Longitudinal development of fatigue after treatment for childhood cancer: a national cohort study

Figures & data

Table 1. Patient demographics for the proxy-reports of the PedsQL^TM Multidimensional Fatigue Scales.

	Individuals	Observations
Number of participants	761	2440
Assessments per patient – median, range, interquartiles	Median 3, range 1–11, interquartiles 1–5
Sex, N (%)
Female	342 (44.9%)	1079 (44.4%)
Proxy-reporter sex, N (%)
Female	590 (77.5%)	1906 (78.1%)
Diagnosis before or after centralization of care
After	496 (65.2%)	1615 (66.2%)
Age at diagnosis – mean years (SD)	2.95 (1.75)	2.75 (1.61)
Range	0.01 − 7.62	0.01 − 7.62
Age at assessment, N (%)
2–4 Years	251 (33.0%)	585 (24.0%)
5–7 Years	510 (67.0%)	1855 (76.0%)
Treatment, N (%)
Chemotherapy	614 (80.7%)	2098 (86.0%)
Radiotherapy	154 (20.2%)	584 (23.9%)
Allogenic stem cell therapy	13 (1.7%)	35 (1.4%)
Brain surgery	138 (18.1%)	358 (14.7%)
Immunotherapy	147 (19.3%)	434 (17.8%)
Diagnoses, N (%)
Hemato-oncology	297 (39.0%)	869 (35.6%)
Acute lymphoblastic leukemia	177 (23.3%)	514 (21.1%)
Acute myeloid leukemia	48 (6.3%)	151 (6.2%)
Langerhans cell histiocytosis	39 (5.1%)	100 (4.1%)
Non-Hodgkin lymphoma	24 (3.2%)	86 (3.5%)
Hodgkin lymphoma	7 (0.9%)	14 (0.6%)
Hemato-oncology other	2 (0.3%)	4 (0.2%)
Solid tumors	291 (38.4%)	1132 (46.4%)
Kidney tumor	110 (14.5%)	503 (20.6%)
Neuroblastoma	82 (10.8%)	301 (12.3%)
Soft tissue tumor	40 (5.3%)	137 (5.6%)
Germ cell tumor non-central nervous system	26 (3.4%)	74 (3.0%)
Liver tumor	17 (2.2%)	77 (3.2%)
Bone tumor	12 (1.6%)	34 (1.4%)
Solid tumor other	5 (0.7%)	6 (0.2%)
Central nervous system tumors	172 (22.6%)	439 (18.0%)
Low grade gliomas	97 (12.7%)	230 (9.4%)
Ependymoma and choroid plexus papilloma	27 (3.5%)	64 (2.6%)
Medulloblastoma	19 (2.5%)	68 (2.8%)
Craniopharyngioma	12 (1.6%)	27 (1.1%)
High grade gliomas	6 (0.8%)	9 (0.4%)
Embryonal tumor	5 (0.7%)	24 (1.0%)
PNET	3 (0.4%)	3 (0.1%)
CNS germ cell tumor	2 (0.3%)	8 (0.3%)
CNS Other	1 (0.1%)	6 (0.2%)
Relapse	84 (11.0%)	243 (10.0%)
Parental education level^a, N (%)	Missing: 159	Missing: 311
Low	19 (3%)	67 (3%)
Medium	196 (33%)	663 (31%)
High	387 (64%)	1399 (66%)
Parental distress risk thermometer, N (%)	Missing: 36	Missing: 47
Not clinical	381 (52.6%)	1348 (53.3%)
Clinical	344 (47.4%)	1045 (43.4%)

^aLow: primary education, lower vocational education, lower and middle secondary education; medium: middle vocational education, higher secondary education, pre-university education; high: higher vocational education, university.

Italic values indicate that they belong to the main diagnostic group.

Figure 1. (A,B) Growth-curves for cognitive fatigue, with predicted means and 95% confidence intervals. None of the groups have a significant interaction with time.

Figure 2. (A,B) Growth-curves for sleep-rest fatigue, with predicted means and 95% confidence intervals. The self-reports for the central-nervous-system group has a significant interaction with time and the scores are decreasing more over time than solid tumors (p=.031).

Figure 3. (A,B) Growth-curves for general fatigue, with predicted means and 95% confidence intervals. None of the groups have a significant interaction with time.

Table 2. Patient demographics for the self-reports of the PedsQL^TM Multidimensional fatigue Scales.

	Individuals	Observations
Number of participants	990	2657
Assessments per patient - median, range, interquartiles	Median 2, range 1–12, interquartiles 1–4
Sex, N (%)
Female	463 (46.1%)	1347 (50.7%)
Diagnosis before or after centralization of care
After	456 (46.1%)	1221 (46.0%)
Age at diagnosis – mean (SD)	10.18 (4.65)	10.60 (4.49)
Range	0.02 − 18.73	0.02 − 18.73
Age at assessment
8–12 Years	480 (48.5%)	1149 (43.2%)
13–18 Years	454 (45.9%)	1071 (40.3%)
Above 18 years	56 (5.7%)	437 (16.4%)
Treatment, N (%)
Chemotherapy	739 (74.6%)	2073 (78.0%)
Radiotherapy	266 (26.9%)	767 (28.9%)
Allogenic stem cell therapy	27 (2.7%)	61 (2.3%)
Brain surgery	246 (24.8%)	590 (22.2%)
Immunotherapy	123 (12.4%)	327 (12.3%)
Diagnoses, N (%)
Hemato-oncology	435 (43.9%)	1198 (45.1%)
Acute lymphoblastic leukemia	190 (19.2%)	454 (17.1%)
Hodgkin lymphoma	115 (11.6%)	380 (14.3%)
Non-Hodgkin lymphoma	75 (7.6%)	230 (8.7)
Acute myeloid leukemia	41 (4.1%)	107 (4.0%)
Langerhans cell histiocytosis	13 (1.3%)	25 (0.9%)
Hemato-oncology other	1 (0.1%)	2 (0.1%)
Solid tumors	256 (25.9%)	743 (28.0%)
Soft tissue tumor	67 (6.8%)	202 (7.6%)
Bone tumor	64 (6.5%)	191 (7.2%)
Kidney tumor	41 (4.1%)	107 (4.0%)
Germ cell tumour non-central nervous system	32 (3.2%)	118 (4.4%)
Solid tumor other	26 (2.6%)	69 (2.6%)
Neuroblastoma	19 (1.9%)	44 (1.7%)
Liver tumor	7 (0.7%)	12 (0.5%)
Central nervous system tumors	299 (30.2%)	716 (26.9%)
Low grade gliomas	155 (15.7%)	357 (13.4%)
Medulloblastoma	50 (5.1%)	146 (5.5%)
Craniopharyngioma	26 (2.6%)	48 (1.8%)
CNS germ cell tumor	20 (2.0%)	46 (1.7%)
Ependymoma and choroid plexus papilloma	20 (2.0%)	49 (1.8%)
CNS other	13 (1.3%)	31 (1.2%)
High grade gliomas	8 (0.9%)	25 (0.9%)
PNET	2 (0.2%)	4 (0.2%)
Embryonal tumor	2 (0.2%)	4 (0.2%)
Relapse	103 (10.4%)	296 (11.1%)
Parental education level,^a N (%)	Missing: 403	Missing: 869
Low	28 (4.8%)	88 (4.9%)
Medium	205 (34.9%)	562 (31.4%)
High	354 (60.3%)	1138 (63.6%)
Parental distress thermometer, N (%)	Missing: 200	Missing: 400
Not clinical	398 (50.4%)	1257 (55.7%)
Clinical	392 (49.6%)	1000 (44.3%)

^aLow: primary education, lower vocational education, lower and middle secondary education; medium: middle vocational education, higher secondary education, pre-university education; high: higher vocational education, university.

Italic values indicate that they belong to the main diagnostic group.

Table 3. Multivariable analysis of variables associated with fatigue development over time for parent-proxy reports, stratified by main diagnosis, N = 761. Unstandardized estimates with 95% confidence intervals.

		Cognitive fatigue			Sleep-rest fatigue			General fatigue
Variables^a		HO	ST	CNS	HO	ST	CNS	HO	ST	CNS
Fatigue score at end of treatment^b		75.63	82.26	70.96	75.86	77.24	75.21	72.31	76.52	68.87
		71.61; 80.20	79.58; 84.94	66.47; 75.38	72.51; 79.21	75.01; 79.48	71.52; 78.88	67.93;76.68	73.62;79.42	64.37;73.36
Demographics	Female sex	4.84*	^c	^c	^c	−3.23*	^c	^c	^c	^c
		0.32;9.36				−6.14;−0.32
	Age ≥4 years	−6.40**	^c	−5.61	4.26*		^c	^c	^c	^c
		−11.09;−1.70		−2.41; 2.05	0.42;8.09
Diagnosis characteristics	Diagnosis at 2–4 years	^c	−3.60	−0.69	10.66	^c	−1.04	^c	−4.83*	^c
			−8.32; 1.95	−8.86; 7.48	−3.09; 4.43		−4.82; 6.89		−8.78;-0.88
	Diagnosis	^c	−7.52**	−11.30*	1.65	^c	3.91	^c	−5.05*	^c
	>4 years		−12.98; −1.91	−20.45;−2.15	−2.93; 6.23		−2.14; 9.96		−9.66;-0.44
	Centralized care	3.71	^c	10.16**	^c	^c	^c	^c	^c	7.98*
		−0.90; 8.33		2.83;17.50						1.98;14.07
	Relapse	^c	−5.27	^c	−7.24*	−5.10*	−1.57	−7.13*	−10.05***	^c
			−10.88;0.34		−9.48;−0.72	−9.48;−0.72	−7.46; 4.33	−13.98-0.28	−15.29;-4.83
Treatment	Chemotherapy	−5.03	^c	^c	−9.84*	−4.04	^c	−6.69	−8.66**	−3.81
		−16.80; 6.73			17.88;−1.86	−9.34; 1.26		−16.41; 3.02	−14.59;-2.72	−9.65; 2.94
	Radiotherapy	^c	^c	−7.93*	^c	^c	^c	^c	−0.71	^c
				−15.20;−0.65					−4.54;3.14
	Immunotherapy	^c	−4.60	^c	^c	^c	−10.66*	^c	−6.25*	−7.31
			−9.96; 0.76				−18.89;-2.43		−11.56;-0.94	−8.36;1.89
Parental distress	DTP	−6.45 ***	−2.52*	^c	−7.37 ***	−3.59***	−4.43**	−9.45***	−4.78***	−4.87**
		−9.36; −3.54	−4.58; −0.45		−9.60;5.14	−5.52;−1.65	−7.47;−1.38	−12.18;-6.72	−6.92;-2.65	−8.36;-1.38

Age (at assessment) defined as below (reference group) or above 4 years. Age at diagnosis defined as below 2 years (reference group), 2–4 years, or above 4 years. Centralized care defined as before (reference group) or after centralization. CI: confidence interval; CNS: central nervous system-tumors; DTP: distress thermometer parents; HO: hemato-oncology; ST, solid tumors. *p .05; **p .01; ***p<.001.

^aBrain surgery and allogenic stem cell therapy were not selected for any of the multivariable models.

^bModelled fatigue score at end of treatment, for the group without any of the included factors. The scale is 0–100, where a higher score represents less fatigue.

^cNot included in multivariable model.

Table 4. Multivariable analysis of variables associated with fatigue development over time for self-reports, stratified by main diagnosis, N = 990.

		Cognitive fatigue			Sleep-rest fatigue			General fatigue
Variables^a		HO	ST	CNS	HO	ST	CNS	HO	ST	CNS
Fatigue score at end of treatment^b		70.01	70.74	63.96	70.29	67.96	69.21	72.98	70.76	69.62
		66.03; 73.99	67.62; 73.85	59.65; 68.27	67.23; 73.34	65.58; 70,35	65.89; 72.52	69.56;76.40	68.09;73.43	65,92;73.33
Demographics	Age 13–18	^c	^c	−2.49	−1.79	−9.70***	2.41	−2.16	−5.79**	−0.78
				−7.00; 2.02	−5.54; 1.96	−13.09;−6.31	−1.73; 6.56	−5.19;0.87	−9.59;-2.00	−4.38;2.82
	Age >18	^c	^c	−9.98*	−0.82	−6.95**	−0.91	−5.94**	−6.89**	−2.38
				−18.13;−1.83	−5.75; 4.10	−11.39;−2.51	−8.28; 6.46	−10.40;-1.48	−11.76;-2.02	−9.36;4.60
Diagnosis characteristics	Diagnosis at 4–12 years	^c	^c	^c	0.14	^c	−10.06**	^c	^c	^c
					−5.11; 5.39		−16.59;−3.52
	Diagnosis >12 years	^c	^c	^c	−5.65	^c	−20.00***	^c	^c	^c
					−12.30; 1.00		−28.35;−11.65
	Centralized care	4.64	^c	10.26**	^c	^c	10.12***	^c	^c	6.00*
		−0.18; 9.47		3.72;16.81			5.46;14.78			1.09;10.91
	Relapse	^c	^c	^c	^c	^c	−11.49***	^c	−5.14	−5.55*
							−16.57;−6.41		−10.79;0.50	−11.06;-0.04
Treatment	Chemotherapy	−6.85	^c	−4.18	^c	^c	0.53	−4.79	^c	−4.41
		−18.38; 4.69		−9.81; 1.45			−3.37;4.44	−13.84;4.26		−8.84;0.03
	Radiotherapy	^c	^c	^c	−3.17	^c	^c	^c	^c	^c
					−7.88; 1.54
	Immunotherapy	^c	−9.38*	^c	^c	^c	^c	−4.64*	^c	^c
			−18.60;−0.15					−8.56;-0.72
Parental distress	DTP	−2.32	^c	−3.99*	^c	^c	−5.28***	−2.70*	^c	−6.85***
		−4.70; 0.16		−7.31;−0.67			−8.05;−2.50	−4.98;-0.42
										−9.71;-3.99

Unstandardized estimates with 95% confidence intervals.

Age (at assessment) defined as below 13 years (reference group), 13–18 or above 18 years. Age at diagnosis defined as below 4 years (reference group), 4–12 years, or above 12 years. Centralized care defined as before (reference group) or after centralization. CI: confidence interval; CNS: central nervous system-tumors; DTP: distress thermometer parents; HO: hemato-oncology; ST: solid tumors. *p .05; **p .01; ***p <.001.

^aFemale sex, brain surgery, and allogenic stem cell therapy were not selected for any of the multivariable models.

^bModelled fatigue score at end of treatment, for the group without any of the included factors. The scale is 0–100, where a higher score represents less fatigue.

^cNot included in multivariable model.

Data availability statement

Deidentified individual participant data (including data dictionaries) will be made available, in addition to the statistical analysis plan. The data will be made available after publication upon request to researchers who provide a methodologically sound proposal and after a signed data sharing agreement is reached. Proposals should be submitted to [email protected].