The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer.
Gregory T. Armstrong, MD, MSCE, and colleagues
In a study reported in The New England Journal of Medicine, Gregory T. Armstrong, MD, MSCE, of St. Jude Children’s Research Hospital, Memphis, and colleagues found that late mortality has decreased over time among 5-year survivors of childhood cancer in the Childhood Cancer Survivor Study cohort.1 The reduction is consistent with efforts during recent decades to modify treatment with the aim of reducing life-threatening late effects.
The study assessed late mortality among 34,033 patients in the Childhood Cancer Survivor Study (https://ccss.stjude.org/) cohort who survived at least 5 years after cancer was diagnosed at age < 21 years during the period from 1970 to 1999.
Among these patients, > 9,000 survivors received an initial cancer diagnosis in the 1970s; > 13,000, in the 1980s; and > 11,000, in the 1990s. Median follow-up was 21 years (range = 5–38 years), providing a total of 705,806 person-years of observation. Survivors had a median age of 28.5 years at last follow-up (range = 5.5–58.5 years), with 30% aged 30 to 39 years and 15% aged > 40 years.
Overall, 57% had received radiotherapy, including 77% from the 1970s vs 41% from the 1990s. More patients from the 1990s received chemotherapy, including anthracyclines and alkylating agents, vs the 1970s—but at lower average cumulative doses. The most common diagnoses were leukemia (n = 10,199), central nervous system tumors (n = 6,369), and Hodgkin lymphoma (n = 4,332).
A total of 3,958 deaths (12%) occurred during the study period; of them, 1,618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. Cumulative 15-year mortality from any cause was 10.7% among patients diagnosed in the 1970s, 7.9% among those diagnosed in the 1980s, and 5.8% among those diagnosed in the 1990s (P < .001). Cumulative 15-year mortality from primary cancer recurrence or progression was 7.1%, 4.9%, and 3.4% (P < .001), respectively. Cumulative 15-year mortality from health-related causes, including the late effects of cancer therapy, decreased from 3.1% to 2.4% and 1.9% (P < .001); these reductions reflected decreases in the rates of death from subsequent malignant neoplasms (eg, 1.8% in those diagnosed in 1970–1974 vs 1.0% in those diagnosed in 1990–1994, P < .001), cardiac-related events (eg, 0.5% vs 0.1%, P = .001), and pulmonary-related events (0.5% vs 0.1%, P = .04).
In a multivariate analysis adjusting for cancer diagnosis, age at diagnosis, sex, and attained age, more recent treatment eras were associated with a reduced rate of death, including a reduced relative rate (RR) per every 5 years for any health-related cause (RR = 0.86, 95% confidence interval [CI] = 0.82–0.89) and death related to subsequent malignant neoplasms (RR = 0.83, 95% CI = 0.78–0.88), cardiac causes (RR = 0.77, 95% CI = 0.68–0.86), and pulmonary causes (RR = 0.77, 95% CI = 0.66–0.89). Similar patterns were observed in standardized mortality ratios.
Mortality From Health-Related Causes
Significant reductions were observed between the 1970s and 1990s in the rate of death from a health-related cause among survivors with acute lymphoblastic leukemia (3.2% vs 2.1%, P < .001), Hodgkin lymphoma (5.3% vs 2.6%, P = .006), Wilms tumor (2.6% vs 0.4%, P = .005), and astrocytoma (4.7% vs 1.8%, P = .02) but not among patients in other primary cancer groups. Reductions in cardiac mortality were observed for acute lymphoblastic leukemia (0.6% vs 0.1%, P = .003), Hodgkin lymphoma (0.9% vs 0.5%, P = .06), Wilms tumor (0.3% vs 0%, P = .04), and astrocytoma (0.9% vs 0%, P = .02). Death from subsequent neoplasms was reduced among survivors with Wilms tumor (1.9% vs 0%, P < .001).
Changes in Treatment
Changes in therapy included reduced use of cranial radiotherapy in acute lymphoblastic leukemia (from 85% in the 1970s to 51% in the 1980s and 19% in the 1990s); abdominal radiotherapy for Wilms tumor (from 78% to 53% and 43%); chest radiotherapy for Hodgkin lymphoma (87% to 79% and 61%); radiotherapy for astrocytoma; and a reduction in the mean cumulative anthracycline dose from 289 to 217 and 158 mg/m2 in acute lymphoblastic leukemia, 295 to 212 and 193 mg/m2 in Hodgkin lymphoma, and 267 to 244 and 179 mg/m2 in Wilms tumor. For survivors of acute lymphoblastic leukemia and Wilms tumor, the temporal reductions in 15-year rates of death from health-related causes were significantly associated with temporal reductions in therapeutic exposure.
The investigators concluded: “The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer.” ■
Disclosure: The study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. For full disclosures of the study authors, visit www.nejm.org. More information about the Childhood Cancer Survivor Study can be found at https://ccss.stjude.org/.
1. Armstrong GT, Chen Y, Yasui Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med. January 13, 2016 (early release online).
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