In all, 16
541 cases of childhood cancer fulfilled the criteria for inclusion in the overall cohort showing a male to female ratio of 1.2. The FPT were diagnosed between 1926 and 1987 with a mean age at diagnosis of 6 years and 8 months (median; 5 years and 10 months). In total, 165
879 person-years of follow-up were accumulated during the study period, a mean follow-up per case of 10 years. Of the 16
541 3-year survivors in the cohort, 12
932 (78%) were followed up to the end point of the study. A total of 3331 (20%) survivors were censored before the end point (210 emigrated and 3121 died), and 278 (2%) developed an SMN.
The relative frequencies of first primary childhood cancers among individuals who developed an SMN were: central nervous system tumours (24.5%), retinoblastoma (15.8%), Hodgkin's disease (12.9%), Wilm's tumour (8.3%) and acute lymphoblastic leukaemia (7.2%). Within the entire cohort of 3-year survivors, 278 SMNs (with ICD9 codes 1400-2089) were observed, of which 33 were nonmelanomatous skin cancers, leaving 245 cases for analysis, compared to 39.4 expected, giving a SIR of 6.2 (95% CI: 5.5, 7.1).
reports the SIR associated with specific types of SMN. The cumulative risk of developing an SMN within 20 years of 3-year survival from the first cancer was 3.1% (s.e.=0.2%) and within 25 years was 4.2% (s.e.=0.3%). The overall AER was 1.2 extra cancers per 1000 survivors per year.
Risk of developing an SMN and selected sites in 3-year survivors of childhood cancer
As the markedly increased risk of SMN following heritable retinoblastoma is well established, this group was excluded, and will be the subject of a separate report. Furthermore, in view of uncertainty about the completeness of ascertainment of family pedigree information in cases recorded as nonheritable retinoblastoma, we have excluded all cases of retinoblastoma as FPT (total 1089) from subsequent analyses.
Nonretinoblastoma childhood cancers
In all, 15
452 cases were included in this cohort, with 147
163 person-years of observation accrued, a mean follow-up of 9 years and 6 months and a median follow-up of 7 years and 2 months.
gives the overall SIR for any SMN and the SIRs for specific sites of SMN. A total of 201 SMNs occurred during the study period (excluding nonmelanomatous skin cancers) against 34.7 expected giving a SIR of 5.8 (95% CI: 5.0, 6.7). Among specific sites of SMNs, the highest SIR was for bone cancer (SIR=25.2) followed by soft tissue (SIR=15.9), endocrine (SIR=13.9) and brain and CNS (SIR=13.4) sites. The cumulative risk of developing an SMN within 20 years of 3-year survival was 2.8% (s.e.=0.24%).
Risk of developing an SMN and selected sites in 3-year survivors of nonretinoblastoma childhood cancer
By duration of follow-up
Variation in risk of SMN with time from diagnosis was examined in the following periods: 3–9, 10–19, 20–29 and 30 years or more survived from diagnosis. The number of survivors entering each risk interval, the observed and expected number of SMNs occurring and the SIR and AER for each of these follow-up groups are given in
Risk of SMN after nonretinoblastoma childhood cancer, by duration of follow-up from original diagnosis
Univariate analysis demonstrated a statistically significant decline (P<0.001) in the SIR over successive decades from diagnosis (), persisting after adjusting for possible confounding (P=0.002) in a multivariate model also including treatment, era of diagnosis and age at diagnosis of the first cancer. There was a statistically significant excess SIR within each decade of follow-up, the excess number of cancers remaining between one and two extra cases per 1000 survivors per year over all follow-up intervals.
SMNs at three sites demonstrated a statistically significant trend in SIR with duration of follow-up: brain and central nervous system, female breast and myeloid leukaemia (
). The risk of myeloid leukaemia was greatest within the first decade from diagnosis and the later decline in risk was quite striking, with SIRs of 28.9, 2 and 4, respectively, over the first three decades of follow-up.
By treatment of first cancer
Survivors were classified into four treatment categories: neither RT nor CT, RT only, CT only and both RT and CT. There was evidence of heterogeneity among the SIRs for any SMN (P<0.001), with the greatest excess risk in cases receiving both RT and CT (SIR 12.5, 95% CI: 9.8, 15.8). This evidence of significant heterogeneity persisted on multivariate analysis, which adjusted for the effect of the other factors on treatment (
). Among SIRs for SMNs at selected sites, there was significant heterogeneity for secondary leukaemia (P<0.001), in particular myeloid leukaemia (P<0.001) ().
The SIR associated with treatment was initially calculated only for the 82% of nonretinoblastoma cases in which treatment information was available. However, since the treatment records of patients with SMN were sought with much more effort than for those not developing an SMN, such an analysis may be biased. The SIR analysis was therefore repeated including the ‘no record’ cases and assuming that all those for whom treatment details were not available received the treatment being analysed, but the results were not substantially different to those reported above (data not shown).
By era and age at first cancer diagnosis
The risk of SMN was calculated for three main periods of diagnosis of the first cancer: pre-1970, 1970–1979 and 1980 and later. The SIR for all SMNs and specifically of the digestive tract and female breast demonstrated a significant trend of increasing excess risk with the more recent era of diagnosis (), particularly for secondary myeloid leukaemia: (P<0.001) across the diagnostic periods pre-1970, 1970–1979 and 1980 onwards, for which the SIRs were 2.7, 11.4 and 69.9, respectively. However, when the SIR for all SMNs was adjusted for other risk factors, the significant trend seen on univariate analysis did not reach formal statistical significance (P=0.093).
shows risk of SMN by age at diagnosis of the first cancer. The SIR for SMN overall was greater with the first cancer under the age of 5 years, a significant trend being observed in the SIR on univariate analysis, which remained after adjustment for the effect of the other factors detailed in the Statistical methods section (P=0.031).
Risk of SMN after selected types of first cancer
The SIRs of developing an SMN and the cumulative risks of developing an SMN within 20 years of 3-year survivorship of specific first cancer diagnoses are displayed in
. The cumulative risks are provided for only those specific types of first cancer for which the mean period of follow-up exceeded 10 years.
Risks of developing an SMN after selected types of first cancer