98</volume><issue>7</issue><spage>441</spage><epage>450</epage><pages>441-450</pages><issn>0027-8874</issn><eissn>1460-2105</eissn><coden>JNCIEQ</coden><abstract>Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.</abstract><cop>Cary, NC</cop><pub>Oxford University Press</pub><pmid>16595780</pmid><doi>10.1093/jnci/djj091</doi><tpages>10</tpages></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Aged Anticarcinogenic Agents - administration & dosage Antineoplastic agents Antineoplastic Agents - administration & dosage Biological and medical sciences Carcinoma, Squamous Cell - prevention & control Carcinoma, Squamous Cell - secondary Chemotherapy Clinical trials Disease-Free Survival Drug Administration Schedule Drugs Female Head & neck cancer Head and Neck Neoplasms - pathology Humans Isotretinoin - administration & dosage Male Medical sciences Multivariate Analysis Neoplasm Staging Neoplasms, Second Primary - etiology Neoplasms, Second Primary - prevention & control Odds Ratio Oncology Patient Selection Pharmacology. Drug treatments Proportional Hazards Models Risk Factors Smoking - adverse effects Survival Analysis Treatment Failure Tumors |
| title | Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients |
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