Clinical Assessment of Late Health Outcomes in Survivors of Wilms Tumor

Abstract

Objective

We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment for Wilms tumor.

Methods

Survivors of Wilms tumor (n=280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow up of individuals treated for childhood cancer at St. Jude Children’s Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n=625). Health conditions were graded per a modified version of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded utilizing age-adjusted z-scores. Impaired physical function was defined by age- and sex-matched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations.

Results

Median age at evaluation was similar between survivors and controls (30.5 years [9.0–58.0] and 31.0 [12.0–70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7–13.8) grade 1–4 and 7.5 (CI 6.7–8.2) grade 2–4 health conditions, compared to 4.2 (CI 3.9–4.6) and 2.3 (CI 2.1–2.5), respectively, among controls. Grade 2–4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments.

Conclusion

Wilms tumor survivors experience a three-fold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance.

Introduction

Wilms tumor, the most common kidney tumor of childhood, accounts for 5% of pediatric malignancies.¹ Sequential multi-institutional clinical trials within the National Wilms Tumor Study Group, the Renal Tumor Committee of the Children’s Oncology Group, and the International Society of Pediatric Oncology have established curative multimodal therapeutic regimens for these children,² yielding progressively higher five-year survival rates, exceeding 90% for those with favorable histology.¹

While treatment regimens are largely successful, exposure to cancer therapy in childhood has long term health implications. The Childhood Cancer Survivor Study (CCSS), using self-reported data, found excess morbidity and mortality among survivors of Wilms tumor compared to a sibling comparison group.^{3, 4} The cumulative incidence of any chronic health condition 25 years from diagnosis was 65% and 24% for severe, life-threatening, or fatal conditions.⁵ Cohort studies across North America and Europe have reported similar excess late morbidity and mortality.^6–9 These descriptions have relied on registry and self-reported data,^5–9 which often lack sufficient detail and likely underestimate the presence of premature, subclinical conditions. Using the clinically assessed St. Jude Lifetime (SJLIFE) cohort, we aimed to comprehensively characterize health conditions and neurocognitive and physical function among survivors of Wilms tumor.

Methods

Study Design and Population

The SJLIFE study, initiated in 2007, is a single center retrospective cohort study with prospective clinical assessments of 5-year survivors of childhood cancer treated at St. Jude Children’s Research Hospital (SJCRH) from 1962–2012.¹⁰ This analysis includes participants diagnosed with Wilms tumor who returned for an on-campus health evaluation (n=280). Additionally, a community control group (n=625) was recruited for comparison (Supplemental Table 1). The study protocol was approved by the SJCRH Institutional Review Board, and informed consent was obtained prior to participation.

Clinical encounters included a history and physical examination; a fasting laboratory battery; questionnaires detailing demographics, medical history, health habits, and quality of life; and standardized neurocognitive and physical function testing.¹⁰ Therapeutic exposures abstracted from the medical record included cumulative chemotherapy doses, radiation fields/doses, surgeries, and major medical events during and after cancer treatment. Participants consented to medical record release for validation and grading of health conditions diagnosed prior to SJLIFE evaluations.

Chronic Health Conditions

One hundred sixty eight chronic health conditions were assessed and graded according to a modified version of the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03¹¹ (grade 1=asymptomatic or mild, 2=moderate requiring minimal intervention, 3=severe or disabling, 4=life threatening). Prevalence of health conditions and psychological outcomes was assessed.

Neurocognitive Assessment

Standardized neurocognitive assessments (Supplemental Table 2), performed by certified examiners, supervised by a board-certified neuropsychologist, measured performance in four domains: attention,¹² executive function,^13–15 memory,¹⁶ and processing speed.¹⁵ Age-adjusted z-scores were used for grading; ≥1 and <2 standard deviations (SD) below the population mean were considered mild (grade 1), ≥2 and <3 SD below the population mean moderate (grade 2), and ≥3 SD below the population mean severe (grade 3). Participants unable to complete a particular test were excluded from analysis for that domain.

Physical Function Assessment

Performance testing (Supplemental Table 3) was conducted by exercise specialists to ascertain physical function in six domains: aerobic capacity,¹⁷ mobility,¹⁸ strength,^{19, 20} endurance,²⁰ flexibility,^{21, 22} and balance.²³ Survivors performing >1.5 SDs below age- and sex-matched z-scores for controls were considered impaired in that domain. Participants unable to perform a particular test were excluded from analysis for that domain.

Statistical analysis

Two-sample t-tests were used to compare continuous variables. Chi-square (χ²) or Fisher’s exact test, as appropriate, were used for categorical variables between participants and eligible non-participants and between survivors and controls.

The prevalence of physical function impairments was compared to the standard population using a one sample t-test. Modified Poisson regression, adjusted for age, sex, and race, was used to compare the prevalence of CTCAE graded conditions, subsequent neoplasms, neurocognitive outcomes, and physical function between survivors and controls. Smoking was added to models for pulmonary outcomes.

The standardized incidence ratio (SIRs) of secondary neoplasms was calculated using age-, sex-, and calendar year-specific cancer incidence from the NCI’s Surveillance, Epidemiology, and End Results program. Non-melanoma skin cancers are not registered in the SEER database and were not included in the SIR calculation.

The mean cumulative count (MCC) was calculated by individual chronic conditions after accounting for clinically relevant chronicity and recurrence measures. The overall cumulative burden of grade 1–4 and 2–4 conditions was calculated after summing the individual MCCs. The age-specific cumulative burden and 95% confidence intervals (CI) were estimated by summing chronic health conditions occurring per individual using the bootstrap percentile method. Statistical testing was considered significant at p<0.05. All analyses were completed using SAS 9.4 and R.

Results

Of 445 eligible Wilms tumor survivors, 280 (63%) returned for evaluation. Sixty-nine (15.5%) agreed but had not yet returned, 16 (3.6%) participated by survey only, 46 (10.3%) declined, 9 (2.0%) could not be located, and 25 (5.6%) were pending recruitment (Supplemental Figure 1).

Participants were more likely to be non-Hispanic white (73.2% vs. 62.4%, p=0.02), older at evaluation (median 30.5 vs. 26.0 years, p=0.01) and farther from cancer diagnosis (26.0 vs. 22.0 years, p<0.01) than non-participants (Supplemental Table 1). Demographic and treatment-related characteristics of study participants are shown in Table 1. Nearly all (92.1%) were diagnosed prior to age six years (median 3.0 years, range: 0.0–15.0), with a median time from diagnosis of 26.0 years (6.0–54.0). Compared to controls, survivors were similar in age (median 30.5 [9.0–58.0] vs. 31.0 [12.0–70.0] years, p=0.32), but more racially diverse (26.8% non-white vs. 17.6%, p <0.01). Survivors (≥25 years old) were less likely to work full time (p<0.01), be married (p<0.01), or complete higher education (p<0.01) than community controls.

Table 1.

Characteristics of study participants and controls

		Wilms Survivors (N=280)		Community Controls (N=625)		p-value
		N	%	N	%
Gender
	Female	165	58.9%	347	55.5%
	Male	115	41.1%	278	44.5%	0.34
Race
	White	205	73.2%	515	82.4%
	Non-White	75	26.8%	110	17.6%	<0.01
Age at last evaluation (years)
	Median (range)	30.5 (9.0–58.0)		31.0 (12.0–70.0)
	<18 years	45	16.1%	19	3.0%
	18–29 years	89	31.8%	250	40.0%
	30–39 years	99	35.4%	196	31.4%
	≥40 years	47	16.8%	160	25.6%	<0.01
Age at diagnosis (years)
	Median (range)	3.0 (0.0–15.0)
	0–3 years	179	63.9%
	4–6 years	79	28.2%
	7–9 years	13	4.6%
	≥10 years	9	3.2%
Time from diagnosis (years)
	Median (range)	26.0 (6.0–54.0)
	5–9 years	13	4.6%
	10–19 years	69	24.6%
	20–29 years	92	32.9%
	30–39 years	77	27.5%
	≥40 years	29	10.4%
Laterality
	Unilateral	259	92.5%
	Bilateral	21	7.5%
Genetic syndrome
	Beckwith Wiedemann	4	1.4%
	WAGR±	2	0.71%
	Denys Drash	1	0.36%
	Polycystic Kidney Disease	1	0.36%
	Hyperparathyroid Jaw Tumor	1	0.36%
Relapse
	Yes	26	9.3%
	No	254	90.7%
Education, among age ≥25
	Less than high school	11	5.9%	13	2.8%
	Completed high school/GED	34	18.3%	52	11.4%
	Vocational training/Some college	68	36.6%	105	22.9%
	College graduate and higher	72	38.7%	283	61.8%
	Unknown	1	0.5%	5	1.1%	<0.01
Employment, among age ≥25
	Full-time	119	64.0%	337	73.6%
	Part-time	20	10.8%	47	10.3%
	Not employed	37	19.9%	41	9.0%
	Student/Homemaker/Retired	5	2.7%	26	5.7%
	Unknown	5	2.7%	7	1.5%	<0.01
Insurance status
	Yes	226	80.7%	510	81.6%
	No	37	13.2%	71	11.4%
	Unknown	17	6.1%	44	7.0%	0.66
Marital status, among age ≥25
	Missing	0	0.0%	9	2.0%
	Single	37	19.9%	52	11.4%
	Married, living as married	113	60.8%	350	76.4%
	Widowed/Divorced/Separated	36	19.4%	47	10.3%
	Unknown	0	0.0%	9	2.0%	<0.01
Smoking status
	Nonsmoker	176	62.9%	417	66.7%
	Ever smoker	49	17.5%	100	16.0%
	Current smoker	34	12.1%	72	11.5%
	Unknown	21	7.5%	36	5.8%	0.64
Treatment characteristics
Surgery
	Unilateral nephrectomy	259	92.5%
	Unilateral partial nephrectomy + contralateral biopsy	4	1.4%
	Unilateral nephrectomy + contralateral partial nephrectomy	11	3.9%
	Bilateral partial nephrectomies	6	2.2%
Chemotherapy
	Vincristine
	Median (range)	22.6 (6.0–92.0)
	None	2	0.7%
	<20 mg/m2	114	40.7%
	20–30 mg/m2	50	17.9%
	≥30 mg/m2	114	40.7%
	Doxorubicin
	Median (range)	175.0 (52.2–490.1)
	None	93	33.2%
	<100 mg/m2	13	4.6%
	100–250 mg/m2	153	54.6%
	≥250 mg/m2	21	7.5%
	Dactinomycin
	Median (range) (mg/m2)	6.7 (1.2–19.4)
	None	6	2.1%
	Yes	274	97.9%
	Alkylating agents
	Median (range) (cyclophosphamide equivalent dose (CED) mg/m2)	7060.6 (2258–35482)
	None	246	87.9%
	Yes	34	12.1%
	Etoposide
	Median (range) (mg/m2)	1282.2 (337.5–3852.1)
	None	243	86.8%
	Yes	37	13.2%
	Cisplatin
	Median (range) (mg/m2)	430.2 (99.3–1219.5)
	None	251	89.6%
	Yes	29	10.4%
Radiation
	Abdominal
	Median dose (range) (cGy)	1200.0 (880.0–6120.0)
	None	114	40.7%
	Hemiabdomen*	75	26.8%
	Whole abdomen**	91	32.5%
	Chest
	Median dose (range) (cGy)	1200.0 (900.0–4400.0)
	None	210	75.0%
	Yes	70	25.0%

cGy, centigray; CED, cyclophosphamide equivalent dose; <, less than; mg/m2, milligrams per square meter; ≥, more than or equal to; N, number; %, percentage; p, probability

^±Wilms tumor, aniridia, genitourinary anomalies, intellectual disability

^*Left hemiabdomen = 36 and right hemiabdomen = 39

^**Whole abdomen also included 12 survivors treated with both whole and hemiabdomen (left = 6) and right = 6)

All Wilms survivors underwent surgery, with the majority being unilateral nephrectomy (96.4%). The most common chemotherapeutic exposures included vincristine (99.3%) and dactinomycin (97.9%), and two-thirds (67%) were treated with doxorubicin. Nearly 60% received abdominal (whole and/or hemiabdomen) radiation (median dose 1200 [880–6120] cGy) and 25% chest radiation (median dose 1200 [900–4400] cGy). Twenty-six survivors (9%) experienced relapse (Table 1).

Chronic Health Conditions

By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7–13.8) grade 1–4 and 7.5 (95% CI 6.7–8.2) grade 2–4 conditions, compared to 4.2 (95% CI 3.9–4.6) and 2.3 (95% CI 2.1–2.5), respectively, among controls (Figure 1). Conditions of the cardiovascular, pulmonary, endocrine, and reproductive systems contributed the largest excess burden (Supplemental Table 4a/4b).

Figure 1.

Cumulative burden and 95% confidence intervals of grade 1–4 and grade 2–4 chronic health conditions in survivors of Wilms tumor and community controls.

Nearly all (99.6%) Wilms tumor survivors had at least one grade 1–4 condition and 91.8% a grade 2–4 condition. The most prevalent conditions, adjusted for sex, current age, and race, are reported in Table 2. Over 50% of survivors had grade 1–4 hypertension and 19.2% were on medication or met criteria for treatment initiation (grade 2–4) compared to 42.6% and 11.2%, respectively, among controls (p<0.01). Grade 2–4 cardiomyopathy was identified in 6.5% of survivors vs. 2.6% of controls (p=0.01). A fifth of survivors had a total cholesterol >200 mg/dL or triglycerides >150 mg/dL (grade 1–4), with 1.8% and 6.3%, respectively, exceeding 300 mg/dL (≥grade 2) and/or already on lipid lowering therapy. Excess grade 2–4 obstructive (11.7% vs. 2.9%, p<0.01), restrictive (9.6% vs. 0.2%, p<0.01) and diffusion (10.4% vs. 0.3%, p<0.01) pulmonary impairments were observed in survivors compared to controls. Adjusting for smoking status, pulmonary diffusion defects were associated with doxorubicin (RR 3.9, 95% CI 1.2–12.6) and restrictive deficits with chest radiation (RR 12.3, 95% CI 1.8–86.4).

Table 2.

Prevalence and severity of chronic health conditions ^*

	Wilms Survivors (n=280)
	Number screened	%	Normal	%	Grade 1	%	Grade 2	%	Grade 3	%	Grade 4	%
Cardiovascular
Cardiomyopathy	278	99.3%	260	93.5%			9	3.2%	9	3.2%	0	0.0%
Heart Valve Disorder	275	98.2%	221	80.4%	50	18.2%	2	0.7%	1	0.4%	1	0.4%
Hypercholesterolemia	280	100.0%	216	77.1%	59	21.1%	5	1.8%	0	0.0%	0	0.0%
Hypertriglyceridemia	272	97.1%	220	80.9%	35	12.9%	13	4.8%	4	1.5%	0	0.0%
Hypertension	280	100.0%	136	48.6%	90	32.1%	41	14.6%	13	4.6%	0	0.0%
Endocrine
Abnormal Glucose Metabolism	276	98.6%	214	77.5%	40	14.5%	11	4.0%	11	4.0%	0	0.0%
Overweight/Obesity	280	100.0%	133	47.5%			79	28.2%	54	19.3%	14	5.0%
Underweight	280	100.0%	264	94.3%			16	5.7%
Gastrointestinal
Hepatopathy	280	100.0%	269	96.1%	11	3.9%	0	0.0%	0	0.0%	0	0.0%
Musculoskeletal
Bone Mineral Density Deficit	238	85.0%	116	48.7%	86	36.1%	36	15.1%	0	0.0%
Neurologic
Peripheral Motor Neuropathy	269	96.1%	253	94.1%	6	2.2%	10	3.7%	0	0.0%	0	0.0%
Peripheral Sensory Neuropathy	268	95.7%	208	77.6%	41	15.3%	17	6.3%	2	0.8%	0	0.0%
Pulmonary
Obstructive Ventilatory Defect	273	97.5%	198	72.5%	43	15.8%	24	8.8%	7	2.6%	1	0.4%
Pulmonary Diffusion Defect	270	96.4%	216	80.0%	26	9.6%	27	10.0%	0	0.0%	1	0.4%
Restrictive Ventilatory Defect	272	97.1%	228	83.8%	18	6.6%	18	6.6%	8	2.9%	0	0.0%
Renal/Urinary Tract
Chronic Kidney Disease	279	99.6%	251	90.0%	8	2.9%	10	3.6%	0	0.0%	10	3.6%
Reproductive/Genital
Leydig Cell Insufficiency	113	98.3%	111	98.2%					2	1.8%
Premature Ovarian Insufficiency┼	150	90.9%	136	90.7%					14	9.3%
Psychological
Anxiety	266	95.0%	167	62.8%	33	12.4%	50	18.8%	15	5.6%	1	0.4%
Depression	280	100.0%	186	66.4%	24	8.6%	46	16.4%	24	8.6%	0	0.0%
Suicide Attempt	254	90.7%	250	98.4%					3	1.2%	1	0.4%

	Controls (n=625)
	Number screened	%	Normal	%	Grade 1	%	Grade 2	%	Grade 3	%	Grade 4	%	p-value
Cardiovascular
Cardiomyopathy	618	98.9%	602	97.4%			14	2.3%	2	0.3%	0	0.0%	<0.01
Heart Valve Disorder	622	99.5%	520	83.6%	99	15.9%	3	0.5%	0	0.0%	0	0.0%	0.02
Hypercholesterolemia	625	100.0%	464	74.2%	159	25.4%	2	0.3%	0	0.0%	0	0.0%	0.88
Hypertriglyceridemia	618	98.9%	506	81.9%	95	15.4%	15	2.4%	2	0.3%	0	0.0%	0.46
Hypertension	625	100.0%	359	57.4%	196	31.4%	59	9.4%	11	1.8%	0	0.0%	<0.01
Endocrine
Abnormal Glucose Metabolism	622	99.5%	513	82.5%	92	14.8%	15	2.4%	2	0.3%	0	0.0%	<0.01
Overweight/Obesity	625	100.0%	258	41.3%			170	27.2%	150	24.0%	47	7.5%	0.13
Underweight	625	100.0%	611	97.8%			14	2.2%					<0.01
Gastrointestinal
Hepatopathy	625	100.0%	605	96.8%	19	3.0%	1	0.2%	0	0.0%	0	0.0%	0.27
Musculoskeletal
Bone Mineral Density Deficit	0^
Neurologic
Peripheral Motor Neuropathy	614	98.2%	608	99.0%	2	0.3%	4	0.7%	0	0.0%	0	0.0%	<0.01
Peripheral Sensory Neuropathy	604	96.6%	528	87.4%	63	10.4%	13	2.2%	0	0.0%	0	0.0%	<0.01
Pulmonary
Obstructive Ventilatory Defect	617	98.7%	561	90.9%	38	6.2%	14	2.3%	3	0.5%	1	0.2%	<0.01
Pulmonary Diffusion Defect	615	98.4%	594	96.6%	19	3.1%	1	0.2%	1	0.2%	0	0.0%	<0.01
Restrictive Ventilatory Defect	615	98.4%	604	98.2%	10	1.6%	1	0.2%	0	0.0%	0	0.0%	<0.01
Renal/Urinary Tract
Chronic Kidney Disease	624	99.8%	620	99.4%	0	0.0%	4	0.6%	0	0.0%	0	0.0%	<0.01
Reproductive/Genital
Leydig Cell Insufficiency	278	100.0%	278	100.0%					0	0.0%			N/A
Premature Ovarian Insufficiency┼	318	91.6%	316	99.4%					2	0.6%			<0.01
Psychological
Anxiety	622	99.5%	466	74.9%	57	9.2%	79	12.7%	20	3.2%	0	0.0%	<0.01
Depression	624	99.8%	496	79.5%	46	7.4%	58	9.3%	23	3.7%	1	0.2%	<0.01
Suicide Attempt	606	97.0%	601	99.2%					4	0.7%	1	0.2%	0.40

^*adjusted for sex, current age, and race

^{^}DEXA scans were not performed on control participants

^┼Premature Ovarian Insufficiency was only assessed among female survivors ≤ age 40 years.

<, less than; N/A, not applicable; N, number; %, percentage

Survivors also experienced a higher rate of abnormal glucose metabolism (22.4% vs. 17.5% grade 1–4 and 8.0% vs. 2.7% grade 2–4, p<0.01), and among survivors this was associated with abdominal radiation (RR 4.8, CI 1.7–13.7). This was not associated with overweight/obesity (52.5% v. 58.7%, p=0.13) in survivors compared to controls, as might be expected in the general population. In fact, 5.7% of survivors were underweight at clinical evaluation compared to 2.2% of controls (p<0.01).

Survivors experienced more kidney dysfunction than controls (10.0% vs. 0.6% grade 1–4; 7.2% v. 0.6% grade 2–4, p<0.01). Among adult (≥18 years old) survivors (n=235) the median estimated glomerular filtration rate (eGFR) was 96.5 ml/min/1.73 m² (range: 3.7–146.7).

Over 8% of survivors experienced grade 2–4 peripheral neuropathy, compared to 2.6% of controls (p<0.01). Females experienced excess ovarian failure prior to age 40 (9.3% vs. 0.6%, p<0.01), while 1.8% of males had evidence of Leydig cell insufficiency.

Subsequent Neoplasms

A mean of 27.7 years from diagnosis, 24 (8.6%) Wilms survivors developed 36 subsequent neoplasms (SN), half occurring in prior radiation fields. Non-melanoma skin cancers were most common (n=22), followed by gastrointestinal (n=3), thyroid (n=2), breast (n=2), sarcomas (n=5), and melanomas (n=2). Survivors had nearly a 4-fold increased risk (SIR 3.8, CI 2.1–6.3) for SN compared to the general population. While suggestive, an association with radiation exposure did not reach statistical significance (RR 3.4, CI 0.9–13.4, p=0.08).

Neurocognitive Function and Psychological Outcomes

Among 246 survivors who completed neurocognitive testing, 52.1% had grades 1–3 and 19.7% grades 2–3 executive function impairment (Figure 2), compared to 45.0% and 11.6%, respectively, among controls (p<0.01). Processing speed (19.7% vs. 8.4%) and memory (20.9% vs. 9.9%) similarly showed a higher prevalence of moderate to severe impairments (grade 2–3) compared to controls (p<0.01). No differences in attention were identified. Associations with treatment exposures were not identified. Non-white survivors were noted to have double the risk of neurocognitive impairment across all domains compared to non-Hispanic white survivors (Supplemental Table 5a). In addition to excess neurocognitive impairment, anxiety (24.8% vs. 15.9% [p<0.01]) and/or depression (25% vs. 13.1% [p<0.01]) were identified more often in survivors than controls.

Figure 2.

Prevalence and grade of neurocognitive impairment among survivors of Wilms tumor and controls by neurocognitive domain.

Physical Function

Two hundred seventy survivors completed physical function testing and impairments exceeded expected rates across all domains (Figure 3). Excess impairments were identified in aerobic function, mobility, strength, endurance, and flexibility (p<0.05). No associations with treatment exposures or level of physical activity were identified. However, having a grade 2–4 cardiac condition was associated with impaired six-minute walk (RR 2.2,95% CI 1.3–3.8), grip strength (RR 2.5, 95% CI 1.1–5.3), and knee extension at 60^◦/second (RR 1.6, 95% CI 1.1–2.5) and 300^◦/second (RR 2.0, 95% CI 1.4–3.0), respectively (Supplemental Table 6).

Figure 3.

Prevalence of physical performance impairment in survivors of Wilms tumor.

^┼ Percent with scores >1.5 SD below age and sex-matched z-score for controls.

* p <0.05

^Λ Percentage of the general population performing >1.5 standard deviations below age- and sex-matched z-scores

Discussion

Multimodal treatment strategies have advanced cure rates for children diagnosed with Wilms tumor. However, treatment exposures have significant impacts on long-term health. Our systematic, clinical evaluations identified nearly a 3-fold increased health burden, largely driven by endocrine and cardiopulmonary conditions. Additionally, we found clinically assessed impairments in neurocognitive and physical function that can impact health and quality of life for this population. In our analysis, nearly all (99.6%) had at least one chronic health condition, with most (92%) requiring clinical intervention (grade 2–4). Survivors had an almost 4-fold increased risk (SIR 3.8, CI 2.1–6.3) for subsequent neoplasms. This excess health burden was accompanied by a higher-than-expected prevalence of mental health disorders, limited neurocognitive performance, and physical function impairments. These factors may contribute to impaired social attainment and lower rates of employment, marriage, and educational attainment in this population. Attention to these unique risk profiles offer opportunities for early detection and treatment of these health consequences to preserve quality of life.

Wilms treatment regimens have historically been associated with an elevated risk of cardiovascular disease,^{24, 25} the leading causes of non-malignant late mortality in survivors of childhood cancer, as well as in the general population.²⁶ This analysis identified excess cardiomyopathy in survivors compared to controls, which is anticipated following cardiotoxic exposures (anthracyclines and chest radiation). Additionally, survivors in our cohort experienced excess cardiovascular risk factors (hypertension, hyperlipidemia, diabetes)²⁷ and nearly a third (29.6%) reported a smoking history. When criteria from the American Heart Association/American College of Cardiology²⁸ for hypertension (Supplemental Table 7) are applied to participant data, 26.6% of survivors meet criteria for a diagnosis of hypertension, with an additional 22% meeting criteria for prehypertension at a median of 31 years of age. Similarly, using American Diabetes Association criteria for diabetes²⁹ (Supplemental Table 7), 33.2% of our survivors met criteria for prediabetes and 7.7% diabetes, compared to 19.8% and 4.5%, respectively, in controls. Modification of these risk factors can play a major role in preserving survivor health. In a CCSS study, the presence of hypertension significantly augmented the risk of developing heart failure (RR 19.4, 95% CI 11.4–33.1) and premature coronary artery disease (RR 6.1, 95% CI 3.4–11.2) among survivors exposed to chest radiation compared to those without hypertension.³⁰ Lifestyle modification (smoking, diet, etc.) and management of chronic conditions may have significant health implications for Wilms tumor survivors.

The increased prevalence of heart disease and cardiovascular risk factors has implications for kidney function.³¹ This study includes survivors of bilateral and syndromic Wilms tumor, which may partially account for the higher prevalence of chronic kidney disease in our study compared with prior studies of unilateral, non-syndromic Wilms tumor survivors.³² Two-thirds of survivors with renal impairment in our study had co-morbid hypertension, diabetes, or both. In three-fourths of these cases, the onset of diabetes and/or hypertension was documented prior to reduced kidney function. Hyperfiltration injury following nephrectomy may also be a contributing factor. Animal studies involving unilateral nephrectomy and five-sixths infarction of the contralateral kidney showed an increase in single nephron glomerular filtration rates, morphological changes, and hypertension, suggesting injury from increased filtration.³³ Lacking longitudinal data from the time of nephrectomy, our cross-sectional analysis may have missed the hyperfiltration period. Studies are needed to elucidate the association of hyperfiltration and adverse kidney function among Wilms tumor survivors.

The identification of a significant burden of SNs in this population is consistent with previous studies of kidney tumors³⁴ and highlights the role of cancer screening and surveillance in survivors exposed to radiation, according to the Children’s Oncology Group Long-term Follow-up Guidelines.³⁵ These survivors should undergo a thorough annual skin exam, and those with chest and/or abdominal radiation are at increased risk of breast^{36, 37} and colon³⁸ cancer, respectively. Early initiation of screening may lead to detection at earlier stages, additional treatment options, and opportunities to improve outcomes.

In addition to increased risk for cardiometabolic, kidney and neoplastic late effects, long-term survivors of Wilms tumor are at increased risk of infertility. Nearly 10% of female survivors experienced premature ovarian insufficiency, likely due to abdominal radiation exposing the ovaries.^{7, 39–42} None of the females exposed to hemi-abdominal radiation experienced premature ovarian insufficiency. Previous reports have also identified structural uterine abnormalities,^{43, 44} and risks for premature deliveries^45–47 among female Wilms survivors exposed to these radiation fields.

Our study uniquely included assessments of mental health and neurocognitive function in this population not exposed to central nervous system (CNS) directed therapies. Current literature is mixed on the prevalence of mental health conditions in survivors of childhood cancer.^{5, 48–50} While some studies have reported that depression and anxiety at similar or even reduced rates compared to the general population, our analysis suggests Wilms survivors experience an increased mental health burden. Nearly a quarter reported symptoms consistent with depression and anxiety. An increased prevalence of moderate to severe impairments of executive function, processing speed, and memory was also observed. Neurocognitive impairment has been described in a smaller sample (n=158) of this same population and similarly did not identify treatment-related associations but did note associations with chronic health conditions.⁵¹ Our analysis expands the prior study by grading neurocognitive findings to quantify specific impairments more explicitly. In the absence of traditional treatment-related risk factors, such as CNS-directed therapies, we performed analyses investigating the possible impact of the presence of cardiopulmonary disease on neurocognitive function. Impairments in processing speed were associated with the presence of grade 2–4 cardiovascular disease. However, associations with other neurocognitive domains were not observed. Traditionally, only survivors exposed to CNS-directed therapies have been considered at risk for neurocognitive impairments, however, the overall burden and duration of chronic health conditions may also contribute. In an analysis from the CCSS, path analysis demonstrated direct effects of cardiopulmonary (RR 1.3 95% CI 1.1–1.4) and endocrine (RR 1.1 95% CI 1.0–1.3) conditions on impaired task efficiency.⁵² Research is needed to determine if early interventions may alter the trajectory of cognitive function in this aging population.

Across all four domains, survivors of non-white race experienced a relative risk of neurocognitive impairment two to three-fold that of white survivors (Supplemental Table 5a), suggesting a differential impact by race. This finding persisted when comparing non-white survivors to non-white controls alone (Supplemental Table 5b). Further research, including social determinants of health and the neurodevelopmental impact of age at treatment, is needed.

Studies of Wilms tumor survivors in the CCSS and British CCSS noted increased physical limitations assessed by self-report.^{5, 8} Using physical performance testing, we observed excess impairments in aerobic function, mobility, strength, endurance, and flexibility. Prior studies including smaller numbers of Wilms survivors have not observed these impairments.^{53, 54} Reports from SJLIFE have suggested that exposure to abdominopelvic radiotherapy may cause body composition changes that affect aerobic function, strength and endurance.⁵⁵ In our study, there were no clear associations between these outcomes and treatment exposures. However, having a cardiac condition was associated with impairment in the aerobic function, strength, and endurance domains, which may have implications for physical and mental health. To our knowledge this is the largest and most comprehensive physical function assessment in Wilms survivors to date, suggesting this population may benefit from a formalized physical training intervention.

Despite systematic health assessments performed in SJLIFE, our study has some limitations. Thirty-seven percent of eligible survivors were not included in the analysis (Supplemental Figure 1) and differed from participants by age and race. Participation required returning to SJCRH, and some survivors who declined participation may have been excluded due to inability to travel; potentially under- or over-estimating the prevalence of conditions. Our findings may not be representative of younger survivors more recently diagnosed due to the limited recruitment to date of these individuals. Despite uniquely characterizing neurocognitive and physical performance, not all participants were able to complete this testing resulting in potential for bias.

Conclusion

Survivors of Wilms tumor experience an excess burden of chronic health conditions threatening quality of life and longevity. Neurocognitive and physical function impairments were more prevalent than anticipated, despite a lack of CNS-directed treatment. Focused health maintenance and surveillance for these unique health risks may provide opportunities for early intervention, with the goal of reducing morbidity and preservation of long-term health.

Article Summary.

Clinically assessed health impacts of curative cancer treatment are limited. We aimed to characterize the health and neurocognitive and physical function among Wilms tumor survivors.

What’s Known on This Subject

Clinical trials have established curative therapeutic regimens for children diagnosed with Wilms tumor yielding progressively higher five-year survival rates and a growing population of survivors. Knowledge of late health outcomes for these children has relied on registry and self-reported data.

What This Study Adds

Lacking clinically assessed details, studies may underestimate the presence of premature or subclinical health conditions among cancer survivors. This study comprehensively characterizes health conditions and neurocognitive and physical function among Wilms tumor survivors evaluated at St. Jude Children’s Research Hospital.

Abbreviations:

p

probability

<

less than

>

more than

≥

more than or equal to

N

number

%

percentage

CCSS

Childhood Cancer Survivor Study

CNS

central nervous system

cGy

centigray

CI

confidence interval

CTCAE

Common Terminology Criteria for Adverse Events

MCC

mean cumulative count

mg/Dl

milligrams per deciliter

NCI

National Cancer Institute

RR

respiratory rate

SD

standard deviation

SIR

standardized incidence ratio

SJCRH

St. Jude Children’s Research Hospital

SJLIFE

St. Jude Lifetime

SN

subsequent neoplasms

vs

versus