The CCSS population includes most major pediatric oncology diagnostic groups (ie, leukemia, CNS tumors, Hodgkin's disease, non-Hodgkin's lymphoma, malignant renal tumors [Wilms], neuroblastoma, soft tissue sarcoma, and bone tumors), diagnosed across a broad time interval (1970 to 1986), from multiple institutions, receiving a wide array of therapies and more than 20 years of mean follow-up. Performing a mortality analysis in such a large, heterogeneous population as the CCSS provides opportunity to identify specific subpopulations that may be at higher risk for late mortality. Furthermore, standardization of mortality data () to the background rates of death in the United States population allows not only a relative assessment of the differences in rate of death compared to this established background rate, but also provides a meaningful way to compare the mortality experience of two populations within the CCSS cohort.
Life Status and SMRs in 5-Year Survivors of the Childhood Cancer Survivor Study
It is not surprising that long-term survivors have higher rates of late mortality in the 5- to 9-year period (SMR, 20.7; 95% CI, 19.6 to 21.8) from diagnosis with decreasing rates of death with ongoing time from diagnosis (). This corresponds with increased rates of death due to recurrence or progression of primary disease seen during this time period. In addition, young patients (those diagnosed and treated in the first 4 years of life) have higher SMRs (SMR, 9.1; 95% CI, 8.5 to 9.8) than those who were older at diagnosis. This may be driven by the fact that certain diagnostic groups, such as ALL and CNS tumors, the two most commonly diagnosed pediatric malignancies, young age is itself a poor prognostic factor ().9
In addition, important therapeutic modalities are often limited in young patients, such as the use of CNS directed radiotherapy, in an attempt to prevent long-term injury. Avoidance of such therapies may also lower the risk of long-term survival.10
Standardized mortality rates among 5-year survivors by age at diagnosis for all major childhood cancer diagnoses. HL, Hodgkin's lymphoma; NHL, non-Hodgkin's lymphoma; NB, neuroblastoma; ST, soft tissue.
Certain primary diagnoses carry greater risk of poor long-term survival. As a group, CNS tumors have the highest SMR of any population (SMR, 12.9; 95% CI, 11.8 to 14.0) largely driven by the high long-term risk for death for patients with medulloblastoma (SMR, 17.7; 95% CI, 14.8 to 21.1). Thus, even after surviving to the 5-year time point, subjects with medulloblastoma or PNET had an almost 18-fold increased risk of death relative to a comparable age- and sex-matched United States population. It is unclear whether this high rate is attributable to the use of CNS directed radiotherapy without adjuvant chemotherapy in this era (1970 to 1986) or to inadequate salvage therapies for relapsed patients. In addition, long-term survivors of acute myelogenous leukemia (SMR, 11.5; 95% CI, 9.1 to 14.3) and Ewing's sarcoma (SMR, 13.3; 95% CI, 11.2 to 15.8) have increased SMRs relative to other diagnostic groups. At the opposite extreme, patients with renal tumors (predominately Wilms' tumor) and neuroblastoma had the best overall survival with cumulative incidence of death of 7.3% and 8.6%, respectively, at 30 years from diagnosis ().
(A and B) All-cause mortality, survival by original cancer diagnosis in the Childhood Cancer Survivor Study. CNS, central nervous system; NHL, non-Hodgkin's lymphoma.
Finally, while males in the CCSS cohort have a greater absolute risk for death than females (B), when standardized to the background rate of death in the United States population, by sex, it is females who have a higher SMR (13.2; 95% CI, 12.5 to 14.0) compared to males (SMR, 6.7; 95% CI, 6.4 to 7.0). Young males in the general population are known to have a higher rate of death due to accidents and injuries; therefore, the use of these data as the denominator for standardization partially explains the lower SMR in males. However, female survivors are at significantly greater risk of second cancers, specifically breast cancer, than their male counterparts which likely increases the gap in the SMRs between the sexes.