Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

Aarti K. Bhatia, Ju Whei Lee, Harlan A. Pinto, Charlotte D. Jacobs, Paul John Limburg, Philip Rubin, Robert M. Arusell, Eamonn P. Dunphy, Janardan D. Khandekar, Seth A. Reiner, Luis Baez-Diaz, Paul Celano, Shuli Li, Yi Li, Barbara A. Burtness, George L. Adams, Kishan J. Pandya

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P =.61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P =.61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P =.14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P =.057) and among women (N = 39; HR, 0.44; P =.065) and never/former smokers (N = 129; HR, 0.61; P =.055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662.

Original languageEnglish (US)
Pages (from-to)4653-4662
Number of pages10
JournalCancer
Volume123
Issue number23
DOIs
StatePublished - Dec 1 2017

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Isotretinoin
Primary Prevention
Head and Neck Neoplasms
Research
Squamous Cell Neoplasms
Neoplasms
Survival
Placebos
Incidence
Cheilitis
Vitamin A
Therapeutics
Weights and Measures
Skin

Keywords

  • chemoprevention
  • head and neck cancer
  • oral cancer
  • randomized controlled trial
  • second primary cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer : Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590). / Bhatia, Aarti K.; Lee, Ju Whei; Pinto, Harlan A.; Jacobs, Charlotte D.; Limburg, Paul John; Rubin, Philip; Arusell, Robert M.; Dunphy, Eamonn P.; Khandekar, Janardan D.; Reiner, Seth A.; Baez-Diaz, Luis; Celano, Paul; Li, Shuli; Li, Yi; Burtness, Barbara A.; Adams, George L.; Pandya, Kishan J.

In: Cancer, Vol. 123, No. 23, 01.12.2017, p. 4653-4662.

Research output: Contribution to journalArticle

Bhatia, AK, Lee, JW, Pinto, HA, Jacobs, CD, Limburg, PJ, Rubin, P, Arusell, RM, Dunphy, EP, Khandekar, JD, Reiner, SA, Baez-Diaz, L, Celano, P, Li, S, Li, Y, Burtness, BA, Adams, GL & Pandya, KJ 2017, 'Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)', Cancer, vol. 123, no. 23, pp. 4653-4662. https://doi.org/10.1002/cncr.30920
Bhatia, Aarti K. ; Lee, Ju Whei ; Pinto, Harlan A. ; Jacobs, Charlotte D. ; Limburg, Paul John ; Rubin, Philip ; Arusell, Robert M. ; Dunphy, Eamonn P. ; Khandekar, Janardan D. ; Reiner, Seth A. ; Baez-Diaz, Luis ; Celano, Paul ; Li, Shuli ; Li, Yi ; Burtness, Barbara A. ; Adams, George L. ; Pandya, Kishan J. / Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer : Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590). In: Cancer. 2017 ; Vol. 123, No. 23. pp. 4653-4662.
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abstract = "BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P =.61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P =.61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P =.14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P =.057) and among women (N = 39; HR, 0.44; P =.065) and never/former smokers (N = 129; HR, 0.61; P =.055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662.",
keywords = "chemoprevention, head and neck cancer, oral cancer, randomized controlled trial, second primary cancer",
author = "Bhatia, {Aarti K.} and Lee, {Ju Whei} and Pinto, {Harlan A.} and Jacobs, {Charlotte D.} and Limburg, {Paul John} and Philip Rubin and Arusell, {Robert M.} and Dunphy, {Eamonn P.} and Khandekar, {Janardan D.} and Reiner, {Seth A.} and Luis Baez-Diaz and Paul Celano and Shuli Li and Yi Li and Burtness, {Barbara A.} and Adams, {George L.} and Pandya, {Kishan J.}",
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T1 - Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer

T2 - Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

AU - Bhatia, Aarti K.

AU - Lee, Ju Whei

AU - Pinto, Harlan A.

AU - Jacobs, Charlotte D.

AU - Limburg, Paul John

AU - Rubin, Philip

AU - Arusell, Robert M.

AU - Dunphy, Eamonn P.

AU - Khandekar, Janardan D.

AU - Reiner, Seth A.

AU - Baez-Diaz, Luis

AU - Celano, Paul

AU - Li, Shuli

AU - Li, Yi

AU - Burtness, Barbara A.

AU - Adams, George L.

AU - Pandya, Kishan J.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P =.61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P =.61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P =.14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P =.057) and among women (N = 39; HR, 0.44; P =.065) and never/former smokers (N = 129; HR, 0.61; P =.055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662.

AB - BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P =.61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P =.61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P =.14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P =.057) and among women (N = 39; HR, 0.44; P =.065) and never/former smokers (N = 129; HR, 0.61; P =.055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662.

KW - chemoprevention

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KW - oral cancer

KW - randomized controlled trial

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