Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer

Scott M. Lippman, J. Jack Lee, Daniel D. Karp, Everett E. Vokes, Steven E. Benner, Gary E. Goodman, Fadlo R. Khuri, Randolph Stuart Marks, Rodger J. Winn, Willard Fry, Stephen L. Graziano, David R. Gandara, Gordon Okawara, Charles L. Woodhouse, Brendell Williams, Cherie Perez, Hyung W. Kim, Reuben Lotan, Jack A. Roth, Waun Ki Hong

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Abstract

Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Original languageEnglish (US)
Pages (from-to)605-617
Number of pages13
JournalJournal of the National Cancer Institute
Volume93
Issue number8
StatePublished - Apr 18 2001

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Isotretinoin
Non-Small Cell Lung Carcinoma
Confidence Intervals
Recurrence
Smoking
Neoplasms
Placebos
Mortality
National Cancer Institute (U.S.)
Retinoids
Histology
Multivariate Analysis
Therapeutics
Chemoprevention
Random Allocation
Proportional Hazards Models
Radiotherapy
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lippman, S. M., Lee, J. J., Karp, D. D., Vokes, E. E., Benner, S. E., Goodman, G. E., ... Hong, W. K. (2001). Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. Journal of the National Cancer Institute, 93(8), 605-617.

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. / Lippman, Scott M.; Lee, J. Jack; Karp, Daniel D.; Vokes, Everett E.; Benner, Steven E.; Goodman, Gary E.; Khuri, Fadlo R.; Marks, Randolph Stuart; Winn, Rodger J.; Fry, Willard; Graziano, Stephen L.; Gandara, David R.; Okawara, Gordon; Woodhouse, Charles L.; Williams, Brendell; Perez, Cherie; Kim, Hyung W.; Lotan, Reuben; Roth, Jack A.; Hong, Waun Ki.

In: Journal of the National Cancer Institute, Vol. 93, No. 8, 18.04.2001, p. 605-617.

Research output: Contribution to journalArticle

Lippman, SM, Lee, JJ, Karp, DD, Vokes, EE, Benner, SE, Goodman, GE, Khuri, FR, Marks, RS, Winn, RJ, Fry, W, Graziano, SL, Gandara, DR, Okawara, G, Woodhouse, CL, Williams, B, Perez, C, Kim, HW, Lotan, R, Roth, JA & Hong, WK 2001, 'Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer', Journal of the National Cancer Institute, vol. 93, no. 8, pp. 605-617.
Lippman, Scott M. ; Lee, J. Jack ; Karp, Daniel D. ; Vokes, Everett E. ; Benner, Steven E. ; Goodman, Gary E. ; Khuri, Fadlo R. ; Marks, Randolph Stuart ; Winn, Rodger J. ; Fry, Willard ; Graziano, Stephen L. ; Gandara, David R. ; Okawara, Gordon ; Woodhouse, Charles L. ; Williams, Brendell ; Perez, Cherie ; Kim, Hyung W. ; Lotan, Reuben ; Roth, Jack A. ; Hong, Waun Ki. / Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. In: Journal of the National Cancer Institute. 2001 ; Vol. 93, No. 8. pp. 605-617.
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title = "Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer",
abstract = "Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95{\%} confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95{\%} CI = 0.76 to 1.29) for recurrence, and 1.07 (95{\%} CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 [95{\%} CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95{\%} CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 [95{\%} CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95{\%} CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95{\%} CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40{\%} versus 25{\%} at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.",
author = "Lippman, {Scott M.} and Lee, {J. Jack} and Karp, {Daniel D.} and Vokes, {Everett E.} and Benner, {Steven E.} and Goodman, {Gary E.} and Khuri, {Fadlo R.} and Marks, {Randolph Stuart} and Winn, {Rodger J.} and Willard Fry and Graziano, {Stephen L.} and Gandara, {David R.} and Gordon Okawara and Woodhouse, {Charles L.} and Brendell Williams and Cherie Perez and Kim, {Hyung W.} and Reuben Lotan and Roth, {Jack A.} and Hong, {Waun Ki}",
year = "2001",
month = "4",
day = "18",
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pages = "605--617",
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TY - JOUR

T1 - Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer

AU - Lippman, Scott M.

AU - Lee, J. Jack

AU - Karp, Daniel D.

AU - Vokes, Everett E.

AU - Benner, Steven E.

AU - Goodman, Gary E.

AU - Khuri, Fadlo R.

AU - Marks, Randolph Stuart

AU - Winn, Rodger J.

AU - Fry, Willard

AU - Graziano, Stephen L.

AU - Gandara, David R.

AU - Okawara, Gordon

AU - Woodhouse, Charles L.

AU - Williams, Brendell

AU - Perez, Cherie

AU - Kim, Hyung W.

AU - Lotan, Reuben

AU - Roth, Jack A.

AU - Hong, Waun Ki

PY - 2001/4/18

Y1 - 2001/4/18

N2 - Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

AB - Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

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