Five-year survivors of childhood cancer face considerable excess mortality risks during their adult years. Using data from the Childhood Cancer Survivors Study (CCSS) based on 26 collaborating U.S. and Canadian institutions that treat children with cancer and thought to be largely representative of the population of U.S. cancer survivors, our findings provide valuable information on the prognosis for cancer survivors by translating mortality risks into losses in life expectancy and distinguishing between late cancer recurrence and other disease- and treatment-related late effects. We estimated that these childhood cancer survivors, depending on their original cancer diagnosis, will live 4 to 18 fewer years on average than like-aged general populations, a reduction in life expectancy of up to 28%. Approximately one in every four survivors is estimated to die from late recurrence or late-effects related to secondary cancer and cardiopulmonary conditions, and another one in twenty from other excess risk. These findings suggest that the combined impact of late-effects on life expectancy are substantial, vary by cancer diagnosis and even tumor type, and underscore the importance of monitoring the health of the growing population of childhood cancer survivors and evaluating therapies for newly diagnosed patients which might be associated with decreased late toxicity.
Several long-term cohort studies on childhood cancer survivors in the published literature (English language MEDLINE search to October 2008) describe the excess mortality risk associated with disease- and treatment late effects, but the most recent data from the CCSS provide the most comprehensive estimates to date on mortality, as well as morbidity. Oeffinger et al. found that survivors of childhood cancer report disabling or life-threatening conditions in over 6% of cases, and severe chronic conditions in an additional 20% (12
). Geenen et al. similarly estimated nearly 25% of survivors had a high or severe burden of adverse events, comprising of at least 2 severe events or 1 or more life-threatening or disabling event (19
). Although many of these conditions might be expected to be associated with cardiac, pulmonary or cancer deaths, survivors self-report higher than expected rates of other conditions such as renal failure, major joint replacement and neurologic and neurosensory dysfunction. In aggregate, these chronic illnesses will likely lead to other disabling conditions via multifactorial pathways, and are likely to adversely affect the progression of other health problems associated with aging. For example, a history of radiation therapy which includes the coronary arteries, as is used in treatment of many adolescent lymphomas, increases the risk for ischemic heart disease and its associated mortality. This ischemia may result, alternatively, in long-term chronic heart disease as a comorbid condition in an aging survivor with illnesses that may be unrelated to the childhood cancer. A recent analysis by Mulrooney et al. found that young adults who survive childhood cancer are clearly at risk for early cardiac morbidity and mortality not typically recognized in the age group, and that the cumulative incidence of adverse cardiac outcomes continues to increase up to 30 years after diagnosis (20
). The excess risk related to childhood cancer therapy may lead to additional excess mortality risks other than those already observed. For some survivors, the increased risk of developing multiple comorbidities at young ages from treatment-related late-effects may lead to even worse survival outcomes.
Our study has several limitations. First, our estimates of excess mortality risk rely on the accuracy of cause-of-death information obtained from the National Death Index (21
). An analysis of the Framingham Heart Study participants found that death certificate data correctly identified 78–97% of coronary heart disease and cancer deaths (23
). Multiple large-scale survivor cohort studies have also reported very similar rates of absolute excess mortality risks, suggesting some reliability of estimates (5
). We also assumed that survivors undergo average patterns of care by using background mortality rates for the general population. Second, we used late-effects mortality risks only from the CCCS, and many variables are uncertain. While other cohort studies also provide mortality risks, the CCSS is the only study to date that provides estimates by time since diagnosis and by tumor type within cancer diagnoses and reflects the underlying variation in mortality risks. Using probabilistic sensitivity analysis, we were able to reflect the uncertainty surrounding model inputs and their impact on model estimates, and provide a range of likely outcomes. Third, given the limited sample size of the CCSS, our subgroup analyses by sex- and cancer diagnosis assumed constant annual excess mortality risks for the entire follow-up period. In the overall cohort of survivors, assuming a constant rate reduced the loss in life expectancy from 10.4 years (17.1%) in the base case to 9.6 years (15.7%), but raised the lifetime likelihood of dying from recurrence from 0.10 in the base case to 0.12 and reduced the likelihood of dying from non-recurrence late-effects from 0.20 to 0.12. As such, our subgroup estimates may underestimate the loss in life expectancy. Fourth, our estimates also do not reflect heterogeneity in mortality risks by treatment within
a given diagnosis. As treatment-specific estimates become available, our model can be used to compare the relative outcomes among different regimens. For example, our model can provide insight into how life expectancy may vary between individuals with Hodgkin’s disease or leukemia treated with and without radiation. Changes in therapies that limit exposure to high dose anthracyclines may also be modeled to determine if the expected reduction in overall mortality will be achieved. With subgroup-specific mortality estimates, we can explore whether disparities in long-term outcomes by race or ethnicity exist, as survival rates have been shown to differ by these factors in childhood leukemia (25
Despite these limitations, our findings have several important implications for the growing population of childhood cancer survivors. First, our results suggest that the impact of late-effects is greatest in the decades immediately following initial diagnosis of childhood cancer. As such, multidisciplinary surveillance of survivors’ health during these years may be most important in reducing mortality associated with late-effects. Clinicians providing ongoing care for these aging childhood cancer survivors should be familiar with late-effects surveillance guidelines, such as those compiled by the Children’s Oncology Group (http://www.survivorshipguidelines.org/
). Dissemination of surveillance guidelines to patients and primary care providers will improve coordination of care and potentially improve the long-term health outcomes of survivors. Our findings suggest that for survivors who do not experience late recurrence of their original cancer, the major determinant of decreased life expectancy is the excess risk associated with subsequent cancers, accounting for approximately 50% of all non-recurrence excess mortality. Careful consideration of increased risk should be incorporated into clinical evaluation of symptoms, and screening should be tailored to take treatment-related risk factors into account. Currently, the majority of adult survivors of childhood cancer do not receive regular medical care focused on their long-term risks based upon exposures. For example, many young female survivors do not undergo screening mammograms, recommended to start at age 25 if chest radiation was a component of childhood cancer treatment (27
Research in health care communication that leads to better physician and patient education in this field will be required. In addition, policies are strongly needed to ensure that survivors have access to their needed medical care. Compared to their siblings, survivors have lower rates of insurance coverage and face more difficulty obtaining coverage (28
). As the long-term health risks of childhood cancer survivors become more widely recognized, governments, insurers, employers and/or patients may face financial challenges in providing or obtaining coverage for survivor health care needs.
Changes in childhood cancer therapy have resulted in increasing cure rates over the past four decades. Consistent with serial improvements over time, we found life expectancy reductions were most pronounced in the group of survivors with the earliest dates of diagnosis (1970–1973), compared with children treated in more recent decades (1978 –1986). This improvement in outcome over time can be attributed, in our model, to better maintenance of primary cancer control as well as to reductions in mortality from late effects. In subgroup analyses, however, we found that even if the risk for late recurrence is negligible, late-effects will reduce life expectancy by 12% or more in survivors of Hodgkin’s disease, select brain tumors and Ewing sarcomas (see appendix
). This finding is consistent with cancer treatment changes for these diseases during this time period; the aggressive combined-modality therapies utilized are associated with significant cardiopulmonary toxicities and second cancer risks. More recent treatments have been developed which are directed toward maintenance of cure, along with reduction of long-term late effects. Therapies which utilize specific cardio-protectant medications, reduced-dose radiation, and dose-limitation of organ-toxic agents may result in improved outcomes, and as such, further analyses of the impact of this strategy on long-term mortality risk is needed.
Our estimates are based on data from survivors treated 20 to 40 years ago. As treatment has changed since then, data on survivors treated more recently can provide insight on how advances in treatment since 1986 have impacted life expectancy. In 2007, the CCSS began recruiting a second set of participants who were treated for cancer as children between 1987 and 1999 (29
); however data are not available yet. Other smaller cohort studies (with 1400 to 2400 patients) provide some data on the absolute excess risk for overall death for patients treated more recently. For example, in the Netherlands cohort, compared to patients diagnosed between 1966 and 1984, the absolute excess risk for death overall was 7% lower among patients diagnosed after 1984 until 1996 (6
). In a Canadian cohort, between the treatment eras of 1980–1989 and 1990–1995, the absolute excess risk increased 5% (7
). Excess mortality risks by late-recurrence and other specific causes were not reported in either study. As better data become available, our model can be used to estimate and compare how the cumulative impact of late-effects on life expectancy has changed for those treated more recently and inform clinical trials on pediatric cancer treatment which are increasingly informed by adverse outcomes experienced by survivors.
While our model predicts significant reductions in life expectancy in childhood cancer survivors treated in previous decades, often with now historical therapies, this work highlights the need to minimize the use of agents associated with late toxicities for newly diagnosed patients, and to follow survivors of these newer therapies to assess late toxicities. The considerable impact of these excess risks on life expectancy emphasizes the need for primary care physicians to attend not only to the risk of cancer recurrence, but risks for non-recurrence side effects. For the now adult group of childhood cancer survivors, increased awareness of the long-term effects of treatment and the need to adhere to guideline recommendations by both patients and physicians can help to minimize their impacts on their long-term survival.