Radiol Oncol 2022; 56(3): 380-389. doi: 10.2478/raon-2022-0027
380
research article
Trends in treatment of childhood cancer and 
subsequent primary neoplasm risk 
Maja Cesen Mazic1, Raoul C. Reulen2, Janez Jazbec1, Lorna Zadravec Zaletel3 
1 University Children’s Hospital Ljubljana, Ljubljana, Slovenia
2  Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, Robert Aikten Building,  
University of Birmingham, Birmingham, United Kingdom 
3 Institute of Oncology Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2022; 56(3): 380-389.
Received 27 Feb 2022 
Accepted 10 May 2022
Correspondence to: Maja Česen Mazić, M.D., University Children’s Hospital Ljubljana, Bohoričeva ulica 20, SI-1000 Ljubljana, Slovenia. 
E-mail: maja.cesenmazic@kclj.si
Disclosure: No potential conflicts of interest were disclosed. 
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background. The aim of the study was to investigate long-term risk and spectrum of subsequent neoplasm (SN) in 
childhood cancer survivors and to identify how trends in therapy influenced cumulative incidence of SN.
Patients and methods. The population-based cohort comprises 3271 childhood cancer patients diagnosed in 
Slovenia aged ≤ 18 years between 1st January 1961 and 31st December 2013 with a follow-up through 31st December 
2018. Main outcome measures are standardised incidence ratios (SIRs), absolute excess risks (AERs), and cumulative 
incidence of SN.
Results. After median follow-up time of 21.5 years for 5-year survivors, 230 patients experienced 273 SN, including 183 
subsequent malignant neoplasm (SMN), 34 meningiomas and 56 nonmelanoma skin cancers. 10.5% patients received 
radiotherapy only, 31% chemotherapy only, 26.9% a combination of chemotherapy and radiotherapy and 16.1% 
surgery only. The overall SIR was almost 3 times more than expected (SIR 2.9), with survivors still at 2-fold increased risk 
after attained age 50 years. The observed cumulative incidence of SMN at 30-year after diagnosis was significantly 
lower for those diagnosed in 1960s, compared with the 1970s and the 1980s (P heterogeneity < 0.001). Despite re-
duced use of radiotherapy over time, the difference in cumulative incidence for the first 15 years after diagnosis was 
not significant for patients treated before or after 1995 (p = 0.11).
Conclusions. Risks of developing a SMN in this study are similar to other European population-based cohorts. The 
intensity of treatment peaked later and use of radiotherapy declined slower compared to high income countries, 
making continuous surveillance even more important in the future.
Key words: population-based study, childhood cancer survivors, subsequent neoplasm
Introduction
Currently, ~ 80% of children with cancer are 
long-term survivors with possible late seque-
lae.1,2 Treatment of childhood cancer depends on 
surgery, radiotherapy, and chemotherapy de-
spite their potential toxicity. Late effects of cancer 
treatment are important causes of morbidity and 
mortality in survivors of childhood cancer.3 The 
burden of therapy was reduced, through clinical 
trials, in childhood cancers with good or excellent 
survival.4 However, for many children with cancer 
relapse of primary disease is still the leading cause 
of death.4 Death due to subsequent neoplasm (SN) 
is the most common non-relapse related event.5
Large population-based studies in childhood 
cancer survivors have been conducted in the 
Nordic countries and Britain with long and almost 
Radiol Oncol 2022; 56(3): 380-389.
Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk 381
complete follow-up.6,7 Cancer registries generally 
have limited or no information on treatment varia-
bles. Multicentre studies conducted in Netherlands 
and US collect data through questionnaires or hos-
pital registries, with up to one third of patients lost 
to follow up.8-14 However, detailed treatment data 
extracted from hospital registries provided impor-
tant information about the risk factors for SN.8-14
Population based analysis of SN after treatment 
of childhood cancer in Slovenia was first published 
in 2004.15 The aims of present analysis were to as-
sess long-term risk and spectrum of SN in Slovenia; 
identify how trends in therapy influenced cumula-
tive incidence of SN.
Patients and methods
Cohort ascertainment and subsequent 
neoplasm ascertainment
The study cohort comprises patients in Slovenia 
aged ≤ 18 years with childhood cancer diagnosis 
between 1st January 1961 and 31st December 2013 
and a follow-up through 31st December 2018. 
The cohort was ascertained through the popula-
tion-based Cancer Registry of Slovenia (CRS). The 
registry combines data from University Children 
Hospital Ljubljana and Institute of Oncology 
Ljubljana, representing all institutions where child-
hood cancer patients are treated and subjected to 
follow-up.16 Data coverage is estimated to be close 
to complete. CRS is linked to the Central popula-
tion registry for information on vital status and 
causes of death. 
Childhood cancers were coded according 
to International Classification of Diseases for 
Oncology (ICD, 3rd version).17 For every patient 
basic treatment information (use of surgery, chem-
otherapy, and radiation) and outcome (recurrence 
of primary cancer, subsequent neoplasms, cause of 
death) were reported. 
Subsequent neoplasms (SNs) for the entire co-
hort were defined as a neoplasm on new location, 
which is not a direct spread or metastasis of the pri-
mary neoplasm, or neoplasm on the same location 
with a different histological type (18.). SNs were 
validated through pathology reports or in some 
cases with other means through a clinical diagno-
sis (e.g., meningioma). SN were classified as subse-
quent malignant neoplasm (SMN), having ICD-O 
behaviour code of 3, meningioma, non-melanoma 
skin cancer (NMSC).
 As registration of neoplasms with ICD-O be-
haviour code 2 is close to complete in CRS, these 
were included in SMN (in situ cervical carcinoma, 
in situ carcinoma of bladder, ductal in situ carcino-
ma of breast and in situ melanoma). As registration 
of meningioma and NMSC is incomplete for gen-
eral population, they were reported for our cohort 
but excluded from further statistical analysis.
Statistical analysis
Time at risk for SN was set at diagnosis of child-
hood cancer (at latest 31st December 2013) and 
ended at the earliest occurrence of loss of follow 
up, death or study exit date (31st December 2018). 
During this period 3350 children were diagnosed 
with cancer, 79 patients were excluded from analy-
sis after reviewing diagnosis (histology missing, 
benign tumours or Langerhans cell histiocytosis).
Standardized incidence ratio (SIR) was calcu-
lated as the observed divided by expected number 
of SMN. The expected number of SMNs were cal-
culated by multiplying the number of person-years 
at risk in the cohort within specific sex, five-year 
age strata and single calendar year interval by cor-
responding neoplasm incidence rates in Slovenian 
population extracted from CRS. Absolute excess 
risk (AER) was calculated as observed minus ex-
pected number of SMN divided by person-years at 
risk and multiplied by 1000, unless otherwise spec-
ified. AER is the number of extra SMN observed 
beyond that expected per 1000 persons per year. 
Meningioma and NMSC were excluded from SIR 
and AER calculations since their ascertainment is 
not complete in CRS. 
SIRs and AERs were stratified by sex, age at di-
agnosis of primary cancer, attained age (age of the 
subjects at the study exit date, death or lost of fol-
low up), primary neoplasm type, treatment period 
of childhood cancer, years from diagnosis of child-
hood cancer and childhood cancer therapy. A mul-
tivariable Poisson regression model was used to 
calculate relative risk (RR) and relative excess risk 
(RER) and analyse the potential simultaneous ef-
fect of this explanatory factors on the SIR and AER. 
Relative risk represents ratio of SIRs adjusted for 
explanatory factors and RER as ratio of AERs ad-
justed for explanatory factors (19.). Results relating 
to overall SIRs and AERs were only reported in text 
whenever there were at least 3 observed SMNs. For 
SIR, AER, RR and RER 95% confidence intervals 
were estimated (95% CI).
The cumulative incidence for the first occur-
rence of SN, SMN, NMSC and meningioma was 
computed as a function of time from childhood 
cancer diagnosis with death due to any other cause 
Radiol Oncol 2022; 56(3): 380-389.
Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk382
prior to developing SN considered as a competing 
event. Expected cumulative incidence for SMNs 
was calculated using the Ederer II method.20 
Five-year relative survival following an SN was 
estimated using the Stata command strs.21All statis-
tical analysis were conducted using Stata statistical 
software, version 17.0. All tests were 2-sided, with 
p value < 0.05 considered statistically significant.
Results 
Cohort characteristics
In this retrospective cohort study 3,271 childhood 
cancer patients accrued a total of 46,464 person-
years of follow-up, with median follow-up time of 
21.5 years (range, 5.25–57.8 years) for 5-year sur-
vivors. The most common types of childhood can-
cer were leukaemia (26.6%), CNS tumours (19.1%), 
Hodgkin’s lymphoma (9.6%) and non-Hodgkin’s 
lymphoma (8.5%) (Table 1). 
In total, 230 patients experienced 273 SN, includ-
ing 183 SMN, 34 meningiomas and 56 NMSC. Of 
all individuals with an SN, 192 had one, 33 two and 
5 three SNs. At the study exit date 53% (n = 1744) 
of patients were alive (Table 2). A total of 10.5% 
patients received radiotherapy only, 31% chemo-
therapy only, 26.9% a combination of chemothera-
py and radiotherapy and 16.1% surgery only. The 
proportion of patients treated with radiotherapy 
was highest for those diagnosed from 1970 to 1989 
(> 50%) and decreased over time (29.7% > 2000). 
Simultaneously, the number of patients treated 
with chemotherapy increased from 49.1% in 1970s 
to 75.2% after year 2000. In the cohort 16% (n = 527) 
patients had no therapy, of whom 75% were diag-
nosed before 1970 and majority died of childhood 
cancer. After 1980 there is approximately 4% of 
children with cancer undergoing observation only 
(e.g., low grade glioma, low risk neuroblastoma) 
(Table 3).
The overall risk of developing an SNs 
and SMNs
The estimated cumulative incidence of developing 
an SMN in the cohort was 2.8% at 20 years and in-
creased to 5.7% at 30 years after childhood cancer 
diagnosis. The cumulative incidence of SNs and 
SMNs increased with attained age without pla-
teauing (Figure 1).
Cumulative incidence of developing an SMN at 
40 years after childhood cancer diagnosis was sig-
nificantly lower for patients having surgery only (P 
FIGURE 3. Cumulative incidence of subsequent malignant neoplasm by 
decade of diagnosis of childhood cancer.
FIGURE 1. Cumulative incidence of all subsequent neoplasms and 
subsequent malignant neoplasms.
FIGURE 2. Cumulative incidence of subsequent malignant neoplasm by 
treatment modality of childhood cancer.
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Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk 383
TABLE 1. Characteristics of all individuals in study and number of subsequent neoplasms
Number (%) Any subsequentmalignant neoplasm
Non-melanoma 
skin  cancer
Benign
meningioma
All survivors 3271 (100%) 183 (100%) 56 (100%) 34 (100%)
Gender 
Male 1830 (55.9%) 77 (42.1%) 30 (54%) 14 (41%)
Female 1441 (44.1%) 106 (57.9%) 26 (46%) 20 (59%)
Childhood cancer 
type
Leukaemia 870 (26.6%) 23 (12.6%) 11 (20%) 14 (41%)
Hodgkin’s lymphoma 315 (9.6%) 51 (27.9%) 17 (30%) 2 (6%)
Non-Hodgkin’s lymphoma 277 (8.5%) 16 (8.7%) 4 (7%) 2 (6%)
Central nervous system tumour 625 (19.1%) 25 (13.7%) 12 (21%) 15 (44%)
Neuroblastoma 124 (3.8%) 6 (3.3%) 1 (2%) 0 (0%)
Retinoblastoma 60 (1.8%) 0 (0%) 0 (0%) 0 (0%)
Wilms’ tumour 143 (4.4%) 9 (4.9%) 1 (2%) 1 (3%)
Bone tumour 199 (6.1%) 13 (7.1%) 0 (0%) 0 (0%)
Soft-tissue sarcoma 224 (6.8%) 14 (7.7%) 4 (7%) 0 (0%)
Germ cell 168 (5.1%) 8 (4.4%) 3 (5%) 0 (0%)
Liver 27 (0.8%) 1 (0.5%) 1 (2%) 0 (0%)
Thyroid 86 (2.6%) 8 (4.4%) 1 (2%) 0 (0%)
Nasopharyngeal carcinoma 13 (0.4%) 4 (2.2%) 1 (2%) 0 (0%)
Melanoma 75 (2.3%) 2 (1.1%) 0 (0%) 0 (0%)
Carcinoma 59 (1.8%) 3 (1.6%) 0 (0%) 0 (0%)
Other 6 (0.2%) 0 (%) 0 (0%) 0 (0%)
Age at childhood 
cancer diagnosis 
(years)
Mean 9.4 (6.0) 11.2 (5.7) 11.3(6.0) 7.0 (4.1)
0–4 1065 (32.6%) 39 (21.3%) 13 (23%) 12 (35%)
5–9 656 (20.1%) 34 (18.6%) 9 (16%) 15 (44%)
10–14 690 (21.1%) 49 (26.8%) 13 (23%) 5 (15%)
15–19 860 (26.3%) 61 (33.3%) 21 (38%) 2 (6%)
Decade of 
diagnosis of 
childhood cancer
< 1970 528 (16.1%) 22 (12.0%) 4 (7%) 3 (9%)
1970–79 560 (17.1%) 50 (27.3%) 18 (32%) 11 (32%)
1980–89 651 (19.9%) 63 (34.4%) 22 (39%) 16 (47%)
1990–2000 679 (20.8%) 32 (17.5%) 9 (16%) 3 (9%)
2000–2018 853 (26.1%) 16 (8.7%) 3 (5%) 1 (3%)
Attained age 
(years)
0–19 1643 (50.2%) 31 (16.9%) 4 (7%) 2 (6%)
20–29 550 (16.8%) 33 (18.0%) 4 (7%) 7 (21%)
30–39 494 (15.1%) 59 (32.2%) 20 (36%) 19 (56%)
40–49 353 (10.8%) 33 (18.0%) 19 (34%) 5 (15%)
50–59 151 (4.6%) 19 (10.4%) 7 (12%) 0 (0%)
60+ 80 (2.4%) 8 (4.4%) 2 (4%) 1 (3%)
Treatment of 
childhood cancer
No therapy 527 (16.1%) 4 (2.2%) 9 (16%) 2 (6%)
Surgery only 506 (15.5%) 24 (13.1%) 3 (5%) 0 (0%)
Chemotherapy 1014 (31.0%) 40 (21.9%) 17 (30%) 2 (6%)
Radiotherapy 345 (10.5%) 44 (24.0%) 27 (48%) 11 (32%)
Radiotherapy and chemotherapy 879 (26.9%) 71 (38.8%) 9 (16%) 19 (56%)
Radiol Oncol 2022; 56(3): 380-389.
Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk384
heterogeneity < 0.001) (Figure 2). The observed cu-
mulative incidence of SMN at 30 years after child-
hood cancer diagnosis was significantly lower for 
those diagnosed in 1960s (P heterogeneity < 0.001) 
(Figure 3). Despite reduced use of radiotherapy af-
ter 1995 difference in cumulative incidence of SMN 
for the first 15 years after diagnosis was not signifi-
cant (Pepe Mori’s test for difference, p = 0.11).
The risk of developing any SMN was almost 
3-fold (SIR 2.9; 95% CI: 2.5–3.3) in the cohort com-
pared with the general population, corresponding 
to an absolute excess risk of 2.6 per 1000 person-
years (95% CI: 2.1–3.2.). Males appeared to be at 
higher risk than females in terms of the SIR (P het-
erogeneity < 0.001). With increasing attained age, 
the SIR gradually decreased, and AER increased 
(Table 4), with survivors still at 2-fold increased 
risk after age 50 years (SIR = 2.0; 95% CI: 1.3–3.1). 
The risk of an SMN was highest among patients 
with nasopharyngeal carcinoma (SIR 7.5; 95% CI: 
2.8–20.0), neuroblastoma (SIR 5.1; 95% CI: 2.3–11.3) 
and Hodgkin’s lymphoma (SIR 5.0; 95% CI: 3.8–
6.6) (Table 4). 
Elevated SIRs and AERs were evident for all 
childhood cancers, except for retinoblastomas, 
melanomas, and carcinomas. Not a single retino-
blastoma patient in cohort developed SN. 
Five-year overall survival was estimated for 
children with different solid tumours through dec-
ades to enable interpretation of results.  Survival 
for patients with retinoblastoma was 50%, 56%, 
88% and 100% for those diagnosed in 1960s, 1970s, 
1980s and after 2000, respectively. Patients with 
central nervous system (CNS) tumours, sarcomas 
and Wilms tumours diagnosed in 1970s and 1990s 
experienced increase of five-year overall survival 
from 44% to 65%, 46% to 62% and 58% to 76%, re-
spectively.
Risk of specific subsequent primary 
neoplasms
The most frequent SMNs were those of the thyroid 
(n = 37), genitourinary (n = 36; 15 cervical carci-
noma in situ) and breast (n = 26) carcinoma. The 
majority of breast (n = 13) and thyroid (n = 19) car-
cinoma occurred in Hodgkin’s lymphoma. Most 
genitourinary cancers occurred among bone and 
soft tissue sarcoma survivors (n = 12). Seventy per-
cent of SN occurred in patients with CNS tumours, 
leukaemia, and lymphoma (Table 5).
The greatest risk for SMN was observed for thy-
roid, (SIR 21.6; 95% CI: 15.2–29.7), CNS (SIR 13.4; 
95% CI: 7.9–21.2), soft tissue sarcoma (SIR 9.5; 95% 
CI: 3.1–22.2) and head and neck carcinoma (SIR 
6.4; 95% CI: 2.9–12.1). SMNs of the thyroid (AER 
76), breast (AER 41) and CNS (AER 36) contributed 
together almost 60% to the total AER. The distri-
bution of observed excess SMN changed with at-
tained age. In patients up to 40 years of age thyroid 
(AER 71), breast (AER 35), CNS tumours (AER 
30) and leukaemia (AER 17) represent the major-
ity of SMNs. After 40 years of age thyroid (AER 
109), genitourinary (AER 87), breast (AER 84), CNS 
(AER 78) and respiratory (AER 75) tumours were 
responsible for 80% of the total AER (Table 6). 
Because follow up commenced at the time of 
childhood cancer diagnosis all subsequent leukae-
TABLE 3. Treatment modality by decade of childhood cancer diagnosis
Treatment < 1970 1970–79 1980–89 1990–99 2000–2013
No therapy 399 (75.6%) 38 (6.8%) 27 (4.2%) 30 (4.4%) 33 (3.9%)
Surgery only 41 (7.8%) 102 (18.2%) 85 (13.1%) 116 (17.1%) 162 (19.0%)
Chemotherapy only 30 (5.7%) 135 (24.1%) 174 (26.7%) 270 (39.8%) 405 (47.5%)
Radiotherapy only 49 (9.3%) 145 (25.9%) 88 (13.5%) 46 (6.8%) 17 (2.0%)
Radiotherapy and chemotherapy 9 (1.7%) 140 (25.0%) 277 (42.6%) 217 (32.0%) 236 (27.7%)
Total 528 (100%) 560 (100%) 651 (100%) 679 (100%) 853 (100%)
TABLE 2. Vital status by decade of childhood cancer diagnosis
Decade of diagnosis
All survivors
Dead Alive
< 1970 447 81
1970–1979 394 166
1980–1989 309 342
1990–2000 222 457
2000–2013 155 698
Total 1527 1744
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Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk 385
TABLE 4. Standardized incidence ratios (SIR), absolute excess risks (AER), relative risk (RR) and relative excess risk (RER) for any subequent malignant 
neoplasm (SMN)
Factor Level
any SMN
AER (95%CI) RER (95%CI)
O SIR (95%CI) RR (95%CI)
Overall All combined 183 2.9 (2.5,3.3) – 2.6 (2.1,3.2) --
Sex
Male 77 4.0 (3.2,5.0) 1.0 (ref.) 2.3 (1.7,3.1) 1.0 (ref.)
Female 106 2.4 (2.0,2.9) 0.7 (0.5-1.0) 2.9 (2.1,4.0) 1.4 (0.9-2.1)
Pheterogeneity* <0.001 0.03 0.30 0.16
Age at 
diagnosis 
of 
childhood 
cancer 
(years)
0–4 39 3.9 (2.8,5.3) 1.0 (ref.) 2.0 (1.3,3.1) 1.0 (ref.)
5–9 34 3.3 (2.3,4.6) 0.9 (0.6-1.6) 2.4 (1.5,4.0) 0.8 (0.4-1.6)
10–14 49 3.1 (2.3,4.1) 0.9 (0.5-1.5) 3.2 (2.1,4.9) 0.7 (0.4-1.5)
15–19 61 2.3 (1.8,2.9) 0.8 (0.5-1.3) 2.7 (1.7,4.3) 0.6 (0.3-1.2)
Ptrend* 0.01 0.3 0.23 0.13
Decade of 
diagnosis 
of 
childhood 
cancer
< 1970 22 1.4 (1.0,2.2) 1.0 (ref.) 1.2 (0.3,4.8) 1.0 (ref.)
1970–1979 50 3.4 (2.6,4.5) 1.7 (1.0-3.0) 4.1 (2.8,6.1) 3.4 (1.0-11.9)
1980–1989 63 4.0 (3.1,5.1) 1.7 (0.9-3.0) 3.8 (2.7,5.3) 3.5 (1.0-12.5)
1990–2000 32 2.7 (1.9,3.8) 1.1 (0.5-2.1) 1.8 (1.0,3.1) 2.6 (0.7-9.7)
2000–2018 16 2.7 (1.7,4.4) 0.9 (0.4-2.0) 1.2 (0.5,2.5) 2.5 (0.6-10.4)
Ptrend* 0.07 0.3 0.02 0.61
Era 
diagnosis
< 1995 151 2.9 (2.5,3.4) 1.0 (ref.) 3.1 (2.4,3.9) 1.0 (ref.)
> = 1995 32 2.8 (2.0,4.0) 0.7 (0.5-1.1) 1.4 (0.8,2.5) 1.0 (0.6-1.8)
Pheterogeneity* 0.88 0.15 0.01 0.9
Attained 
Age (yrs)
< 20 31 10.6 (7.4,15.0) 1.0 (ref.) 1.5 (1.0,2.2) 1.0 (ref.)
20–29 33 2.2 (1.6,3.1) 0.2 (0.1-0.4) 1.4 (0.7,2.5) 1.0 (0.5-2.0)
30–39 59 3.5 (2.7,4.5) 0.3 (0.2-0.5) 5.1 (3.6,7.3) 3.4 (1.9-6.1)
40–49 33 2.7 (1.9,3.8) 0.2 (0.1-0.4) 5.2 (3.0,9.0) 3.4 (1.5-7.4)
50–59 19 2.0 (1.3,3.1) 0.2 (0.1-0.4) 6.6 (2.7,16.3) 7.5 (2.8-20.4)
60+ 8 1.3 (0.6,2.6) 0.1 (0.1-0.4) 3.7 (0.2,90.4) 10.8 (1.6-74.0)
Ptrend* <0.001 <0.001 <0.001 <0.001
Time since 
diagnosis 
of 
childhood 
cancer 
(years)
0–9 38 6.0 (4.3,8.2) 1.0 (ref.) 1.6 (1.1,2.3) 1.0 (ref.)
10–19 37 2.6 (1.9,3.6) 0.4 (0.3-0.7) 1.7 (1.0,2.9) 1.1 (0.6-2.0)
20–29 51 3.1 (2.4,4.1) 0.4 (0.2-0.6) 4.3 (2.9,6.5) 2.5 (1.4-4.4)
20–39 36 2.6 (1.9,3.6) 0.3 (0.2-0.6) 5.7 (3.4,9.6) 3.4 (1.7-6.9)
40+ 21 1.7 (1.1,2.5) 0.2 (0.1-0.4) 5.3 (1.8,15.5) 5.2 (2.1-12.4)
Ptrend* <0.001 <0.001 <0.001 <0.001
Type of 
childhood 
cancer
Leukaemia 23 2.7 (1.8,4.0) 1.0 (ref.) 1.6 (0.8,3.0) 1.0 (ref.)
Hodgkin’s lymphoma 51 5.0 (3.8,6.6) 2.5 (1.4-4.2) 6.5 (4.6,9.1) 2.8 (1.4-5.7)
non-Hodgkin’s lymphoma 16 4.3 (2.7,7.1) 1.7 (0.9-3.3) 3.3 (1.7,6.2) 1.3 (0.5-3.6)
Central nervous system tumour 25 2.8 (1.9,4.2) 1.2 (0.7-2.2) 2.1 (1.1,3.8) 1.1 (0.5-2.4)
Neuroblastoma 6 5.1 (2.3,11.3) 1.8 (0.7-4.5) 3.2 (1.2,8.6) 1.8 (0.6-5.5)
Retinoblastoma 0  0 -  0 -
Wilms Tumour 9 3.8 (2.0,7.3) 1.4 (0.6-3.1) 2.6 (1.1,6.3) 1.0 (0.3-3.3)
Bone sarcoma 13 2.7 (1.6,4.6) 1.6 (0.8-3.3) 3.3 (1.4,7.8) 1.8 (0.6-5.0)
Soft-tissue sarcoma 14 2.6 (1.5,4.4) 1.2 (0.6-2.3) 2.3 (1.0,5.4) 1.1 (0.4-2.9)
Germ-cell 8 1.6 (0.8,3.1) 0.9 (0.4-2.1) 1.0 (0.1,6.7) 0.6 (0.1-3.0)
Liver 1 7.9 (1.1,56.1) 2.2 (0.3-16.3) 3.2 (0.3,30.4) 2.1 (0.2-19.2)
Thyroid 8 2.0 (1.0,4.0) 1.2 (0.5-2.7) 2.3 (0.6,8.9) 0.9 (0.2-4.0)
Nasopharyngeal carcinoma 4 7.5 (2.8,20.0) 4.2 (1.4-12.8) 12.6 (4.1,39.1) 6.9 (1.9-24.6)
Melanoma 2 0.4 (0.1,1.8) 0.3 (0.1-1.4)  0.1 0
Carcinoma 3 1.1 (0.4,3.4) 0.8 (0.2-2.6) 0.2 0
Pheterogeneity* <0.001 <0.001 <0.001 <0.001
Treatment of 
childhood 
cancer
No therapy treatment of childhood 4 0.4 (0.2,1.1) 0.3 (0.1-0.8)  0 -
Surgery only 24 1.7 (1.1,2.5) 1.0 (ref.) 1.0 (0.4,2.7) 1.0 (ref.)
Chemotherapy 40 3.3 (2.4,4.4) 1.8 (1.1-3.1) 2.2 (1.4,3.4) 4.6 (1.0-20.9)
Radiotherapy 44 4.4 (3.3,5.9) 2.6 (1.6-4.3) 5.7 (3.9,8.4) 7.3 (1.6-33.5)
Radio and chemotherapy 71 4.3 (3.4,5.4)    2.4 (1.5-3.9) 3.8 (2.8,5.2) 7.0 (1.6-30.8)
Pheterogeneity* <0.001 <0.001 <0.001 <0.001
* = observed
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Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk386
mias (SL) were reported. There were 9 cases of sub-
sequent leukaemia. Compared to general popula-
tion, childhood cancer survivors had a 6-fold over-
all increased risk of leukaemia and an 8-fold (95% 
CI: 3.5–15.8) increased risk before age 40 (Table 6). 
Six patients developed SL within first 5 years of 
childhood cancer diagnosis. Only two out of nine 
patients survived the disease.
Mortality and survival following SMN
Fifty-nine patients out of 183 with SMN died within 
study period (1961 – 2018); 52 due to SMN and 7 of 
other causes. Five-year relative survival for patients 
with a SMN was 69 % (95% CI: 61–76). Most deaths 
were attributed to CNS tumours, SL, gastrointesti-
nal, respiratory, head and neck carcinomas. Six pa-
tients developed lethal SMNs outside the radiother-
apy field or without radiotherapy, two of them were 
with a known cancer predisposition syndrome.
Discussion
Main findings
Our study reports almost 3-fold increase in SMN 
among survivors of childhood cancer compared 
with general population. The SIRs reported by at-
tained age are similar to other population-based 
studies, but somewhat lower than in non-popula-
tion-based studies, particularly for those after age 
40 years.22 
For the first time we provided treatment data 
for our cohort. Intensive radiotherapy and chemo-
therapy started in 1970s, with highest proportion 
of patients having radiotherapy in 1980s. Low in-
tensity treatment in 1960s consequently resulted in 
only sporadic survival. Childhood cancer patients 
diagnosed in 1980s had the most intensive cancer 
treatment (56% radiotherapy and 70% chemo-
therapy). In high income countries radiotherapy 
for childhood cancer was already declining from 
75% before 1980 to 43% after 1980 and chemother-
apy was given to more than 80% of patients after 
1980.11,13,23 The maximum proportion of patients 
treated with radiotherapy and chemotherapy at 
any time was lower in our cohort and became com-
parable only recently, with approximately 30% of 
children with cancer having radiotherapy and 75% 
chemotherapy.11,13 The previous study on our co-
hort reported 48 SNs compared to 273 in current 
study, emphasizing need for continuous follow up 
despite lower risk.15 This is even more important 
since use of radiotherapy declined later. Namely, 
TABLE 5. Number and type of subsequent neoplasms (SN) by childhood cancer type
Childhood cancer 
type / SN
ALL  
AML HL NHL CNS Neuroblastoma Retinoblastoma Wilms
Bone 
sarcoma
Soft tissue 
sarcoma Germ cell Liver Thyroid
Nasopharyngeal 
carcinoma Melanoma Carcinoma Total
Meningioma 14 2 2 15 0 0 1 0 0 0 0 0 0 0 0 34
NMSC 11 17 4 12 1 0 1 0 4 3 1 1 1 0 0 56
Breast (C50 D05) 1 14 0 0 0 0 1 1 2 2 0 1 1 1 2 26
CNS (C70-C72) 6 0 0 11 1 0 0 0 0 0 0 0 0 0 0 18
Digestive (C15-C26) 1 3 4 0 1 0 0 2 1 0 0 1 0 0 0 13
Genitourinary  
(C51-C68, D09, D06) 3 3 2 4 0 0 2 5 7 3 1 5 0 1 0 36
Leukaemia (C90-C93) 3 2 1 1 0 0 0 1 1 0 0 0 0 0 0 9
Lymphoma (C81-C85) 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3
Melanoma (C43, D03) 0 0 1 1 0 0 1 0 0 1 0 0 0 0 0 4
Bone (C40-C41) 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 2
Head&Neck (C00-C14) 2 1 1 1 0 0 0 2 0 0 0 0 1 0 1 9
Other 1 3 1 1 0 0 2 0 0 0 0 1 0 0 0 9
Respiratory (C30-C39) 0 4 3 0 1 0 0 0 2 1 0 0 1 0 0 12
Soft-tissue (C49) 0 2 0 0 2 0 0 0 0 1 0 0 0 0 0 5
Thyroid (C73) 2 19 3 6 1 0 3 1 1 0 0 0 1 0 0 37
Total 48 70 22 52 7 0 11 13 18 11 2 9 5 2 3 273
ALL/AML = acute lymphoblastic/myelolastic leukaemia; CNS = central nervous system; HL = Hodgkin’s lymphoma; NHL = non-Hodgkin’s lymphoma; NMSC = non-melanoma skin 
cancer
Radiol Oncol 2022; 56(3): 380-389.
Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk 387
prophylactic cranial radiotherapy (CRT) in pa-
tients with acute lymphoblastic leukaemia (ALL) 
was gradually omitted in Slovenia after 1995 and 
for majority of patients after year 2002. Systematic 
review of randomized trials addressing prophy-
lactic CRT in ALL patients conducted between 
the 1970s and 1990s showed that radiotherapy 
can generally be replaced by intrathecal therapy.24 
There is substantial variation in percentage of ir-
radiated patients between different childhood ALL 
treatment groups, however children from high in-
come countries included in randomized trials had 
prophylactic CRT omitted a decade earlier then our 
patients.25 How different trends in treatment will 
correlate with cumulative incidence of SN in our 
cohort needs longer observation time.
Risk of SMNs in retinoblastoma survivors
In our cohort, no SNs were observed among retino-
blastoma patients, which is likely related to the fact 
that less than 20% had external beam radiotherapy. 
In countries using external beam radiotherapy, 
five-year overall survival of retinoblastoma pa-
tients diagnosed in 1966–1970 and 1996–2000 in-
creased from 86% to 96%.26 In Slovenia only half of 
patients with retinoblastoma survived the disease 
in the 1960s and 1970s. With the use of chemother-
apy and modern local therapies, survival increased 
to 88% in the 1980s and is 100% nowadays.27 The 
risk for SMN in nonhereditary retinoblastoma pa-
tients treated with surgery only, is comparable to 
general population and only hereditary retinoblas-
toma patients treated with radiotherapy have high-
er risk for SMN.28 In our study only four long term 
survivors with probable hereditary retinoblastoma 
had radiotherapy. 
Risk of subsequent sarcomas 
In our study the risk of subsequent soft tissue (SIR 
9.5, 95% CI: 3.1–22.2 vs. 15.7 95% CI: 14–17.6) and 
bone sarcomas (SIR 5.1, 95% CI: 0.6–18.3 vs. 21.65, 
95% CI: 18.97–24.6) was significantly lower than in 
PanCareSurFup cohort, that comprises data from 
12 European countries.29,30 The risk of subsequent 
soft tissue (SIR 12.1, 95% CI: 9.1–16) and bone sarco-
ma (SIR 10.1, 95% CI: 7.2–14) is more comparable to 
Nordic population-based cohort study then British, 
where highest overall SIR for any specific subse-
quent neoplasm was observed for subsequent bone 
neoplasms (SIR, 30.5; 95% CI, 24.9–37.3).6,7 Again, 
the greatest risk for subsequent primary sarcomas 
was observed in survivors of hereditary retino-
blastoma treated with radiotherapy, but there are 
only few of such patients in our cohort. 29,30 Similar 
TABLE 6. Standardized incidence ratios and absolute excess risks for specific subsequent malignant neoplasm overall and by attained age (0-39, 40+ 
years). Absolute excess risks are per 100,000 person-years
SMN (ICD10)
All ages 0-39 years 40+ years
Obs Exp SIR (95%CI) AER (95%CI) Obs Exp SIR (95%CI) AER (95%CI) Obs Exp SIR (95%CI) AER (95%CI)
All sites  183 63.2 2.9 (2.5,3.3) 257 (213,307) 123 34.9 3.5 (2.9,4.2) 216 (173,266) 60 28.2 2.1 (1.6,2.7) 545 (372,770)
Head & Neck (C00-C14) 9 1.4 6.4 (2.9,12.1) 16 (7,33) 5 0.3 17.8 (5.8,41.5) 12 (4,28) 4 1.1 3.5 (1.0,9.0) 49 (10,147)
Digestive organs (C15-C26) 13 5.5 2.4 (1.3,4.1) 16 (7,32) 7 1.0 6.8 (2.8,14.1) 15 (5,32) 6 4.4 1.4 (0.5,2.9) 27 (2,112)
Respiratory organs (C30-C39) 12 2.9 4.2 (2.2,7.4) 20 (9,37) 5 0.2 23.3 (7.6,54.5) 12 (4,28) 7 2.6 2.7 (1.1,5.5) 75 (22,185)
Bone (C40-C41) 2 0.4 5.1 (0.6,18.3) 3 (0,14) 2 0.3 5.8 (0.7,21.0) 4 (0,16) 0 0.0 0.0 (.,73.9) 0
Melanoma of skin (C43, D03) 4 4.2 1.0 (0.3,2.4) 0 3 2.2 1.4 (0.3,4.0) 2 (0,13) 1 2.0 0.5 (0.0,2.8) 0
Soft tissue (C49) 5 0.5 9.5 (3.1,22.2) 10 (3,23) 4 0.4 11.2 (3.1,28.7) 9 (2,24) 1 0.2 5.9 (0.1,32.9) 14 (0,90)
Breast (C50, D05) 26 6.6 3.9 (2.6,5.7) 41 (25,65) 16 1.6 10.3 (5.9,16.7) 35 (20,59) 10 5.1 2.0 (0.9,3.6) 84 (27,198)
Genitourinary (C51-C68, D09, D06) 36 32.2 1.1 (0.8,1.5) 8 (2,21) 22 23.3 0.9 (0.6,1.4) 0 14 8.9 1.6 (0.9,2.6) 87 (28,201)
Central nervous system (C70-C72) 18 1.3 13.4 (7.9,21.2) 36 (21,57) 13 0.9
14.3 
(7.6,24.4) 30 (15,52) 5 0.4
11.6 
(3.8,27.0) 78 (24,190)
Thyroid gland (C73) 37 1.7 21.6 (15.2,29.7) 76 (53,105) 30 1.1
27.3 
(18.5,39.0) 71 (47,102) 7 0.6
11.3 
(4.6,23.4) 109 (42,233)
Lymphoma (C81-C85) 3 2.8 1.1 (0.2,3.2) 0 (0,9) 3 2.0 1.5 (0.3,4.4) 3 (0,14) 0 0.8 0.0 (.,4.6) 0
Leukemia (C90-C93) 9 1.5 6.0 (2.8,11.4) 16 (7,32) 8 1.0 8.0 (3.5,15.8) 17 (7,35) 1 0.5 2.0 (0.1,11.2) 9 (0,80)
AER = absolute excess risks; Exp = expected; Obs = observed; SIR -  Standardized incidence ratios; SMN - subequent malignant neoplasm
Radiol Oncol 2022; 56(3): 380-389.
Cesen Mazic et al. / Childhood cancer and subsequent primary neoplasm risk388
trends in survival are seen for other childhood can-
cers contributing to subsequent sarcomas, namely 
patients with CNS tumours, sarcomas, and Wilms 
tumours.7,29,30 Survival of children diagnosed with 
CNS tumours, sarcomas, and Wilms tumours in 
1970s and 1990s increased from 44% to 65%, 46% 
to 62% and 58% to 76%, respectively. As radio-
therapy and chemotherapy are known risk factors 
for subsequent sarcomas, we might never see such 
an increase as in British and PanCareSurFup stud-
ies, since less patients were exposed to high-dose, 
high-volume radiotherapy and chemotherapy at 
any time. 31,32 As the most intensive treatment in 
our cohort was implemented later, we might ex-
pect increased risk with continued follow up.
Risk of subsequent leukaemia (SL)
In our cohort risk of SL is somewhat higher (SIR 
6.0, 95% CI 2.8–11.4) compared to PanCareSurFup 
cohort (SIR 3.7, 95% CI 3.1–4.5).33 The risk of SL 
is estimated for five-year survivors in published 
studies, making comparison difficult.6,33,34 By stud-
ying five-year survivors two thirds of SL in our co-
hort would be lost, with majority of patients dead 
due to high mortality of SL. Determining risk of SL 
before patients became 5-year survivors may have 
implications for other studies despite low numbers 
in our cohort.
Mortality and causes of death following 
SMNs
Recurrence of primary cancer is still the leading 
cause of death in childhood cancer patients up to 
15 years after diagnosis, afterwards death due to 
SMN takes the lead.5,35 Ten percent of patients that 
died of SMN had either no radiotherapy or SMN 
outside radiotherapy field. One third had known 
genetic cancer predisposition syndrome. Even 
these small numbers could stress the importance of 
surveillance for patients after radiotherapy or with 
known genetic predisposition syndromes.22
Clinical implications
The fact that the risks of developing an SMN in this 
study are similar to other European population-
based cohorts is important knowledge as it shows 
that follow-up guidelines for potential surveillance 
of SMNs developed for European survivors are 
relevant to the Slovenian childhood cancer sur-
vivor population. Follow up provided by a dedi-
cated physician applying current guidelines, as 
in Slovenia, is probably the best care possible for 
long-term survivors. 
Study limitations
Strength of our study is almost complete follow up 
in population-based setting with little heterogene-
ity in data collection and patient’s management. 
Potential limitations are the relatively small num-
ber of SPNs and unavailable detailed treatment 
information not allowing for investigations into 
the risks by specific cumulative radiotherapy and 
chemotherapy doses.
Conclusions
Within this population-based study with nearly 
complete follow we observed almost 3-fold in-
creased risk for SMN among childhood cancer 
survivors. What is new, are treatment data for our 
cohort, showing that most intensive treatment with 
radiotherapy and chemotherapy was implemented 
later in practice and radiotherapy also declined 
slower compared to high income countries. The 
evidence assembled in this study stresses the im-
portance of continuous surveillance according to 
European guidelines and further studies to assess 
whether risk of SMNs in childhood cancers survi-
vors in Slovenia will be different in the future.
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