Since our original analysis 7 years ago,13
the number of SMNs has increased 2.3 fold, from 314 SMNs in 298 individuals to 802 SMNs in 730 individuals. We can now estimate a 30-year cumulative incidence of 9.3% compared with the 20-year incidence of 3.2%. Although the cohort has aged over this period, the SIRs might be expected to decrease with increased likelihood of cancer in the general age-matched population. However, this has not come to pass. SIRs remain elevated in the CCSS cohort. These data highlight the increasing incidence of SNs with continued follow-up of the CCSS cohort and the need for ongoing surveillance of survivors. The lifetime risk and the period of excess risk for SNs is still not known.
Although survivors of HL comprised only 13.4% of the cohort, they experienced 33.8% of the reported SMNs and 37.9% of the NMSCs. For the SMNs, this is largely driven by breast cancer, with 94 (59.9%) of 157 second breast cancers in the CCSS occurring in HL survivors. This finding is consistent with reports by others.28,29
However, the significant proportion of NMSC among HL survivors has not been previously reported. As this study's cohort was derived from patients surviving 5 years or more, it is not surprising that leukemia was not a common SMN and occurred in only 43 individuals.
Although rarely fatal, NMSC is an important late effect of childhood cancer therapy and an important public health issue. In the CCSS, the largest proportion of NMSC occurred in survivors of HL (37.9%), leukemia (32.1%), and CNS tumors (9.3%). The SEER Program does not collect incidence data on NMSC; thus we have a limited ability to track overall NMSC rates and trends in the United States and to compare the results of the CCSS with that of the general population. However, the CCSS rates of NMSC exceed those reported in a population-based study done in New Hampshire.30
The locations of basal cell carcinomas observed in the subjects of the New Hampshire study were also quite different from those in the CCSS group, which reflect the sites of radiotherapy. In the New Hampshire group, basal cell carcinomas were reported as head/neck (68%), back/chest (21%), or extremity (11%), and in the CCSS group, head/neck (43%), back/chest (51%), or extremity (3%). Similarly high rates of NMSC have been identified in survivors of hematopoietic stem-cell transplantation, in whom the risk of basal cell carcinoma is increased by total-body irradiation during childhood, and that of basal cell and squamous cell carcinomas is increased by graft-versus-host disease.31
Survivors of bone cancers or soft-tissue sarcomas comprise 17% of the CCSS cohort and 21% of all survivors who experienced SMNs, 20% of which were breast cancer. Risk of cancer was increased among siblings of sarcoma survivors and those of survivors with SMNs.24
Risk of breast cancer was increased among sarcoma survivors not treated with radiotherapy,22
and risk of secondary sarcoma was increased in primary sarcoma survivors and those with a family history of cancer.16
This is consistent with data showing an association between soft tissue sarcoma and breast cancer or sarcomas as SMNs in patients or close relatives32
and suggests the need for further study of the interactions between genetic predisposition, disease, and treatment. The collection of genomic DNA from the CCSS cohort has provided an opportunity to investigate genetic susceptibility to subsequent cancers. Of particular interest is the demonstration of a strong association between exposure to radiation therapy and the high risk of SNs. Molecular epidemiology studies will be necessary to address the role of genetics in the observed interindividual variation in risk of subsequent cancers and will be possible only with continuing follow-up of this cohort.
Radiotherapy increased the risk of SNs in our analyses, which is consistent with previous reports in which radiation dose responses have been demonstrated.33–35
Detailed information about radiotherapy exposures has been collected by CCSS investigators to enable dosimetric analyses of organs of interest. The thyroid gland is highly susceptible to the carcinogenic effects of ionizing radiation, but the dose-response relations had not previously been well characterized over a wide range of doses. Our study is one of the first to demonstrate a reduction in radiation-related risk of SNs associated with treatment of solid tumors with high-doses of radiation.18,20
We also detected a linear relation between the radiation dose received during treatment for childhood cancer and the relative risk of subsequent gliomas or meningiomas.17
During the past 35 years, pediatric chemotherapy and radiotherapy protocols have been modified to better balance toxicity and efficacy. Therefore, it will be important to observe patients treated during the latter treatment era (eg, after the mid-1980s) of this cohort, as well as those treated on contemporary protocols for many more years, to determine whether the risk of SNs decreases with changes in chemotherapy and radiotherapy (ie, lower doses, smaller volumes, and improvements in techniques). During the interim, it is important that the childhood cancer survivors treated between 1970 and 1986 and their health care providers are aware of the risk of SNs over a prolonged follow-up period. This cohort is still young (median age, 34 years), and cancer in their age group in the general population is low. Our data suggest the need for targeted surveillance as this cohort ages. Specific cancer screening at younger ages than that recommended for the general population, regular physical examinations, and patient education are essential components of the follow-up for all childhood cancer survivors.