Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008–2019

Figures & data

Figure 1. Number of patients per diagnosis according to International Classification of Childhood Cancer (ICCC-3). the exact number is given within parentheses. All three patients with ’other malignant disorders’ (ICCC-3 group XI) had parotid cancer. Among the five patients with benign disorders, four had an arteriovenous malformation (AVM) and one had a relapsing choroidal haemangioma.

Table 1. Acute complications for all treatment courses with a follow-up (FU) registration at end of RT (N = 200).

	All Patients (N = 200)			CNS (N = 132)			Non-CNS (N = 68)
	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)
Performance status	127	73(37)		74	58(44)		53	15(22)
Skin/subcut. tissue	59	131(66)	7(4)	49	80(61)		10	51(75)	7(10)
Hair	59	100(50)		33	92(70)		26	8(12)
Mucous membrane	163	13(7)	10(5)	122	3(2)		41	10(15)	10(15)
Salivary glands	172	9(5)		121	1(1)		51	8(12)
Pharynx/oesophagus	170	9(5)	2(1)	117	4(3)	1(1)	53	5(3)	1(2)
Larynx	95	2(1)	1(0.5)	39			56	2(3)	2(2)
Lungs	98			39			59
Heart	97			39			58
Upper GI tract	71	23(12)	8(4)	20	17(13)	4(3)	51	6(9)	4(6)
Lower GI tract	98	1(0.5)	1(0.5)	40	1(1)		58		1(2)
Liver	92			37			55
Genitourinary tract	88			37			51
Urethra/bladder	91			36			55
Bones	161			108			53
Joints	151	2(1)		102			49	2(3)
CNS	175	18(9)		113	18(14)		62
PNS	98	2(1)		37	1(1)		61	1(1)
Eyes	169	11(6)	1(0.5)	125	1(1)		44	10(15)	1(2)
Ears	183	2(1)	1(0.5)	127		1(1)	56	2(3)

RT: Radiotherapy; Gr: grade; GI: gastrointestinal.

Patients with CNS tumours (primary CNS germ-cell tumours included) and tumours outside CNS are shown separately. N: number of patients with a registered FU. In columns for grade 0, symptoms not related to RT are included, since these patients are considered to have baseline symptoms. In columns for grades 1–4, only complications related to RT are included. For patients with more than one treatment course, each treatment course is reported separately.

Table 2. Late complications for all treatment courses. Patients with CNS tumours (primary CNS germ-cell tumours included) and tumours outside CNS are shown separately.

FU 1 year	All treatments, N = 151			CNS tumours, N = 106			Non-CNS tumours, N = 45
	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)	Gr 0	Gr 1–2 (%)	Gr 3–4 (%)
Performance status	112	38(25)		70	36(34)		42	2(4)
Skin	115	28(19)		88	13(12)		27	15(33)
Subcutaneous tissue	123	9(6)		93	1(1)		30	8(18)
Hair	67	50(33)		46	44(42)		21	6(13)
Mucous membrane	128	4(3)		97			31	4(9)
Salivary glands	125	2(1)		96			29	2(4)
Pharynx/oesophagus	129			97			32
Larynx	125	1(1)		95			30	1(2)
Lungs	129			93			36
Heart	126			91			35
Upper GI tract	130	4(3)	2(1)	97	4(4)	1(1)	33		1(2)
Lower GI tract	135	2(1.3)		101			34	2(4)
Liver	120			87			33
Urethra/bladder	123	1(1)		91			32	1(2)
Bones	87	1(1)	1(1)	64	1(1)		23		1(2)
Joints	85	2(1)		59			26	2(4)
Extremity function	41			32			9
CNS	112	31(21)		77	29(27)		35	2(4)
PNS	113	2(1)	1(1)	82	1(1)		31	1(2)	1(2)
Eyes	134	5(3)		102	1(1)		32	4(9)
Ears	126	7(3)	4(3)	92	6(6)	3(3)	34	1(2)	1(2)
FU 3 years	All treatments, N = 80			CNS tumours, N = 55			Non-CNS tumours, N = 25
	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4
Performance status	60	19(24)		37	18(33)		23	1(4)
Skin	65	10(13)	1(1)	48	4(7)	0	17	6(24)	1(4)
Subcutaneous tissue	65	6(8)	2(3)	52			13	6(24)	2(8)
Hair	39	30(38)		26	24(45)		13	6(24)
Mucous membrane	58	5(6)	1(1)	45			13	5(20)	1(1)
Salivary glands	53	5(6)		43			10	5(20)
Pharynx/oesophagus	63			46			17
Larynx	62			46			16
Lungs	63	1(1)		46			17	1(4)
Heart	61			43			18
Upper GI tract	59	1(1)		46	1(2)		13
Lower GI tract	62			47			15
Liver	62			46			16
Urethra/bladder	60			45			15
Bones	35	4(5)	3(4)	28	2(4)		7	2(8)	3(12)
Joints	36	5(6)	1(1)	27			9	5(20)	1(4)
Extremity function	23	1(1)		19			4	1(4)
CNS	48	24(30)	1(1)	31	22(40)	1(2)	17	2(8)
PNS	61	1(1)		45			16	1(4)
Eyes	68	2(3)		50	1(2)		18	1(4)
Ears	60	9(11)		42	8(15)		18	1(4)
FU 5 years	All treatments, N = 56			CNS tumours, N = 41			Non-CNS tumours, N = 15
	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4
Performance status	45	11(20)		31	10(24)		14	1(7)
Skin	44	12(21)	1(2)	39	2(5)		5	10(67)	1(7)
Subcutaneous tissue	49	4(7)	1(2)	39	1(2)		10	3(20)	1(7)
Hair	28	23(41)		23	18(44)		5	5(33)
Mucous membrane	52	1(2)	1(2)	40			12	1(7)	1(7)
Salivary glands	51	1(2)	1(2)	39			12	1(7)	1(7)
Pharynx/oesophagus	53	1(2)		40			13	1(7)
Larynx	51			39			12
Lungs	52			38			14
Heart	52			38			14
Upper GI tract	45			35			10
Lower GI tract	45			35			10
Liver	43			34			9
Urethra/bladder	44			36			8
Bones	20	5(9)	5(9)	19	2(5)		1	3(20)	5(33)
Joints	27	3(5)	2(4)	21			6	3(20)	2(13)
Extremity function	22	1(2)		20			2	1(7)
CNS	35	18(32)	1(2)	24	16(39)	1(2)	11	2(13)
PNS	37	3(5)		26	1(2)		11	2(13)
Eyes	45	5(9)	1(2)	37	2(5)		8	3(20)	1(7)
Ears	51	1(2)	2(4)	38	1(2)	1(2)	13		1(7)
FU 10 years	All treatments, N = 28			CNS tumours, N = 20			Non-CNS tumours, N = 8
	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4	Gr 0	Gr 1–2	Gr 3–4
Performance status	20	7(25)		15	5(25)		5	2(25)
Skin	19	7(25)		17	2(10)		2	5(63)
Subcutaneous tissue	22	3(11)	1(4)	19	1(5)		3	2(25)	1(13)
Hair	11	16(57)		8	12(60)		3	4(50)
Mucous membrane	21	1(4)		17			4	1(13)
Salivary glands	23			17			6
Pharynx/oesophagus	23			17			6
Larynx	23			17			6
Bones	2	2(7)	1(4)	1	1(5)		1	1(13)	1(13)
Joints	8		1(4)	6		1(5)	2
CNS	17	9(32)		12	8(40)		5	1(13)
PNS	17		1(4)	14		1(5)	3
Eyes	23	2(7)		18	1(5)		5	1(13)
Ears	24	1(4)		19	1(5)		5

CNS: Central nervous system; FU: follow-up; RT: radiotherapy; Gr: grade; GI: gastrointestinal; PNS: peripheral nervous system. N: number of patients with a registered follow-up (FU) at each time-point. In columns for grade 0, symptoms not related to RT are included, since these patients are considered to have baseline symptoms. In columns for grades 1–4, only complications related to RT are included. For FU after 10 years some types of complications were omitted from the table, since all these patients were treated at TSL with no treatment field below the neck. For patients with more than one treatment course, each treatment course is reported separately.

Table 3. Description of all 15 patients with late complications grades 3 or 4. Proton target doses in GyRBE, photon RT and brachytherapy in Gy, fraction doses within parentheses.

Pt no	Diagnosis/Tumour site/Age at RT	Target Dose (Gy/GyRBE)	Late complications
1 TSL	Rhabdomyosarcoma, maxillary sinus. 9 years old	55.8 (1.8/fr)	10 years: Severe atrophy of subcutaneous tissue (gr 3), growth inhibition of bones (gr 3) and muscle atrophy. Missing permanent teeth.
2 TSL	Ganglioglioma, right temporal lobe. 10 years old	54 (1.8/fr)	5 years: Brain fatigue, panhypopituitarism (CNS gr 3).
3 TSL	Rhabdomyosarcoma, cheek, base of skull,middle fossa. 9 years old	55.9 (1.8/fr)	5 years: Severe atrophy of subcutaneous tissue (gr 3), complete xerostomia (gr 3), short teeth roots, growth inhibition of bones (gr 3), severe tinnitus (ears gr 3).
4 TSL	Rhabdomyosarcoma, right parotid gland. 5 years old	Parotid gland + neck 50.4, boost parotid gland total 55.8 (1.8/fr)	3 and 5 years: Growth inhibition of bones (gr 3). Fibrotic subcutaneous tissue (gr 3). Jaw joint stiffness (gr 2). Missing teeth, shortteeth roots. Dry mucous membranes (gr 2).
5 TSL	Ewing sarcoma, Th9. 7 years old	52.2 (1.8/fr)	3 and 5 years: Spontaneous vertebral fracture (bones gr 4).
6 TSL	Rhabdomyosarcoma, upper middle part of left orbit. 3 years old	45.0 (1.8/fr)	5 years: Blind left eye (gr 4). Growth inhibition of facial bones (gr 3).
7 TSL	Fibromatosis, mouth. 12 years old	2011: 59.4 (1.8/fr) 2013: 51.0 (3.0/fr) 2013: 51.0 (3.0/fr) 2014: 64.0 (2.0/fr) Fields partially overlapping.	3 and 5 years: Ulceration and necrosis of the skin, subcutaneous tissue and mucosa (gr 4), growth inhibition of bones (gr 3), severe jaw joint stiffness (gr3). Died from tumour five years post end of first proton RT. Treatments 2011 and 2014 were given with photons.
8 TSL	ATRT, cerebellum. 4 years old	54.0 (1.8/fr)	5 years: Hearing loss (ears gr 3).
9 SC	Craniopharyngioma. 5 years old	54.0 (1.8/fr)	3 years: stroke due to moyamoya syndrome (CNS gr 4). The patient survived and has mild sequelae.
10 SC	Rhabdomyosarcoma, left nose wing. 9 years old	Brachytherapy 51 (3/fr)to primary tumour 54.0 (1.8/fr)to left maxilla due to relapse (no overlap)	1 year: Osteonecrosis in the jaw (bones gr 4). No evidence of infection during RT. No NF-1.
11 SC	Neuroblastoma, sacrum. 2 years old	36 (1.5/fr)	1 year: Remaining urinary and faeces incontinence (PNS gr 3). Not eligible for a 3-year follow up within the study period.
12 SC	Medulloblastoma. 5 years old	CSI + boost to posterior fossa 23.4 + 30.6 (1.8/fr)	1 year: Gastric feeding tube initiated during Rt (upper GI gr 3), hearing loss (ears gr 3) Apr 2018, no tumour near cochleae. Died from tumour two years post end of RT.
13 SC	Germ cell tumour, pineal corpus. 14 years old	2017: 54 (1.8/fr) 2018: 30.6 (1.8/fr)	1 year past last RT: Hearing loss (ears gr 3).
14 SC	Medulloblastoma. 12 years old	CSI + boost to posterior fossa 35.2(1.6/fr) + 19.8 (1.8/fr)	1 year: Hearing loss (ears gr 3) directly after cisplatin therapy.
15 SC	Rhabdomyosarcoma, Base of skull, left temporal lobe. 5 years old	50.4 (1.8/fr)	1 year: External otitis, perforated tympanic membrane (ears gr 3). Complete recovery after surgery. 3 years: Ears normal(gr 0)

RT: Radiotherapy; Pt: Patient; TSL: The Svedberg Laboratory; SC: Skandion Clinic; CNS: Central nervous system; NF-1: Neurofibromatosis 1; PNS: Peripheral nervous system; CSI: Craniospinal irradiation; GI: Gastrointestinal; ATRT: Atypical teratoid rhabdoid tumour.

Data availability statement

Raw data is available from the corresponding author on request.