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A Model-Based Estimate of Cumulative Excess Mortality in Survivors of Childhood Cancer

Jennifer M. Yeh, PhD; Larissa Nekhlyudov, MD, MPH; Sue J. Goldie, MD, MPH; Ann C. Mertens, PhD; and Lisa Diller, MD
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From Harvard School of Public Health, Harvard Medical School/Harvard Pilgrim Health Care Institute and Harvard Vanguard Medical Associates, Dana-Farber Cancer Institute and Children's Hospital, Boston, Massachusetts, and Emory University, Atlanta, Georgia.

Acknowledgment: The authors thank Drs. Qi Liu and Yutaka Yasui for providing additional CCSS data, and Dr. Karen Kuntz for her methodological expertise.

Grant Support: By the National Cancer Institute (R25-CA057711; Dr. Yeh).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-2014.

Reproducible Research Statement:Study protocol: Available from Dr. Yeh (e-mail, jyeh@hsph.harvard.edu). Statistical code and data set: Not available.

Requests for Single Reprints: Jennifer M. Yeh, PhD, Center for Health Decision Science, Harvard School of Public Health, 718 Huntington Avenue, Second Floor, Boston, MA 02115; e-mail, jyeh@hsph.harvard.edu.

Current Author Addresses: Drs. Yeh and Goldie: Center for Health Decision Science, Harvard School of Public Health, 718 Huntington Avenue, Second Floor, Boston, MA 02115.

Dr. Nekhlyudov: Department of Population Medicine, Harvard Medical School, 133 Brookline Avenue, 6th Floor, Boston, MA 02115.

Dr. Mertens: Emory University, Emory-Children's Center, 2015 Uppergate Drive, Atlanta, GA 30322.

Dr. Diller: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Author Contributions: Conception and design: J.M. Yeh, L. Nekhlyudov, S.J. Goldie, L. Diller.

Analysis and interpretation of the data: J.M. Yeh, L. Nekhlyudov, S.J. Goldie, A.C. Mertens, L. Diller.

Drafting of the article: J.M. Yeh, S.J. Goldie, L. Diller.

Critical revision of the article for important intellectual content: J.M. Yeh, L. Nekhlyudov, S.J. Goldie, L. Diller.

Final approval of the article: J.M. Yeh, L. Nekhlyudov, S.J. Goldie, A.C. Mertens, L. Diller.

Provision of study materials or patients: L. Diller.

Statistical expertise: J.M. Yeh, L. Diller.

Obtaining of funding: J.M. Yeh, L. Diller.

Administrative, technical, or logistic support: J.M. Yeh, S.J. Goldie, L. Diller.

Collection and assembly of data: J.M. Yeh, A.C. Mertens, L. Diller.

Ann Intern Med. 2010;152(7):409-417. doi:10.7326/0003-4819-152-7-201004060-00005
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Background: Although childhood cancer survival rates have dramatically increased, survivors face elevated risk for life-threatening late effects, including secondary cancer.

Objective: To estimate the cumulative effect of disease- and treatment-related mortality risks on survivor life expectancy.

Design: State-transition model to simulate the lifetime clinical course of childhood cancer survivors.

Setting: Childhood Cancer Survivor Study.

Patients: Five-year survivors of childhood cancer.

Measurements: Probabilities of risk for death from the original cancer diagnosis, excess mortality from subsequent cancer and cardiac, pulmonary, external, and other complications, and background mortality (age-specific mortality rates for the general population) were estimated over the lifetime of survivors of childhood cancer.

Results: For a cohort of 5-year survivors aged 15 years who received a diagnosis of cancer at age 10 years, the average lifetime probability was 0.10 for late-recurrence mortality; 0.15 for treatment-related subsequent cancer and death from cardiac, pulmonary, and external causes; and 0.05 for death from other excess risks. Life expectancy for the cohort of persons aged 15 years was 50.6 years, a loss of 10.4 years (17.1%) compared with the general population. Reduction in life expectancy varied by diagnosis, ranging from 4.0 years (6.0%) for kidney tumor survivors to more than 17.8 years (≥28.0%) for brain and bone tumor survivors, and was sensitive to late-recurrence mortality risk and duration of excess mortality risk.

Limitation: Estimates are based on data for survivors who received treatment 20 to 40 years ago; patients who received treatment more recently may have more favorable outcomes.

Conclusion: Childhood cancer survivors face considerable mortality during adulthood, with excess risks reducing life expectancy by as much as 28%. Monitoring the health of current survivors and carefully evaluating therapies with known late toxicities in patients with newly diagnosed cancer are needed.

Primary Funding Source: National Cancer Institute.


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Figure 1.
Model structure.

At the start of the simulation, a cohort of 5-year survivors of childhood cancer enters the model. Each month, they face a risk for late-recurrence mortality, nonrecurrence excess mortality, and background mortality. Nonrecurrence excess mortality includes risks associated with subsequent cancer; cardiac, pulmonary, and external causes; and other causes. Persons are followed throughout their lifetime.

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Figure 2.
Cause-specific attributable proportion of overall mortality risk.

As survivors age, the cumulative proportion of overall mortality attributable to background mortality increases relative to the proportion for all late effects from cancer or cancer treatment combined.

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Appendix Figure 1.
Model validation on proportion of all deaths attributable to specific causes at 15 years since diagnosis.

The proportion of deaths attributable to late recurrence, subsequent cancer, and all other noncancer causes approximates published estimates from other large population- and hospital-based cohort studies of 5-year childhood cancer survivors. Solid circles indicate model estimates, and bars indicate the range among publiindicate the range among published estimates (5–7).

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Appendix Figure 2.
Lifetime cause-specific mortality probability.

Top. Incremental lifetime cause-specific mortality probability for late recurrence; excess risk for subsequent cancer and cardiac, pulmonary, and external causes; excess risk for other causes; and background mortality. Bottom. Overall lifetime mortality probability for a cohort of 5-year childhood cancer survivors and the general U.S. population. The area between the curves represents a loss in life expectancy of 10.4 years.

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Appendix Figure 3.
Tornado diagram of sensitivity analysis on selected model variables.

Variables are ranked to show their relative influence on the base-case results. The effect of changes in selected variables on the loss in life-years for the base-case estimate is shown. Information in parentheses is the upper and lower bounds used in the sensitivity analysis. The shaded bars indicate the variation in the loss of life-years caused by changes in the value of the specified variable while all other variables were held constant; longer bars indicate greater sensitivity. The vertical dashed line indicates the base-case estimate of loss in life-years.

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Appendix Figure 4.
Probabilistic sensitivity analysis for selected subgroups.

Lines within the bars indicate the mean reduction in life expectancy. Top. Uncertainty intervals for treatment-era subgroups, using 1000 second-order Monte Carlo simulations. Bottom. Uncertainty intervals estimated for diagnosis age subgroups.

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Summary for Patients

Decreased Life Expectancy of Childhood Cancer Survivors

The summary below is from the full report titled “A Model-Based Estimate of Cumulative Excess Mortality in Survivors of Childhood Cancer.” It is in the 6 April 2010 issue of Annals of Internal Medicine (volume 152, pages 409-417). The authors are J.M. Yeh, L. Nekhlyudov, S.J. Goldie, A.C. Mertens, and L. Diller.


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