Trends in treatment of childhood cancer and subsequent primary neoplasm risk

Cesen Mazic, Maja; Reulen, Raoul C.; Jazbec, Janez; Zadravec Zaletel, Lorna

doi:10.2478/raon-2022-0027

Figures & Tables

Cumulative incidence of all subsequent neoplasms and subsequent malignant neoplasms.

Cumulative incidence of subsequent malignant neoplasm by treatment modality 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	Wilms	Bone sarcoma	Soft tissue sarcoma	Germ cell	Liver	Thyroid	Nasopharyngeal carcinoma	Melanoma	Carcinoma	Total
Meningioma	14	2	2	15	0	1	0	0	0	0	0	0	0	0	34
NMSC	11	17	4	12	1	1	0	4	3	1	1	1	0	0	56
Breast (C50 D05)	1	14	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	18
Digestive (C15-C26)	1	3	4	0	1	0	2	1	0	0	1	0	0	0	13
Genitourinary (C51-C68, D09, D06)	3	3	2	4	0	2	5	7	3	1	5	0	1	0	36
Leukaemia (C90-C93)	3	2	1	1	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	3
Melanoma (C43, D03)	0	0	1	1	0	1	0	0	1	0	0	0	0	0	4
Bone (C40-C41)	1	0	0	0	0	0	1	0	0	0	0	0	0	0	2
Head&Neck (C00-C14)	2	1	1	1	0	0	2	0	0	0	0	1	0	1	9
Other	1	3	1	1	0	2	0	0	0	0	1	0	0	0	9
Respiratory (C30-C39)	0	4	3	0	1	0	0	2	1	0	0	1	0	0	12
Soft-tissue (C49)	0	2	0	0	2	0	0	0	1	0	0	0	0	0	5
Thyroid (C73)	2	19	3	6	1	3	1	1	0	0	0	1	0	0	37
Total	48	70	22	52	7	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)
Factor	Level	O	SIR (95%CI)	RR (95%CI)	AER (95%CI)	RER (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)
	P_{heterogeneity*}		<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)	P_trend*		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)
	P_trend*		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 P_{heterogeneity*}	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)
	P_trend*		<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)
	P_trend*		<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
	P_{heterogeneity*}		<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)
	P_{heterogeneity*}		<0.001	<0.001	<0.001	<0.001

Vital status by decade of childhood cancer diagnosis

Decade of diagnosis	All survivors
Decade of diagnosis	Dead	Alive
< 1970	447	81
1970–1979	394	166
1980–1989	309	342
1990–2000	222	457
2000–2013	155	698
Total	1527	1744

Trends in treatment of childhood cancer and subsequent primary neoplasm risk

Figures & Tables

Figure 1

Figure 2

Figure 3

Treatment modality by decade of childhood cancer diagnosis

Characteristics of all individuals in study and number of subsequent neoplasms

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

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

Standardized incidence ratios (SIR), absolute excess risks (AER), relative risk (RR) and relative excess risk (RER) for any subequent malignant neoplasm (SMN)

Vital status by decade of childhood cancer diagnosis

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