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Trends in treatment of childhood cancer and subsequent primary neoplasm risk

Maja Cesen Mazic
Maja Cesen Mazic
, 
Raoul C. Reulen
Raoul C. Reulen
, 
Janez Jazbec
Janez Jazbec
 and 
Lorna Zadravec Zaletel
Lorna Zadravec Zaletel
   | Aug 14, 2022
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Article Category: research article
Published Online: Aug 14, 2022
Page range: 380 - 389
Received: Feb 27, 2022
Accepted: May 10, 2022
DOI: https://doi.org/10.2478/raon-2022-0027
© 2022 Maja Cesen Mazic, Raoul C. Reulen, Janez Jazbec, Lorna Zadravec Zaletel, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1

Cumulative incidence of all subsequent neoplasms and subsequent malignant neoplasms.
Cumulative incidence of all subsequent neoplasms and subsequent malignant neoplasms.

Figure 2

Cumulative incidence of subsequent malignant neoplasm by treatment modality of childhood cancer.
Cumulative incidence of subsequent malignant neoplasm by treatment modality of childhood cancer.

Figure 3

Cumulative incidence of subsequent malignant neoplasm by decade of diagnosis of childhood cancer.
Cumulative incidence of subsequent malignant neoplasm by decade of diagnosis of childhood cancer.

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%)

Characteristics of all individuals in study and number of subsequent neoplasms

Number (%) Any subsequent malignant 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%)
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%)
Childhood cancer Bone tumour 199 (6.1%) 13 (7.1%) 0 (0%) 0 (0%)
type 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%)
Mean 9.4 (6.0) 11.2 (5.7) 11.3(6.0) 7.0 (4.1)
Age at childhood 0–4 1065 (32.6%) 39 (21.3%) 13 (23%) 12 (35%)
cancer diagnosis (years) 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%)
< 1970 528 (16.1%) 22 (12.0%) 4 (7%) 3 (9%)
Decade of 1970–79 560 (17.1%) 50 (27.3%) 18 (32%) 11 (32%)
diagnosis of childhood cancer 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%)
0–19 1643 (50.2%) 31 (16.9%) 4 (7%) 2 (6%)
20–29 550 (16.8%) 33 (18.0%) 4 (7%) 7 (21%)
Attained age 30–39 494 (15.1%) 59 (32.2%) 20 (36%) 19 (56%)
(years) 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%)
No therapy 527 (16.1%) 4 (2.2%) 9 (16%) 2 (6%)
Surgery only 506 (15.5%) 24 (13.1%) 3 (5%) 0 (0%)
Treatment childhood of cancer 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%)

Number and type of subsequent neoplasms (SN) by childhood cancer type

Childhood type / SN cancer 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

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 (5.8,41.517.8 ) 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 (7.6,54.523.3 ) 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 (3.1,28.711.2 ) 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 (5.9,16.710.3 ) 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 (7.9,21.213.4 ) 36 (21,57) 13 0.9 (7.6,24.414.3 ) 30 (15,52) 5 0.4 (3.8,27.011.6 ) 78 (24,190)
Thyroid gland (C73) 37 1.7 (15.2,29.721.6 ) 76 (53,105) 30 1.1 (18.5,39.027.3 ) 71 (47,102) 7 0.6 (4.6,23.411.3 ) 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)

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) --
Male 77 4.0 (3.2,5.0) 1.0 (ref.) 2.3 (1.7,3.1) 1.0 (ref.)
Sex 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 0–4 39 3.9 (2.8,5.3) 1.0 (ref.) 2.0 (1.3,3.1) 1.0 (ref.)
diagnosis 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)
of childhood 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)
cancer 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)
(years) Ptrend* 0.01 0.3 0.23 0.13
< 1970 22 1.4 (1.0,2.2) 1.0 (ref.) 1.2 (0.3,4.8) 1.0 (ref.)
Decade of 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)
diagnosis of 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)
childhood 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)
cancer 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 < 1995 151 2.9 (2.5,3.4) 1.0 (ref.) 3.1 (2.4,3.9) 1.0 (ref.)
diagnosis > = 1995 Pheterogeneity* 32 2.8 (2.0,4.0) 0.88 0.7 (0.5-1.1) 0.15 1.4 (0.8,2.5) 0.01 1.0 (0.6-1.8) 0.9
< 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)
Attained 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)
Age (yrs) 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
0–9 38 6.0 (4.3,8.2) 1.0 (ref.) 1.6 (1.1,2.3) 1.0 (ref.)
Time diagnosis since 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)
of 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)
childhood 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)
cancer (years) 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
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)
Type of 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)
childhood cancer 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
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.)
Treatment of 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)
childhood cancer 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

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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