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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2021 Sep 28:10.1158/1055-9965.EPI-21-0644. doi: 10.1158/1055-9965.EPI-21-0644

Concordance between self-reported symptoms and clinically ascertained peripheral neuropathy among childhood cancer survivors: the St. Jude Lifetime Cohort Study

Samah Hayek 1, Rikeenkumar Dhaduk 2, Yadav Sapkota 2, William E Evans 3, Barthelemy Diouf 3, Kari Bjornard 4, Carmen L Wilson 2, Melissa M Hudson 2,4, Leslie L Robison 2, Raja B Khan 5, Deo Kumar Srivastava 6, Kevin R Krull 2, Kirsten K Ness 2
PMCID: PMC8643312  NIHMSID: NIHMS1745028  PMID: 34583966

Abstract

Background

Childhood cancer survivors are at elevated risk for motor and/or sensory neuropathy.

The study aims to evaluate the concordance between self-report peripheral-neuropathy (PN) compared to clinically ascertained PN, and to identify factors associated with misclassification of PN among survivors.

Methods

The concordance between self-report and clinically ascertained PN was evaluated among 2,933 5+ year childhood cancer survivors (mean age 33.3, SD=8.9). The sensitivity, specificity, and accuracy of self-report peripheral motor neuropathy (PMN) and peripheral sensory neuropathy (PSN) were calculated with reference to clinically-assessed PN.

Results

Female survivors were more likely than male survivors to have clinically ascertained PMN (8.4% vs. 5.6%, P=0.004). For females, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (43.2%, 90.3%, and 85.2%, respectively), with kappa of 0.304. For males, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (38.8%, 90.5%, and 86.3%, respectively) with kappa of 0.242. Age at diagnosis, emotional-distress, and reporting pain in legs in the past 4-weeks were associated with an increased risk for false-positive reporting of PN. Race-White, age at assessment, and emotional -distress were associated with increased risk for false-negative reporting of PN.

Conclusions

Agreement between self-report and clinically-ascertained PN was poor in survivors. Choosing self-report versus clinical ascertain PN should be carefully considered.

Impact

The current study identifies the need for a self-report questionnaire that accurately assesses symptoms of PN among cancer survivors.

Keywords: Peripheral neuropathy, clinical ascertained neuropathy, self-reported neuropathy, concordance

Introduction

Five-year survival after treatment for childhood cancer exceeds 85% (1). However, children with cancer experience acute toxicities during treatment. Some toxicities, including chemotherapy induced peripheral neuropathy (2), are not always transient, and may persist throughout life (3, 4). Clinical evaluation of a large group of survivors of pediatric onset hematological and solid malignancies as well as central nervous system tumors identified peripheral neuropathy among 21.9% of survivors who were, on average, 25 years from diagnosis (5). When investigating self-reported symptoms in the same cohort, 17% endorsed impaired motor function and movement problems, and 34.2% sensory abnormalities (6). Persistent peripheral neuropathy is concerning because of its impact on physical function, limiting mobility, and participation in daily activities, which can eventually impact quality of life (QOL) (7–10). Thus, identification of signs and symptoms of motor or sensory deficits among childhood cancer survivors (CCS) is important, as referral for interventions to remediate or teach survivors to compensate for impairments has potential to impact participation in daily activities and improve QOL.

The best way to determine the presence of CIPN among survivors is a comprehensive clinical evaluation that includes motor and sensory testing. However, such evaluations are not always feasible in the context of an overall medical visit because they require specific resources and are time consuming (11, 12). Simple screening measures are needed to identify those in need of referral for specialized testing and potential treatment. While studies have been conducted to assess concordance between self-report and clinical testing-based diagnoses of neuropathy in breast cancer survivors (13, 14), comparison studies to determine agreement between self-reported symptoms and clinically ascertained CIPN among adult survivors of childhood cancer have not been published. The overall goal of the current study was to evaluate the concordance between self-reported peripheral neuropathy compared to clinically ascertained neuropathy in adult survivors of childhood cancer, to see if self-report of symptoms accurately identified persons with clinically ascertained neuropathy. Further, we explored the host characteristics associated with misclassification of peripheral neuropathy by self-report among adult survivors of childhood cancer to determine if there is a subset of survivors who can only be identified with comprehensive clinical measurement.

Materials and Methods

Study participants

Participants were members of the St. Jude Lifetime Cohort Study (SJLIFE), a study that aims to facilitate longitudinal evaluation of health outcomes among adult survivors of childhood cancer treated at St. Jude Children’s Research Hospital (SJCRH) (15–17). Participants complete an in-person clinical assessment with laboratory testing and imaging, and five questionnaires that query sociodemographic characteristics and health status, psychosocial well-being, health behaviors, sexual and reproductive health and diet. For these analyses, survivors were ≥5 years from their initial diagnosis, ≥18 years of age, and completed both self-reported and clinical assessments characterizing neuropathy by June 30, 2017. Persons eligible who died prior to participating and those invited but who had not yet had an opportunity to participate were not included. This analysis also excluded participants with diabetes mellitus, amputation, hemiplegia, and peripheral vascular disease. Study documents were approved by the SJCRH institutional review board. Participants provided written informed consent prior to assessment.

Measures

Outcomes: Clinically ascertained peripheral neuropathy was considered present in persons whose examination indicated a grade 2 or higher adverse event according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (18). Signs and symptoms of neuropathy were assessed with the Modified Total Neuropathy Score (mTNS), a measure that evaluates both sensory and motor integrity with scores ranging from 0 (no neuropathy) to 24 (severe neuropathy) (19). These data were combined with performance data to determine CTCAE Grades. Grade 2 sensory neuropathy (PSN) was assigned to participants with at least one mTNS based sign or symptom of sensory impairment and either a sensory organization test composite score from computerized dynamic posturography of less than <70 (indicative of impending fall risk) (20), or taking longer than 20 seconds to write a short sentence (indicative of fine motor impairment) from the physical performance test (21). Grade 2 motor neuropathy (PMN) was assigned to participants with at least one mTNS-based sign or symptom of motor impairment, and either ankle dorsiflexion or hand grip strength values at least 1.3 standard deviations below age- and sex- predicted values. Isokinetic ankle dorsiflexion was measured at 60 degrees per second with the participant sitting with full back, thigh and knee support (Biodex System 4, Shirley, NY) (22). Hand grip was measured with a hand held dynamometer (Sammons Preston Roylan, Nottinghamshire, UK) with the participant sitting, the shoulder in neutral, the elbow in flexion and the forearm midway between pronation and supination. (23).

Self-report PN

Self-reported symptoms of PN were determined using questionnaires modeled after the National Health Interview Survey (24), and used previously to characterize neuromuscular function in childhood cancer survivors (25). Symptoms were quantified by a score generated from the answers on specific sensory and motor queries. To identify symptoms of sensory neuropathy, participants were asked: “Have you ever been told by a doctor or other health care professional that you have or have had: (1) Decreased sense of touch or feeling in hands, fingers, arms, or legs; (2) Prolonged pain arms, legs, or back?; (3) Abnormal sensation in arms, legs, or back?”. If the participant answered “yes, and the condition is still present” then the participant was classified as having sensory symptoms. To identify symptoms of motor neuropathy, participants were asked: “Have you ever been told by a doctor or other health care professional that you have, or have had: (1) “Weakness or inability to move arm (s)?”; (2) Weakness or inability to move legs?”; If the participant answered “yes, and the condition is still present” then the participant was classified as having motor symptoms.

Covariates

Diagnosis and treatment information were abstracted from medical records by trained abstractors, and included diagnosis, age at diagnosis, chemotherapy exposures and doses, radiation exposures and doses, and surgery. Participant sex, age at assessment, race and ethnicity, smoking status, and alcohol use were obtained from self-report questionnaires. Smoking status classified as never, ever or current smoker, and were ever smokers were those who reported smoking at least 100 cigarettes in their lifetime (26). Risky/heavy drinkers were males who reported five or more drinks in a single day, or an average of 14 drink/week, or females who reported four or more drinks in a single day, or an average of seven drinks/week in the year prior to the questionnaire (27). Height and weight were measured with a wall mounted stadiometer (SECA, Hanover, MD) and an electric scale (Scale-Tronix, White Plains, NY), and obesity defined as a body mass index (BMI) of ≥30 kilograms/meter2 (kg/m2) (28). Emotional distress was classified according to participant responses to the 18 item Brief Symptom Inventory (BSI-18), which asks respondents to rate their level of distress within the previous seven days. The BSI- includes three subscales, anxiety, depression and somatization (bodily symptoms not fully explained by any known medical condition), and a summary score, the Global Severity Index (GSI). The GSI and subscale scores were converted to t-scores using sex-specific normative data. T-scores ≥63 were considered relevant emotional distress (29). Final analysis included the three subscales. Cognition was evaluated with the Wechsler Abbreviated Scale of Intelligence (full-scale IQ) (30), with those whose age-adjusted z-score was ≤−2 considered impaired. Prevalent pain was defined as answering “yes” to: “Do you have pain in legs in past 4 weeks?” or “do you have pain in hands/arms in the past 4 weeks?”.

Statistical analysis

Descriptive statistics were used to characterize the study population, differences between participants and excluded survivors, and between male and female participants, were determined by chi-square tests for categorical measures and t-tests for continuous measures. Sensitivity (correctly reported presence PSN or PMN among those with clinically ascertained PSN or PMN), specificity (correctly reported absence PSN or PMN among those who did not have clinically ascertained PSN or PMN) and accuracy/total agreement (correctly reported positive and negative PSN or PMN from total reports of both tools) were estimated (31). Variations in the results of the two tests (self-report and clinical test) were evaluated by calculating Kappa coefficients (32). A kappa value <0.4 was considered poor-to-fair agreement, a kappa value of 0.41 to 0.60 moderate agreement, a kappa value of 0.61 to 0.80 substantial agreement, and a kappa value of 0.81 to 1.00 excellent agreement (33). Analyses were conducted for each reported symptom and the overall sensory and motor scores and stratified by sex. Generalized linear models with a binomial distribution and a log-link function (34) were used to estimate the extent that self-reported symptoms were associated with the likelihood of having clinically ascertained PSN or PMN, and to identify factors associated with reporting neuropathy symptoms when neuropathy was not clinically present, or with not reporting neuropathy symptoms when it was clinically present. Results are presented as Prevalence Rate Ratio (PRR) and 95% Confidence Intervals (CI). Analysis were done with and without inverse probability weights to account for the differences between participants and non-participants by demographic, diagnosis and treatment factors (35, 36). Adding weights to the analysis did not change the results. Thus, the unweighted results are presented.

Results

Participants

Among 3,509 potentially eligible study participants, 2,933 (83.6%) were included in the final analysis. Excluded survivors were 136 (3.9%) persons with amputation, 101 (2.9%) with peripheral vascular disease, 50 (1.4%) with diabetes, 5 (0.14%) with paralysis, 23 (0.65%) with missing clinical data, and 58 (1.6%) with missing questionnaires. An additional 203 (5.8%) were excluded from analysis because a proxy completed their questionnaires (Study Diagram). Compared to excluded survivors, participant survivors were more likely to be female (49.0% vs. 40.0%), younger at diagnosis (mean (SD), 8.4 (5.6) vs. 9.0 (6.0)), younger at assessment (mean (SD), 33.4 (8.9) vs. 36.4 (10.9)), and survivors of leukemia (37.4% vs. 26.6%). Participants were also less likely than excluded survivors to have been treated with carboplatin (5.5% vs. 8.3%), cisplatin (7.4% vs. 17.4%), and high-dose methotrexate (27.0% vs. 28.8%). Participants were less likely to be cognitively impaired (full scale IQ 3.2% vs. 20.7%, verbal impairment 6.3% vs. 26.6%, nonverbal impairment 4.3% vs. 21.6%) than excluded survivors. Participants compared to excluded survivors were less likely to report pain in past four weeks in legs (29.8% vs. 36.2%, respectively) or hands/arms (13.2% vs. 17.7%, respectively) (Table 1).

Table 1:

Characteristics of participants and excluded childhood cancer survivors

Participants (N=2,933) Excluded survivors (N=576) P-value
N % N %
Sex <0.001
 Female 1436 49.0 230 40.0
 Male 1497 51.0 346 60.0
Race 0.34
 White 2456 83.7 468 81.3
 Black 425 14.5 96 16.7
 Others 52 1.8 12 2.1
Ethnicity 0.15
 Hispanic 76 2.6 9 1.6
 Non-Hispanic 2847 97.4 563 98.4
 Unknown 10 4
Age at diagnosis (yrs) 0.01
 Mean (SD) 8.37 5.6 9.0 6.0
 Median 7.53 8.4
 Min-Max 0–22.7 0–24.8
Age at assessment (yrs) <0.001
 Mean (SD) 33.3 (8.9) 36.4 (10.9)
 Median 32.3 35.7
 Min-Max 18.0–65.9 18.0–69.1
 18–24 602 20.5 109 18.9 <0.001
 25–29 568 19.4 81 14.1
 30–34 605 20.6 90 15.6
 35–39 491 16.7 73 12.7
 40–44 331 11.3 73 12.7
 ≥45 336 11.5 150 26.0
Diagnosis and treatment
Diagnosis <0.001
 Leukemia 1096 37.4 153 26.6
 Hodgkin lymphoma 373 12.7 49 8.5
 Non-Hodgkin lymphoma 215 7.3 31 5.4
 Central nervous system (CNS) 310 10.6 106 18.4
 Neuroblastoma 138 4.7 12 2.1
 Wilms tumor 189 6.4 32 5.6
 Soft tissue sarcoma 197 6.7 34 5.9
 Bone tumor 199 6.8 134 23.3
 Others 216 7.4 25 4.3
Time since diagnosis (yrs) <0.001
 Mean (SD) 24.93 (9.2) 27.41 (10.1)
 Median 20.4 27.3
 Min-Max 6.40–53.68 6.68–53.84
Vincristine, N (%) <0.001
 Yes 2024 (69.0) 350 (60.8)
 No 909 (31.0) 226 (39.2)
Cumulative dose of Vincristine (mg/m2) 0.90
 Mean (SD) 30.9 (24.5) 69.7 (103.4)
 Median 24.37 39.3
 Min-Max 1.2 −152.6 13.5 −397.1
Vinblastine, N (%) <0.001
 Yes 314 (10.7) 33 (5.7)
 No 2619 (89.3) 543 (94.3)
Cumulative dose of Vinblastine (mg/m2) 0.83
 Mean (SD) 82.2 (285.6) 69.7 (103.4)
 Median 45.4
 Min-Max 10.0–4477.7 - 13.5–597.1
Carboplatin, N (%) 0.009
 Yes 162 (5.5) 48 (8.3)
 No 2771 (94.5) 528 (91.7)
Cumulative dose of Carboplatin (mg/m2) 0.13
 Mean (SD) 3039.7 (1987.1) 3581.6 (2583.3)
 Median 2763.19 2800.0
 Min-Max 291.43–11646.9 172.7–11058.9
Cisplatin, N (%) <0.001
 Yes 216 (7.4) 100 (17.4)
 No 2717 (92.6) 476 (82.6)
Cumulative dose of Cisplatin (mg/m2) 0.22
 Mean (SD) 410.2 (200.2) 381.1 (190.1)
 Median 394.5 386.8
 Min-Max 42.9–1380.8 64.0–1322.5
Cytarabine, N (%) <0.001
 Yes 1040 (35.5) 137 (23.8)
 No 1893 (64.5) 439 (76.2)
Methotrexate, N (%) <0.001
 Yes 1419 (48.4) 189 (32.8)
 No 1514 (51.6) 387 (67.2)
Cumulative dose of Methotrexate (mg/m2) 0.99
 Mean (SD) 2105.3 (2801.7) 2105.1 (1645.3)
 Median 1789.1 1926.9
 Min-Max 5.58–83350.0 17.1–83350.0
HD Methotrexate, N (%) 0.37
 Yes 792 (27.0) 166 (28.8)
 No 2141 (73.0) 410 (71.2)
Cumulative dose of HD Methotrexate2 (mg/m2) <0.001
 Mean (SD) 16037.1 (15979.7) 53437.9 (49041.4)
 Median 15261.9 33967.3
 Min-Max 829.6- 137034.0 2000.0- 211900.0
Health behavior
Smoking status, N (%) 0.52
 Never 1992 (68.6) 348 (66.2)
 Current 535 (18.4) 103 (19.6)
 Former 375 (12.9) 75 (14.3)
 Missing 31 50
Current risky drinking, N (%) 0.01
 Yes 117 (4.7) 30 (7.5)
 No 2399 (95.3) 371 (92.5)
 Missing 417 175
Obesity (BMI ≥30 kg/m2), N (%) 0.11
 Yes 1072 (36.6) 228 (40.1)
 No 1860 (63.4) 341 (59.9)
 Not-reported 1 7
Emotional distress
Global emotional distress,a N (%) 0.80
 Yes 397 (13.8) 76 (14.7)
 No 2480 (86.2) 440 (85.3)
 Not-reported 56 60
Anxiety,a N (%) 0.15
 Yes 332 (11.5) 71 (13.8)
 No 2545 (88.5) 444 (86.2)
 Not-reported 56 61
Depression,a N (%) 0.80
 Yes 412 (14.3) 76 (14.7)
 No 2467 (85.7) 440 (85.3)
 Not-reported 54 60
Somatization, a N (%) <0.001
 Yes 502 (17.4) 128 (24.8)
 No 2377 (82.6) 388 (75.2)
 Not-reported 54 60
Cognitive impairment
Severe cognitive impairment b <0.001
Full scale IQ, N (%)
 Yes 86 (3.2) 106 (20.7)
 No 2615 (96.8) 407 (79.3)
 Not reported 232 63
Verbal, N (%) <0.001
 Yes 170 (6.3) 139 (26.6)
 No 2539 (93.7) 384 (73.4)
 Not reported 224 53
Nonverbal, N (%) <0.001
 Yes 117 (4.3) 111 (21.6)
 No 2594 (95.7) 404 (78.5)
 Not reported 222 61
Pain
Pain in legs in past 4 weeks, N (%) 0.003
 Yes 868 (29.8) 192 (36.2)
 No 2050 (70.3) 339 (63.8)
 Not reported 15 45
Pain in hands/arms in past 4 weeks, N (%) 0.006
 Yes 386 (13.2) 94 (17.7)
 No 2532 (86.8) 437 (82.3)
 Not reported 15 45
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a

T-scores ≥63 were defined as elevated distress.

b

Impairment z scores ≤−2.

<: less than; ≥: more than or equal to; %: percent; BMI: Body Mass Index; HD: High Dose; IQ: Intelligence Quotient; kg: kilograms; mg: milligrams; N: number; P: probability; m2: square meters; SD: Standard Deviation; yrs: years;

Prevalence of peripheral neuropathy among childhood cancer survivors by sex

Female survivors were more likely than male survivors to have clinically ascertained peripheral motor (PMN) (8.4% vs. 5.6%, P=0.004) but not sensory (PSN) (4.7%, 4.2%, P=0.591, respectively) neuropathy. Females were also more likely than males (22.1% vs. 17.7%, P=0.003) to report prolonged pain in arms, legs, or back weakness or inability to move arms (6.1% vs. 3.4%, P<0.001) (Table 2).

Table 2:

Prevalence of peripheral sensory neuropathy and motor neuropathy among childhood cancer survivors from the clinical evaluation and self-report questionnaire, by sex

Females (N=1,436) Males (N=1,497) P-value
Clinical evaluation
PSN (N, %) 0.591
 Yes 67 (4.7%) 63 (4.2%)
 No 1369 (95.3%) 1434 (95.8%)
PMN (N, %) 0.004
 Yes 120 (8.4 %) 84 (5.6 %)
 No 1316 (91.6 %) 1413 (94.4 %)
Both PSN and PMN (N, %)
 Yes 31 (2.2 %) 23 (1.5 %) 0.219
 No 1405 (97.8 %) 1474 (98.5 %)
Either PSN or PMN (N, %)
 Yes 156 (10.9 %) 124 (8.3 %) 0.019
 No 1280 (89.1 %) 1373 (91.7 %)
Self-report questionnaire
Decreased sense of touch or feeling in hands, fingers, arms, or legs (N, %) 0.430
 Yes 131 (9.2 %) 124 (8.4 %)
 No 1288 (90.8 %) 1352 (91.6 %)
Prolonged pain in arms, legs, or back (N, %) 0.003
 Yes 313 (22.1 %) 261 (17.7 %)
 No 1104 (77.9 %) 1212 (82.3 %)
Abnormal sensation in arms, legs, or back (N, %) 0.507
 Yes 145 (10.3 %) 140 (9.5 %)
 No 1268 (89.7 %) 1330 (90.5 %)
Weakness or inability to move arm(s) (N, %) <0.001
 Yes 87 (6.1 %) 50 (3.4 %)
 No 1329 (93.9 %) 1422 (96.6 %)
Weakness or inability to move legs (N, %) 0.105
 Yes 90 (6.3 %) 73 (5.0 %)
 No 1327 (93.7 %) 1399 (95.0 %)
≥2 of 5 symptoms (N, %) 0.229
 Yes 191 (13.4 %) 177 (11.9 %)
 No 1237 (86.6 %) 1311 (88.1 %)
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<: less than; ≥: more than or equal to; %: percent; N: number; P: Probability; PMN: Clinically ascertained peripheral motor neuropathy; PSN: Clinically ascertained peripheral sensory neuropathy

Concordance between self-report PN and clinical PN

Tables 3a and 3b show the degree of concordance between clinically ascertained PN and self-reported symptoms of PN. Among females, for PSN the most sensitive, specific and accurate self-reported symptom was prolonged pain in arms, legs, or back (42.4%, 78.9%, and 77.2%, respectively). For PMN, the most sensitive, specific and accurate self-reported symptom was weakness or inability to move legs (38.1%, 96.5%, and 91.7%, respectively). For having both PSN and PMN the most sensitive, specific and accurate self-reported symptom was weakness or inability to move legs (58.6%, 94.7%, and 94.0%, respectively). For having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was prolonged pain in arms, legs,or back (45.2%, 80.7%, and 76.9%, respectively). After accounting for chance, agreement between self-reported, and clinically ascertained PN was poor (Kappa: 0.057–0.389) (Table 3a).

Table 3a:

Concordance between self-reported and clinically ascertained peripheral neuropathy among females (N=1,436)

Self- Report symptoms Sensitivity Specificity Accuracy Kappa
Clinically ascertained PSN (N=67)
Yes No
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 22 109 33.3% 91.9% 89.2% 0.172
No 44 1244
Prolonged pain in arms, legs, or back, (N) Yes 28 285 42.4% 78.9% 77.2% 0.076
No 38 1066
Abnormal sensation in arms, legs, or back, (N) Yes 19 126 29.2% 90.7% 87.8% 0.125
No 46 1222
Having ≥2 symptoms Yes 29 162 43.9% 88.1% 86.1% 0.169
No 37 1200
Clinically ascertained PMN (N=120)
Weakness or inability to move arm(s), (N) Yes 41 46 34.5% 96.5% 91.2% 0.352
No 78 1251
Weakness or inability to move legs, (N) Yes 45 45 38.1% 96.5% 91.7% 0.389
No 73 1254
≥2 of 5 symptoms Yes 59 132 49.6% 89.9% 86.6% 0.310
No 60 1177
Both PSN and PMN1 (N=31)
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 15 116 50.0% 91.6% 90.8% 0.157
No 15 1273
Prolonged pain in arms, legs, or back, (N) Yes 16 297 53.3% 78.6% 78.1% 0.057
No 14 1090
Abnormal sensation in arms, legs, or back, (N) Yes 12 133 40.0% 90.4% 89.3% 0.106
No 18 1250
Weakness or inability to move arm(s), (N) Yes 16 71 53.3% 94.9% 94.0% 0.250
No 14 1315
Weakness or inability to move legs, (N) Yes 17 73 58.6% 94.7% 94.0% 0.263
No 12 1315
≥2 of 5 symptoms, (N) Yes 21 170 70.0% 87.8% 87.5% 0.160
No 9 1228
Either PSN or PMN2 (N=156)
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 50 81 32.3% 93.6% 86.9% 0.277
No 105 1183
Prolonged pain in arms, legs, or back, (N) Yes 70 243 45.2% 80.7% 76.9% 0.179
No 85 1019
Abnormal sensation in arms, legs, or back, (N) Yes 43 102 28.1% 91.9% 85.0% 0.205
No 110 1158
Weakness or inability to move arm(s), (N) Yes 47 40 30.5% 96.8% 89.6% 0.338
No 107 1222
Weakness or inability to move legs, (N) Yes 50 40 32.7% 96.8% 89.9% 0.360
No 103 1224
≥2 of 5 symptoms, (N) Yes 67 124 43.2% 90.3% 85.2% 0.304
No 88 1149
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1

Both PSN and PMN: Individuals with clinically ascertained both PSN and PMN.

2

Either PSN or PMN: Individuals with clinically ascertained either PSN or PMN.

≥: more than or equal to; %: percent; N: number; PMN: Clinically ascertained peripheral motor neuropathy; PSN: Clinically ascertained peripheral sensory neuropathy

Table 3b:

Concordance between self-reported and clinically ascertained peripheral neuropathy among males (N=1,497)

Self-Report symptoms Sensitivity Specificity Accuracy Kappa
Clinically ascertained PSN (N=63)
Yes No
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 15 109 24.6% 92.3% 89.5% 0.113
No 46 1306
Prolonged pain in arms, legs, or back, (N) Yes 27 234 44.3% 83.4% 81.8% 0.108
No 34 1178
Abnormal sensation in arms, legs, or back, (N) Yes 15 125 25.4% 91.1% 88.5% 0.100
No 44 1286
≥2 of 5 symptoms, (N) Yes 20 157 32.8% 89.0% 86.7% 0.114
No 41 1270
Clinically ascertained PMN (N=84)
Weakness or inability to move arm(s), (N) Yes 19 31 23.8% 97.8% 93.8% 0.261
No 61 1361
Weakness or inability to move legs, (N) Yes 28 45 35.4% 96.8% 93.5% 0.334
No 51 1348
≥2 of 5 symptoms, (N) Yes 40 137 48.2% 90.2% 87.9% 0.251
No 43 1268
Both PSN and PMN1 (N=23)
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 11 113 47.8% 92.2% 91.5% 0.127
No 12 1340
Prolonged pain in arms, legs, or back, (N) Yes 12 249 40.0% 92.3% 91.8% 0.058
No 11 1201
Abnormal sensation in arms, legs, or back, (N) Yes 9 131 42.9% 91.0% 90.3% 0.089
No 12 1318
Weakness or inability to move arm(s), (N) Yes 7 43 31.8% 97.0% 96.1% 0.177
No 15 1407
Weakness or inability to move legs, (N) Yes 11 62 52.4% 95.7% 95.1% 0.217
No 10 1389
≥2 of 5 symptoms, (N) Yes 13 164 56.5% 88.9% 88.3% 0.105
No 10 1301
Either PSN or PMN2 (N=124)
Decreased sense of touch or feeling in hands, fingers, arms, or legs, (N) Yes 38 86 31.4% 93.7% 88.6% 0.248
No 83 1269
Prolonged pain in arms, legs, or back, (N) Yes 55 206 45.8% 84.8% 81.6% 0.199
No 65 1147
Abnormal sensation in arms, legs, or back, (N) Yes 32 108 27.1% 92.0% 86.8% 0.176
No 86 1244
Weakness or inability to move arm(s), (N) Yes 19 31 16.1% 97.7% 91.2% 0.187
No 99 1323
Weakness or inability to move legs, (N) Yes 33 40 28.2% 97.0% 91.6% 0.305
No 84 1315
≥2 of 5 symptoms, (N) Yes 47 130 38.8% 90.5% 86.3% 0.242
No 74 1237
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1

Both PSN and PMN: Individuals with clinically ascertained both PSN and PMN.

2

Either PSN or PMN: Individuals with clinically ascertained either PSN or PMN.

≥: more than or equal to; %: percent; N: number; PMN: Clinically ascertained peripheral motor neuropathy; PSN: Clinically ascertained peripheral sensory neuropathy

Among males, for PSN, the most sensitive, specific and accurate self-reported symptom was prolonged pain in arms, legs, or back (44.3%, 83.4%, and 81.8%, respectively). For PMN, the most sensitive, specific and accurate self-reported symptom was weakness or inability to move legs (35.4%, 96.8%, and 93.5%, respectively). For having both PSN and PMN the most sensitive, specific and accurate self-reported symptom was weakness or inability to move legs (52.4%, 95.7%, and 95.1%, respectively). For having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was prolonged pain in arms, legs, or back (45.8%, 84.8%, and 81.6%, respectively). Agreement between self-report and clinically ascertained neuropathy was poor (Kappa: 0.058–0.334) among males after accounting for chance (Table 3b).

Associations between self-report PN and clinical PN

In models, stratified on sex and adjusted for age at assessment and race, survivors who endorsed decreased sense of touch or feeling in hands, fingers, arms or legs, weakness or inability to move arm(s), or weakness or inability to move legs, were more likely than those who did not endorse these symptoms to have clinically ascertained PSN or PMN. Survivors who endorsed two or more symptoms were six times more likely than those who endorsed fewer than two symptoms to have clinically ascertained PSN or PMN (PRR, 6.54, 95% CI: 4.50–9.51, P<0.001, females; PRR, 5.24; 95% CI: 3.45–7.95, P<0.001, males) (Table 4).

Table 4:

Associations between clinically ascertained and self-report PN,1 by sex

Females (N=1436) Males (N=1497)
PRR (95% CI) P-value PRR (95% CI) P-value
Decreased sense of touch or feeling in hands, fingers, arms, or legs
Yes 6.43 (4.25–9.72) <.001 6.06 (3.84–9.54) <.001
No Ref Ref
Abnormal sensation in arms, legs, or back
Yes 4.10 (2.71–6.20) <.001 3.73 (2.36–5.92) <.001
No Ref Ref
Prolonged pain in arms, legs, or back
Yes 3.35 (2.36–4.76) <.001 4.28 (2.87–6.38) <.001
No Ref Ref
Weakness or inability to move arm(s)
Yes 12.36 (7.70–19.84) <.001 7.12 (3.81–13.29) <.001
No Ref Ref
Weakness or inability to move legs
Yes 14.19 (8.86–22.75) <.001 12.06 (7.13–20.37) <.001
No Ref Ref
≥2 of 5 symptoms, N 1
Yes 6.54 (4.50–9.51) <.001 5.24 (3.45–7.95) <.001
No Ref Ref
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1

PN: For the current analysis, we defined our outcome as having clinical ascertainment of either PSN or PMN. The model was adjusted for age at assessment and race.

<: less than; ≥: more than or equal to; %: percent; CI: Confidence Interval; N: number; P: probability; PN: Peripheral Neuropathy; PMN: Clinically ascertained peripheral motor neuropathy; PRR: Prevalence Rate Ratio; PSN: Clinically ascertained peripheral sensory neuropathy; Ref: Reference

Factors associated with misclassification of identifying self-reported neuropathy

The proportion of survivors classified incorrectly (false-positives and false-negatives) are shown in Supplemental Figure 1 and Table 5. Females and males were at similar risk for misclassification (false-positive 6.3% vs. 5.3%, P=0.22, false-negative 6.9% vs 5.4%, P=0.09). Among females, factors associated with risk for being classified as positive when neuropathy was not clinically present were older age at diagnosis, and somatization. Factors associated with risk for being classified as not having neuropathy when neuropathy was clinically present were older age at assessment, being black, somatization, and depression.

Table 5a:

Factors associated with misclassification of peripheral neuropathy among females (N=1,436)

FP (N=91)1 FN (N=99)2
PRR 95% CI P- value PRR 95% CI P-value
Race
 White Ref Ref
 Black 0.64 0.31–1.31 0.223 2.3 1.17–4.50 0.015
 Others 1.53 0.30–7.84 0.611 1.82 0.18–18.78 0.615
Ethnicity
 Hispanic 0.63 0.13–3.12 0.567 0.73 0.07–7.44 0.794
 Non-Hispanic Ref Ref
Smoking status
 Current 1.21 0.71–2.08 0.481 0.77 0.36–1.63 0.494
 Former 1.07 0.55–2.06 0.847 1.67 0.79–3.52 0.176
 Never Ref Ref
Current risky drinking
 Yes 1.07 0.34–3.40 0.906 0.53 0.07–4.22 0.55
 No Ref Ref
Obesity
 Yes 1.3 0.83–2.04 0.259 1.33 0.76–2.32 0.316
 No Ref Ref
Anxiety
 Yes 1.46 0.75–2.86 0.266 0.7 0.30–1.64 0.41
 No Ref Ref
Depression
 Yes 0.74 0.37–1.45 0.373 3.16 1.51–6.62 0.002
 No Ref Ref
Somatization
 Yes 3.55 2.13–5.93 <.001 2.08 1.09–3.95 0.026
 No Ref Ref
Full scale IQ 3
 Yes 0.91 0.25–3.35 0.892 1.15 0.30–4.41 0.834
 No Ref Ref
Pain in legs in past 4 weeks
 Yes 0.66 0.41–1.06 0.084 1.23 0.68–2.23 0.497
 No Ref Ref
Pain in hands/arms in the past 4 weeks
 Yes 0.69 0.40–1.19 0.182 1.33 0.68–2.61 0.399
 No Ref Ref Ref Ref
Age at assessment (yr) 1 0.98–1.03 0.889 1.05 1.02–1.09 0.001
Age at diagnosis (yrs) 1.06 1.02–1.11 0.002 0.98 0.93–1.03 0.417
Open in a new tab
1

FP: False positive (self-report (endorsing ≥2 symptoms) confirmed either PSN or PMN, but clinically it was not ascertained).

2

FN: False Negative (self-report did not confirm either PSN or PMN (endorsing ≥2 symptoms) but clinically it was ascertained).

3

Impairment defined as z scores ≤−2.

<: less than; CI: Confidence Interval; FN: False Negative; FP: False Positive; IQ: Intelligence Quotient; N: number; P: probability; PRR: Prevalence Rate Ratio; Ref: reference; yr: year; yrs: years

Among males, factors associated with risk for being classified as positive when neuropathy was not clinically present were current smoking, somatization, and having pain in legs in past four weeks. Factors associated with risk for being classified as not having neuropathy when neuropathy was clinically present was only older age at assessment.

Discussion

This study provides a novel comparison of concordance between patient self-reported symptoms (by questionnaire) of peripheral neuropathy and clinically ascertained peripheral motor and sensory neuropathy among adult survivors of childhood cancer. We found poor concordance between self-report and clinically ascertained neuropathy. Survivors who endorsed ≥2 symptoms on the self-report questionnaire were six times more likely than those who endorsed fewer than two symptoms to have clinically ascertained either PSN or PMN. Age at diagnosis, emotional distress, and reporting pain in legs in the past four weeks were associated with an increased risk for symptom-based positive neuropathy classification when neuropathy was not clinically present. Race (White), age at assessment, and emotional distress were associated with increased risk for symptom-based negative neuropathy classification when neuropathy was clinically present.

The current study underscores the need to develop a more valid tool to accurately assess symptoms of PN. Our finding of moderate sensitivity (range 23.8%–58.6%) indicates that the symptoms questions we used for self report do not accurately identify those with either PSN or PMN. This may result from too general questions, reflecting symptoms associated not only with neuropathy, but also with other chronic health conditions experienced by survivors (37), or because survivors whose symptoms have been present for years no longer recognize their impairments (8). On the other hand, our symptom questions accurately identified survivors without either PSN or PMN (specificity range 78.9%–97.7%). Because of the low overall accuracy of the symptom questions, excellent specificity here likely identifies only survivors with a lower overall burden of chronic disease.

In this cohort, we observed that female survivors who reported emotional distress were more likely than those without emotional distress to be misclassified as having either PSN or PMN when not clinically present. Studies have shown that anxiety and depression are highly prevalent among patients with chronic pain and neuropathic pain (38). For example, a study among colorectal cancer survivors an average of 5.6 years after diagnosis showed that survivors with high CIPN report higher rates of depression and anxiety (39). Our cross-sectional design limited our ability to determine temporal association between reasons for misclassification. The nature of our discovered associations is potentially bidirectional. That is, peripheral neuropathy can cause emotional distress, or emotional distress can result in somatosensory symptoms and/or limit motor and physical function. Among females, age at diagnosis was associated with increased risk for reporting symptoms of either PSN and PMN when the condition was not clinically present. This could be explained by differential recall bias by age as older survivors are more likely to remember the treatment experience and its effect on activities of daily living compared to those who were at younger at diagnosis. White female survivors were less likely to report symptoms of either PSN or PMN when clinically present. This can be explained by the higher prevalence of functional impairment among non-White cancer survivors and older adults (40, 41), that is not reported among White survivors. Older women were also more likely to deny the presence of either PSN or PMN when clinically present. Increased age is associated with decreased ability to perform daily activities and increased risk for falling (42). Thus, survivors may misclassify the neuropathy symptoms by attributing increase in functional limitation to the normal aging process.

Male survivors with somatization and leg pain were more likely than those without these symptoms to report neuropathy symptoms when not clinically present. This finding is likely due to the lack of specificity of our questions to detect neuropathy and may reflect the overall burden of pain and/or disease. Pain remains difficult to manage among cancer survivors and may be a symptom of more than one underlying cause (43). In addition, survivors may have difficutly discerning differences between symptoms of sensory or motor neuropathy and symptoms of emotional distress. These data support a need for better self-report questionnaires that consider the impact of emotional distress and pain on self-reported sensory or motor neuropathy among long-term survivors of childhood cancer.

This study is subject to potential limitations. First, we excluded subsets of survivors from this analysis based on functional limitations (amputation) or potential confounding co-morbidities (peripheral vascular disease, diabetes, paralysis). The excluded survivors were more likely to be male, non-White, treated with platinum analogues and high dose methotrexate, and cognitively impaired. Even those applying inverse probability weighting to account fro differences did not impact results, these differences may have biased our estimates. Second, all participants in our study were diagnosed and treated at a single institution. Although the characteristics and treatment exposures for this population are similar to national protocols for pediatric cancer patients, our finding may not be generalizable to individuals treated in other centers and with different treatment protocols. Third, participants who were included in the current study survived ≥5 years after diagnosis, survival bias may influence the prevalence for both self-report and clinically ascertained neuropathy and may not apply to populations of survivors closer to diagnosis. Fourth, these questions were not originally designed with sufficient specificity to determine the presence of either PSN or PMN in survivors of childhood cancer.

In conclusion, the symptom questions used in this study are a poor proxy for identification of CCS with clinically ascertained PN, likely because our questions were not specific enough. Older female survivors who are black, or who have emotional distress, are at high risk for not being classified with PN when it is truly present. These results emphasize the need for the development of a comprehensive questionnaire to more accurately assess PN among adult survivors of childhood cancer.

Supplementary Material

1

Figure 1:

Figure 1:

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Study Diagram: Selection of study participants from St. Jude Lifetime Cohort Study

>: more than or equal to; MTNS: Modified Total Neuropathy Score; N: number; PVD: Peripheral Vascular Disease

Table 5b:

Factors associated with misclassification of peripheral neuropathy among males (N=1,497)

FP (N=79)1 FN (N=81)2
PRR1 95% CI P- value PRR1 95% CI P-value
Race
 White Ref Ref
 Black 0.59 0.27–1.30 0.191 1.71 0.78–3.79 0.183
 Others 0.00 0.00 1 0.00 0.00 1
Ethnicity
 Hispanic 1.31 0.15–11.35 0.807 NA
 Non-Hispanic Ref Ref
Smoking status
 Current 2.38 1.40–4.03 0.001 0.93 0.43–1.97 0.841
 Former 1.36 0.74–2.51 0.328 1 0.46–2.21 0.991
 Never Ref Ref
Current risky drinking
 Yes 0.95 0.41–2.20 0.911 1.24 0.41–3.79 0.703
 No Ref Ref
Obesity
 Yes 1.33 0.84–2.10 0.22 1.37 0.76–2.47 0.293
 No Ref Ref
Anxiety
 Yes 0.98 0.50–1.90 0.95 0.56 0.21–1.55 0.266
 No Ref Ref
Depression
 Yes 1.13 0.62–2.06 0.69 1.8 0.81–4.03 0.151
 No Ref Ref
Somatization
 Yes 5.26 3.06–9.04 <.001 1.8 0.82–3.95 0.141
 No Ref Ref
Full scale IQ 3
 Yes 2.69 0.87–8.29 0.086 2.08 0.56–7.67 0.272
 No Ref Ref
Pain in legs in past 4 weeks
 Yes 2.32 1.45–3.71 <.001 1.44 0.77–2.67 0.254
 No Ref Ref
Pain in hands/arms in the past 4 weeks
 Yes 0.94 0.52–1.69 0.84 0.93 0.42–2.07 0.862
 No Ref Ref Ref Ref
Age at assessment (yrs) 1.02 0.99–1.04 0.212 1.05 1.01–1.08 0.011
Age at diagnosis (yrs) 1 0.96–1.04 0.999 1 0.95–1.06 0.885
Open in a new tab
1

FP: False positive (self-report (endorsing≥2 symptoms) confirmed either PSN or PMN, but clinically it was not ascertained).

2

FN: False Negative (self-report did not confirm either PSN or PMN (endorsing ≥2 symptoms) but clinically it was ascertained).

3

Impairment defined as z scores ≤−2.

<: less than; CI: Confidence Interval; FN: False Negative; FP: False Positive; IQ: Intelligence Quotient; N: number; NA: not applicable; P: probability; PRR: Prevalence Rate Ratio; Ref: reference; yr: year; yrs: years

Acknowledgements:

Tracie Gatewood (St. Jude Children’s Research Hospital, Memphis) assisted with manuscript preparation; there was no financial compensation outside of salary.

Financial Support: This study was supported by research funding from the National Cancer Institute (U01CA195547 Melissa M. Hudson; P30CA021765 Charles Roberts) and by the American Lebanese Syrian Associated Charities (ALSAC).

Footnotes

Conflict of Interest Disclosure Statement: The authors declare no potential conflicts of interest.

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