Simulation Modeling of Cancer Clinical Trials

Application to Omitting Radiotherapy in Low-risk Breast Cancer

CISNET-BOLD Collaborative Group

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

Original languageEnglish (US)
Pages (from-to)1360-1369
Number of pages10
JournalJournal of the National Cancer Institute
Volume110
Issue number12
DOIs
StatePublished - Dec 1 2018

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Radiotherapy
Clinical Trials
Breast Neoplasms
Recurrence
Neoplasms
Segmental Mastectomy
Proportional Hazards Models
Hormones
Confidence Intervals
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Simulation Modeling of Cancer Clinical Trials : Application to Omitting Radiotherapy in Low-risk Breast Cancer. / CISNET-BOLD Collaborative Group .

In: Journal of the National Cancer Institute, Vol. 110, No. 12, 01.12.2018, p. 1360-1369.

Research output: Contribution to journalArticle

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title = "Simulation Modeling of Cancer Clinical Trials: Application to Omitting Radiotherapy in Low-risk Breast Cancer",
abstract = "Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90{\%} confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0{\%} and 3.7{\%} for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7{\%} (2.9{\%}) vs 95.5{\%} (2.2{\%}) and 88.4{\%} (2.0{\%}) vs 94.5{\%} (1.6{\%}). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.",
author = "{CISNET-BOLD Collaborative Group} and Jinani Jayasekera and Schechter, {Clyde B.} and Schechter, {Clyde B.} and Reshma Jagsi and Juhee Song and Julia White and George Luta and Chapman, {Judith Anne W.} and Feuer, {Eric J.} and Zellars, {Richard C.} and Natasha Stout and Julian, {Thomas B.} and Timothy Whelan and Xuelin Huang and {Shelley Hwang}, E. and Sparano, {Joseph A.} and Sparano, {Joseph A.} and Anderson, {Stewart J.} and Fyles, {Anthony W.} and Robert Gray and Willi Sauerbrei and Jeanne Mandelblatt and Berry, {Donald A.}",
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T1 - Simulation Modeling of Cancer Clinical Trials

T2 - Application to Omitting Radiotherapy in Low-risk Breast Cancer

AU - CISNET-BOLD Collaborative Group

AU - Jayasekera, Jinani

AU - Schechter, Clyde B.

AU - Schechter, Clyde B.

AU - Jagsi, Reshma

AU - Song, Juhee

AU - White, Julia

AU - Luta, George

AU - Chapman, Judith Anne W.

AU - Feuer, Eric J.

AU - Zellars, Richard C.

AU - Stout, Natasha

AU - Julian, Thomas B.

AU - Whelan, Timothy

AU - Huang, Xuelin

AU - Shelley Hwang, E.

AU - Sparano, Joseph A.

AU - Sparano, Joseph A.

AU - Anderson, Stewart J.

AU - Fyles, Anthony W.

AU - Gray, Robert

AU - Sauerbrei, Willi

AU - Mandelblatt, Jeanne

AU - Berry, Donald A.

PY - 2018/12/1

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N2 - Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

AB - Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

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DO - 10.1093/jnci/djy059

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JF - Journal of the National Cancer Institute

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