Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: A population-based case-control study in the five Nordic countries

Figures & data

Table I.  Second malignant solid tumors (ICD-O classification) by primary IARC group (according to Birch and Marsden) in the cases.

		Second malignant solid tumors
IARC group	First malignant diagnosis	Digest	Bone	Conn	Skin	Breast	CNS	Thyr	Other	Total
I	Leukemia	0	0	0	0	1	6	2	3	12
II	Lymphomas	9	2	1	4	13	4	7	5	45
III	CNS neoplasms	4	0	4	1	1	26	0	5	41
IV	Sympathetic nerv. system	0	1	0	1	0	1	0	1	4
V	Retinoblastoma	2	7	2	3	0	1	0	1	16
VI	Renal tumors	3	1	1	0	0	1	1	0	7
VII	Hepatic tumors	0	0	0	0	0	0	0	0	0
VIII	Bone tumors	0	1	2	0	4	1	1	1	10
IX	Soft tissue sarcomas	0	2	3	1	0	4	0	1	11
X	Germ-cell neoplasms	1	0	2	3	1	1	1	14	23
XI	Carcinomas	3	0	2	6	4	2	2	7	26
XII	Other malign. neoplasms	0	0	0	0	0	1	0	0	1
Total		22	14	17	19	24	48	14	38	196

Digest (ICD < = 159) – Tumors in digestive tract, incl. oral cavity and pharynx.

Bone(ICD = 170) – Tumors in bones.

Conn(ICD = 171) – Tumors in connective tissues.

Skin (ICD = 173) – Tumors in skin.

Breast (ICD = 175) – Tumors in breast.

CNS (ICD = 191–192) – Brain tumors and other nervous system tumors.

Thyr(ICD = 193) – Thyroid carcinoma.

Other – Other malignant neoplasms.

Table II.  Radiation therapy (RT) and chemotherapy (CHT) in cases and in controls.

Exposure	Percentage of cases (n = 196)	Percentage of controls (n = 567)	Percentage of total material (n = 763)
RT−, CHT −	27.5	40.7	37.4
RT+, CHT −	33.7	29.5	30.5
RT−, CHT +	3.1	11.5	9.3
RT+, CHT +	35.7	18.3	22.8

Table III.  Exposure to different categories of chemotherapy in cases and controls.

	Cases (n = 196)		Controls (n = 567)
Type of patients (number)	Percentage treated	Median and largest dose*	Percentage treated	Median and largest dose*
Category of chemotherapy
Electrophilic agents	29.1	19.4; 256.4	18.5	24.5; 434.4
Spindle inhibitors	29.1	0.03; 0.97	22.4	0.03; 0.57
Inhibitors of nucleoside synthesis	11.2	137.5; 571.7	11.3	219.8; 934.2
Inhibitors of topoisomerase II	16.8	0.3; 4.2	13.8	0.2; 7.2

* Median and largest dose in moles per square meter body surface, in those treated (dose >0).

Table IV.  Percentage of cases and controls and relative risk (with 95% confidence interval) to develop SMST of all types by different treatments and relapse.

Exposure	Percentage of cases (n = 196)	Percentage of controls (n = 567)	RR	95% CI
RT* 0 Gy	38.8	62.6	1.0	Ref. group
RT* >0 – 1 Gy	16.3	19.8	1.8	1.1 – 3.1
RT* >1 – 5 Gy	8.7	4.4	3.7	1.8 – 7.5
RT* >5 – 30 Gy	17.9	6.0	7.1	3.7 – 13.5
RT* >30 Gy	12.2	1.6	18.3	7.3 – 45.8
RT unknown dose	6.1	5.6	1.5	0.7 – 3.3
No CHT & no RT**	35.2	49.6	1.0	Ref. group
CHT without RT**	9.2	17.3	0.5	0.3 – 1.1
RT** without CHT	26.0	20.6	2.3	1.4 – 3.7
CHT and RT**	29.6	12.5	4.3	2.6 – 7.0
No relapse	71.4	87.3	1.0	Ref. group
Relapse	28.6	12.7	2.7	1.8 – 4.1
Relapse adjusted for CHT&RT**			2.4	1.5 – 3.7

* Radiotherapy with latency 5 years at site of SMST.

** Radiotherapy with latency 5 years at any site.

Table V.  Additive excess relative risks (95% CI) and deviances for models including dose of radiation (Gy, latency 5 years) at the site of the SMST as a continuous exposure, CHT (without latency), interaction between CHT and RT and relapse before SMST.

Exposure	Model A	Model B	Model C	Model D	Model E*
Radiation (per Gy)	0.32 (0.16,0.63)	0.32 (0.16, 0.63)	0.27 (0.12, 0.55)	0.28 (0.13, 0.59)	0.35 (0.14, 0.81)
CHT (yes vs. no)	–	−0.12 (−0.48, 0.44)	−0.49 (−0.75, −0.03)	−0.53 (−0.79, −0.07)	−0.36 (−0.72, 0.40)
CHT and RT (yes vs. no)	–	–	1.31 (0.34, 2.86)	1.10 (0.11, 2.72)	1.85 (0.23, 5.35)
Relapse before SMST (yes vs. no)	–	–	–	0.93 (0.16, 2.28)	1.21 (0.21, 3.10)
Deviance (530.64 for no model)	461.98^a)	461.73	453.97^b)	447.61^c)	431.63^d)

* Model adjusted with multiplicative effects of 12 IARC groups for first cancer.

^a) Model A compared with no model, p < 0.001 (1 df).

^b) Model C vs. model A, p = 0.018 (2 df).

^c) Model D vs. model C, p = 0.011 (1 df).

^d) Model E vs. model D, p = 0.14 (11 df).

Table VI.  Relative risk (with 95% confidence interval) to develop SMST of all types by different treatments and relapse in the four age groups.

	0–4 years (47 cases, 138 contr)	5–9 years (18 cases, 54 contr)	10–14 years (40 cases, 117 contr)	15–19 years (91 cases, 258 contr)
Exposure/Age group	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)
RT* 0 Gy	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
RT* > 0–1 Gy	1.1 (0.4–3.6)	4.8 (0.8–28.7)	0.9 (0.3–2.6)	2.6 (1.1–6.1)
RT* > 1–5 Gy	7.9 (1.7–36.6)	8.9 (1.0–77.5)	1.2 (0.2–7.2)	3.3 (1.1–9.9)
RT* > 5–30 Gy	9.2 (1.8–46.4)	3.6 (0.4–36.5)	4.6 (1.1–18.9)	9.7 (3.8–24.7)
RT* > 30 Gy	19.1 (3.4–108.9)	4.5 (0.2–82.1)	8.5 (0.8–90.7)	30.5 (7.4–126.6)
RT unknown dose	2. 9 (0.8–11.0)	–	1.1 (0.4–3.7)	1.4 (0.3–6.9)
No CHT & no RT**	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
CHT without RT**	0.4 (0.1–1.4)	0.9 (0.1–7.8)	1.3 (0.4–4.4)	0.3 (0.1–1.2)
RT** without CHT	2.6 (0.9–7.1)	6.4 (1.0–40.2)	0.8 (0.3–2.4)	3.1 (1.4–6.5)
CHT and RT**	2.3 (0.9–5.7)	4.9 (0.9–26.9)	3.3 (1.1–9.6)	7.8 (3.4–17.8)
No relapse	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
Relapse	6.1 (2.3–16.1)	2.3 (0.7–7.5)	1.6 (0.7–3.5)	2.8 (1.5–5.1)
Relapse adjusted for CHT&RT**	5.1 (1.9–14.1)	3.3 (0.8–13.7)	1.2 (0.5–2.9)	2.1 (1.0–4.6)

* Radiotherapy with latency 5 years at site of SMST.

** Radiotherapy with latency 5 years at any site.

Table VII.  Relative risk (with 95% confidence interval) to develop some types of SMST by different treatments and relapse.

	Digestive tract (22 cases, 60 contr)	Bone (14 cases, 42 contr)	Connective tissue (17 cases, 47 contr)	Skin (19 cases, 54 contr)
Exposure/Type of SMST	RR (95% CI)	RR (95% CI)	RR (95% CI)	RR (95% CI)
RT* 0 Gy	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
RT* > 0–1 Gy	3.7 (0.8–17.2)	1.7 (0.2–12.9)	1.0 (0.1–13.2)	1.1 (0.2–6.3)
RT* > 1–5 Gy	7.2 (0.8–64.0)	24.5 (1.2–497.6)	9.9 (0.6–169.7)	–
RT* > 5–30 Gy	6.5 (0.7–60.2)	38.4 (1.4–1066.2)	5.8 (0.1–471.5)	–
RT* > 30 Gy	17.6 (2.1–148.4)	34.7 (1.3–957.3)	29.6 (1.8–490.8)	–
RT unknown dose	8.5 (1.0–70.2)	15.8 (0.6–389.4)	3.0 (0.2–48.0)	0.8 (0.1–5.0)
No CHT & no RT**	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
CHT without RT**	0.6 (0.1–3.8)	0.8 (0.1–8.8)	–	–
RT** without CHT	1.3 (0.3–6.1)	3.0 (0.6–15.6)	2.8 (0.5–16.3)	0.5 (0.1–3.1)
CHT and RT**	8.6 (1.5–49.3)	2.2 (0.5–9.9)	4.7 (0.7–31.7)	3.7 (0.8–16.8)
No relapse	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
Relapse	2.4 (0.7–8.2)	2.7 (0.8–9.2)	1.8 (0.4–8.3)	4.4 (0.8–24.9)
Relapse adjusted for CHT&RT**	0.7 (0.1–3.9)	2.9 (0.8–11.0)	1.5 (0.3–8.5)	2.4 (0.3–18.1)
Additive excess relative risk per Gy at the SMST site	0.1 (0.0–0.8)	3.1 (0.1–53.0)	0.8 (0.0–21.4)	0.2 (0.0–1.7)

* Radiotherapy with latency 5 years at site of SMST.

** Radiotherapy with latency 5 years at any site.

Table VIII.  Relative risk (with 95% confidence interval) to develop some types of SMST by different treatments and relapse.

	Breast (24 cases, 71 contr)	Central nervous system (48 cases, 143 contr)	Thyroid (14 cases, 41 contr)
Exposure/Type of SMST	RR (95% CI)	RR (95% CI)	RR (95% CI)
RT* 0 Gy	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
RT* > 0–1 Gy	10.6 (1.7–65.6)	0.7 (0.2–2.7)	3.4 (0.3–40.9)
RT* > 1–5 Gy	2.7 (0.3–21.2)	1.5 (0.3–8.4)	40.6 (1.3–1226.2)
RT* > 5–30 Gy	74.7 (6.4–869.4)	3.4 (1.1–10.2)	51.0 (2.0 -1329.5)
RT* > 30 Gy	–	10.0 (1.9–52.8)	21.3 (0.3–1568.0)
RT unknown dose	-	0.7 (0.1–3.2)	11.8 (0.4–373.7)
No CHT & no RT**	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
CHT without RT**	-	0.4 (0.1–1.3)	0.6 (0.0–7.0)
RT** without CHT	8.0 (1.6–40.2)	2.3 (0.9–6.1)	1.7 (0.3–11.9)
CHT and RT**	27.5 (4.1–185.9)	1.6 (0.6–4.6)	–
No relapse	1.0 (Ref. group)	1.0 (Ref. group)	1.0 (Ref. group)
Relapse	9.0 (2.5–33.0)	1.9 (0.8–4.6)	4.9 (1.5–16.4)
Relapse adjusted for CHT&RT**	18.6 (1.5–234.8)	2.3 (0.9–5.9)	3.6 (0.7–19.3)
Additive excess relative risk per Gy at the SMST site	0.7 (0.2–2.9)	0.1 (0.0–0.5)	1.7 (0.1–22.1)

* Radiotherapy with latency 5 years at site of SMST.

** Radiotherapy with latency 5 years at any site.