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 compared with clinically ascertained peripheral neuropathy, and to identify factors associated with misclassification of peripheral neuropathy among survivors.

Methods:

The concordance between self-report and clinically ascertained peripheral neuropathy was evaluated among 2,933 5+ years old 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 peripheral neuropathy.

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 peripheral neuropathy. Race (White), age at assessment, and emotional distress were associated with increased risk for false-negative reporting of peripheral neuropathy.

Conclusions:

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

Impact:

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

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 (CIPN; ref. 2), are not always transient, and may persist throughout life (3, 4). Clinical evaluation of a large group of survivors of pediatric onset hematologic 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; refs. 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 with clinically ascertained neuropathy in adult survivors of childhood cancer, to see if self-reporting 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.

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; ref. 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 (Fig. 1). 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.

Figure 1.

Study diagram: Selection of study participants from SJLIFE.

Figure 1.

Study diagram: Selection of study participants from SJLIFE.

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Measures

Outcomes: Clinically ascertained peripheral neuropathy was considered present in persons whose examination indicated a grade 2 or higher adverse event according to the NCI 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; ref. 19). These data were combined with performance data to determine CTCAE Grades. Grade 2 sensory neuropathy [peripheral 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; ref. 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 [peripheral 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 SDs 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; ref. 22). Hand grip was measured with a hand-held dynamometer (Sammons Preston Roylan) with the participant sitting, the shoulder in neutral, the elbow in flexion, and the forearm midway between pronation and supination. (23).

Self-report peripheral neuropathy

Self-reported symptoms of peripheral neuropathy were determined using questionnaires modeled after the National Health Interview Survey (24), and used previously to characterize neuromuscular function in CCSs (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: (i) decreased sense of touch or feeling in hands, fingers, arms, or legs; (ii) prolonged pain arms, legs, or back?; (iii) 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: (i) weakness or inability to move arm (s)?; (ii) 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 ever smokers were those who reported smoking at least 100 cigarettes in their lifetime (26). Risky/heavy drinkers were males who reported 5 or more drinks in a single day, or an average of 14 drinks per week, or females who reported 4 or more drinks in a single day, or an average of 7 drinks per week in the year prior to the questionnaire (27). Height and weight were measured with a wall mounted stadiometer (SECA) and an electric scale (Scale-Tronix), and obesity defined as a body mass index (BMI) of ≥30 kg/m2; ref. 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; ref. 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 χ2 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 less than 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 nonparticipants by demographic, diagnosis, and treatment factors (35, 36). Adding weights to the analysis did not change the results. Thus, the unweighted results are presented.

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 with 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 with excluded survivors were less likely to report pain in past 4 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 CCSs.

Participants (N = 2,933)Excluded survivors (N = 576)P value
 N (%) N (%)  
Sex   <0.001 
 Female 1,436 (49.0) 230 (40.0)  
 Male 1,497 (51.0) 346 (60.0)  
Race   0.34 
 White 2,456 (83.7) 468 (81.3)  
 Black 425 (14.5) 96 (16.7)  
 Others 52 (1.8) 12 (2.1)  
 Female 1,436 (49.0) 230 (40.0)  
 Male 1,497 (51.0) 346 (60.0)  
Ethnicity   0.15 
 Hispanic 76 (2.6) 9 (1.6)  
 Non-Hispanic 2,847 (97.4) 563 (98.4)  
 Unknown 10  
Age at diagnosis, y   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, y   <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 1,096 (37.4) 153 (26.6)  
 Hodgkin lymphoma 373 (12.7) 49 (8.5)  
 Non–Hodgkin lymphoma 215 (7.3) 31 (5.4)  
 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, y   <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 2,024 (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 2,619 (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 42.9  
 Min–Max 10.0–477.7 13.5–597.1  
Carboplatin, n (%)   0.009 
 Yes 162 (5.5) 48 (8.3)  
 No 2,771 (94.5) 528 (91.7)  
Cumulative dose of carboplatin (mg/m2  0.13 
 Mean (SD) 3,039.7 (1,987.1) 3,581.6 (2,583.3)  
 Median 2,763.19 2,800.0  
 Min–Max 291.43–11,646.9 172.7–11,058.9  
Cisplatin, n (%)   <0.001 
 Yes 216 (7.4) 100 (17.4)  
 No 2,717 (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 42.9–1,380.8 64.0–1,322.5  
Cytarabine, n (%)   <0.001 
 Yes 1,040 (35.5) 137 (23.8)  
 No 1,893 (64.5) 439 (76.2)  
Methotrexate, n (%)   <0.001 
 Yes 1,419 (48.4) 189 (32.8)  
 No 1,514 (51.6) 387 (67.2)  
Cumulative dose of methotrexate (mg/m2  0.99 
 Mean (SD) 2,105.3 (2,801.7) 2,105.1 (1,645.3)  
 Median 1,789.1 1,926.9  
 Min–Max 5.58–83,350.0 17.1–83,350.0  
HD Methotrexate, n (%)   0.37 
 Yes 792 (27.0) 166 (28.8)  
 No 2,141 (73.0) 410 (71.2)  
Cumulative dose of HD methotrexate (mg/m2  <0.001 
 Mean (SD) 16,037.1 (15,979.7) 53,437.9 (49,041.4)  
 Median 15,261.9 33,967.3  
 Min–Max 829.6–137,034.0 2,000.0–211,900.0  
Health behavior 
Smoking status, n (%)   0.52 
 Never 1,992 (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 2,399 (95.3) 371 (92.5)  
 Missing 417 175  
Obesity (BMI ≥30 kg/m2), n (%)   0.11 
 Yes 1,072 (36.6) 228 (40.1)  
 No 1,860 (63.4) 341 (59.9)  
 Not reported  
Emotional distress 
Global emotional distress,an (%)   0.80 
 Yes 397 (13.8) 76 (14.7)  
 No 2,480 (86.2) 440 (85.3)  
 Not reported 56 60  
Anxiety,an (%)   0.15 
 Yes 332 (11.5) 71 (13.8)  
 No 2,545 (88.5) 444 (86.2)  
 Not reported 56 61  
Depression,an (%)   0.80 
 Yes 412 (14.3) 76 (14.7)  
 No 2,467 (85.7) 440 (85.3)  
 Not reported 54 60  
Somatization,an (%)   <0.001 
 Yes 502 (17.4) 128 (24.8)  
 No 2,377 (82.6) 388 (75.2)  
 Not reported 54 60  
Cognitive impairment 
Severe cognitive impairmentb   <0.001 
Full scale IQ, n (%)    
 Yes 86 (3.2) 106 (20.7)  
 No 2,615 (96.8) 407 (79.3)  
 Not reported 232 63  
Verbal, n (%)   <0.001 
 Yes 170 (6.3) 139 (26.6)  
 No 2,539 (93.7) 384 (73.4)  
 Not reported 224 53  
Nonverbal, n (%)   <0.001 
 Yes 117 (4.3) 111 (21.6)  
 No 2,594 (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 2,050 (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 2,532 (86.8) 437 (82.3)  
 Not reported 15 45  
Participants (N = 2,933)Excluded survivors (N = 576)P value
 N (%) N (%)  
Sex   <0.001 
 Female 1,436 (49.0) 230 (40.0)  
 Male 1,497 (51.0) 346 (60.0)  
Race   0.34 
 White 2,456 (83.7) 468 (81.3)  
 Black 425 (14.5) 96 (16.7)  
 Others 52 (1.8) 12 (2.1)  
 Female 1,436 (49.0) 230 (40.0)  
 Male 1,497 (51.0) 346 (60.0)  
Ethnicity   0.15 
 Hispanic 76 (2.6) 9 (1.6)  
 Non-Hispanic 2,847 (97.4) 563 (98.4)  
 Unknown 10  
Age at diagnosis, y   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, y   <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 1,096 (37.4) 153 (26.6)  
 Hodgkin lymphoma 373 (12.7) 49 (8.5)  
 Non–Hodgkin lymphoma 215 (7.3) 31 (5.4)  
 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, y   <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 2,024 (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 2,619 (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 42.9  
 Min–Max 10.0–477.7 13.5–597.1  
Carboplatin, n (%)   0.009 
 Yes 162 (5.5) 48 (8.3)  
 No 2,771 (94.5) 528 (91.7)  
Cumulative dose of carboplatin (mg/m2  0.13 
 Mean (SD) 3,039.7 (1,987.1) 3,581.6 (2,583.3)  
 Median 2,763.19 2,800.0  
 Min–Max 291.43–11,646.9 172.7–11,058.9  
Cisplatin, n (%)   <0.001 
 Yes 216 (7.4) 100 (17.4)  
 No 2,717 (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 42.9–1,380.8 64.0–1,322.5  
Cytarabine, n (%)   <0.001 
 Yes 1,040 (35.5) 137 (23.8)  
 No 1,893 (64.5) 439 (76.2)  
Methotrexate, n (%)   <0.001 
 Yes 1,419 (48.4) 189 (32.8)  
 No 1,514 (51.6) 387 (67.2)  
Cumulative dose of methotrexate (mg/m2  0.99 
 Mean (SD) 2,105.3 (2,801.7) 2,105.1 (1,645.3)  
 Median 1,789.1 1,926.9  
 Min–Max 5.58–83,350.0 17.1–83,350.0  
HD Methotrexate, n (%)   0.37 
 Yes 792 (27.0) 166 (28.8)  
 No 2,141 (73.0) 410 (71.2)  
Cumulative dose of HD methotrexate (mg/m2  <0.001 
 Mean (SD) 16,037.1 (15,979.7) 53,437.9 (49,041.4)  
 Median 15,261.9 33,967.3  
 Min–Max 829.6–137,034.0 2,000.0–211,900.0  
Health behavior 
Smoking status, n (%)   0.52 
 Never 1,992 (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 2,399 (95.3) 371 (92.5)  
 Missing 417 175  
Obesity (BMI ≥30 kg/m2), n (%)   0.11 
 Yes 1,072 (36.6) 228 (40.1)  
 No 1,860 (63.4) 341 (59.9)  
 Not reported  
Emotional distress 
Global emotional distress,an (%)   0.80 
 Yes 397 (13.8) 76 (14.7)  
 No 2,480 (86.2) 440 (85.3)  
 Not reported 56 60  
Anxiety,an (%)   0.15 
 Yes 332 (11.5) 71 (13.8)  
 No 2,545 (88.5) 444 (86.2)  
 Not reported 56 61  
Depression,an (%)   0.80 
 Yes 412 (14.3) 76 (14.7)  
 No 2,467 (85.7) 440 (85.3)  
 Not reported 54 60  
Somatization,an (%)   <0.001 
 Yes 502 (17.4) 128 (24.8)  
 No 2,377 (82.6) 388 (75.2)  
 Not reported 54 60  
Cognitive impairment 
Severe cognitive impairmentb   <0.001 
Full scale IQ, n (%)    
 Yes 86 (3.2) 106 (20.7)  
 No 2,615 (96.8) 407 (79.3)  
 Not reported 232 63  
Verbal, n (%)   <0.001 
 Yes 170 (6.3) 139 (26.6)  
 No 2,539 (93.7) 384 (73.4)  
 Not reported 224 53  
Nonverbal, n (%)   <0.001 
 Yes 117 (4.3) 111 (21.6)  
 No 2,594 (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 2,050 (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 2,532 (86.8) 437 (82.3)  
 Not reported 15 45  

Abbreviations: CCS, childhood cancer survivor; CNS, central nervous system; HD, high dose; Min, minimum; Max, maximum; IQ, intelligence quotient; y, years.

aT scores ≥63 were defined as elevated distress.

bImpairment z scores ≤−2.

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 PSN and PMN among CCSs from the clinical evaluation and self-report questionnaire, by sex.

Females (N = 1,436)Males (N = 1,497)P
Clinical evaluation 
PSN (n, %)   0.591 
 Yes 67 (4.7%) 63 (4.2%)  
 No 1,369 (95.3%) 1,434 (95.8%)  
PMN (n, %)   0.004 
 Yes 120 (8.4%) 84 (5.6%)  
 No 1,316 (91.6%) 1,413 (94.4%)  
Both PSN and PMN (n, %)    
 Yes 31 (2.2%) 23 (1.5%) 0.219 
 No 1,405 (97.8%) 1,474 (98.5%)  
Either PSN or PMN (n, %)    
 Yes 156 (10.9%) 124 (8.3%) 0.019 
 No 1,280 (89.1%) 1,373 (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 1,288 (90.8%) 1,352 (91.6%)  
Prolonged pain in arms, legs, or back (n, %)   0.003 
 Yes 313 (22.1%) 261 (17.7%)  
 No 1,104 (77.9%) 1,212 (82.3%)  
Abnormal sensation in arms, legs, or back (n, %)   0.507 
 Yes 145 (10.3%) 140 (9.5%)  
 No 1,268 (89.7%) 1,330 (90.5%)  
Weakness or inability to move arm(s) (n, %)   <0.001 
 Yes 87 (6.1%) 50 (3.4%)  
 No 1,329 (93.9%) 1,422 (96.6%)  
Weakness or inability to move legs (N, %)   0.105 
 Yes 90 (6.3%) 73 (5.0%)  
 No 1,327 (93.7%) 1,399 (95.0%)  
≥2 of 5 symptoms (n, %)   0.229 
 Yes 191 (13.4%) 177 (11.9%)  
 No 1,237 (86.6%) 1,311 (88.1%)  
Females (N = 1,436)Males (N = 1,497)P
Clinical evaluation 
PSN (n, %)   0.591 
 Yes 67 (4.7%) 63 (4.2%)  
 No 1,369 (95.3%) 1,434 (95.8%)  
PMN (n, %)   0.004 
 Yes 120 (8.4%) 84 (5.6%)  
 No 1,316 (91.6%) 1,413 (94.4%)  
Both PSN and PMN (n, %)    
 Yes 31 (2.2%) 23 (1.5%) 0.219 
 No 1,405 (97.8%) 1,474 (98.5%)  
Either PSN or PMN (n, %)    
 Yes 156 (10.9%) 124 (8.3%) 0.019 
 No 1,280 (89.1%) 1,373 (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 1,288 (90.8%) 1,352 (91.6%)  
Prolonged pain in arms, legs, or back (n, %)   0.003 
 Yes 313 (22.1%) 261 (17.7%)  
 No 1,104 (77.9%) 1,212 (82.3%)  
Abnormal sensation in arms, legs, or back (n, %)   0.507 
 Yes 145 (10.3%) 140 (9.5%)  
 No 1,268 (89.7%) 1,330 (90.5%)  
Weakness or inability to move arm(s) (n, %)   <0.001 
 Yes 87 (6.1%) 50 (3.4%)  
 No 1,329 (93.9%) 1,422 (96.6%)  
Weakness or inability to move legs (N, %)   0.105 
 Yes 90 (6.3%) 73 (5.0%)  
 No 1,327 (93.7%) 1,399 (95.0%)  
≥2 of 5 symptoms (n, %)   0.229 
 Yes 191 (13.4%) 177 (11.9%)  
 No 1,237 (86.6%) 1,311 (88.1%)  

Concordance between self-report peripheral neuropathy and clinical peripheral neuropathy

Tables 3a and 3b show the degree of concordance between clinically ascertained peripheral neuropathy and self-reported symptoms of peripheral neuropathy. 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 peripheral neuropathy 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 symptomsSensitivitySpecificityAccuracyKappa
 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 1,244     
Prolonged pain in arms, legs, or back, n Yes 28 285 42.4% 78.9% 77.2% 0.076 
 No 38 1,066     
Abnormal sensation in arms, legs, or back, n Yes 19 126 29.2% 90.7% 87.8% 0.125 
 No 46 1,222     
Having ≥2 symptoms Yes 29 162 43.9% 88.1% 86.1% 0.169 
 No 37 1,200     
 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 1,251     
Weakness or inability to move legs, n Yes 45 45 38.1% 96.5% 91.7% 0.389 
 No 73 1,254     
≥2 of 5 symptoms Yes 59 132 49.6% 89.9% 86.6% 0.310 
 No 60 1,177     
 Both PSN and PMNa (n = 30)     
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 1,273     
Prolonged pain in arms, legs, or back, n Yes 16 297 53.3% 78.6% 78.1% 0.057 
 No 14 1,090     
Abnormal sensation in arms, legs, or back, n Yes 12 133 40.0% 90.4% 89.3% 0.106 
 No 18 1,250     
Weakness or inability to move arm(s), n Yes 16 71 53.3% 94.9% 94.0% 0.250 
 No 14 1,315     
Weakness or inability to move legs, n Yes 17 73 58.6% 94.7% 94.0% 0.263 
 No 12 1,315     
≥2 of 5 symptoms, n Yes 21 170 70.0% 87.8% 87.5% 0.160 
 No 1,228     
 Either PSN or PMNb (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 1,183     
Prolonged pain in arms, legs, or back, n Yes 70 243 45.2% 80.7% 76.9% 0.179 
 No 85 1,019     
Abnormal sensation in arms, legs, or back, n Yes 43 102 28.1% 91.9% 85.0% 0.205 
 No 110 1,158     
Weakness or inability to move arm(s), n Yes 47 40 30.5% 96.8% 89.6% 0.338 
 No 107 1,222     
Weakness or inability to move legs, n Yes 50 40 32.7% 96.8% 89.9% 0.360 
 No 103 1,224     
≥2 of 5 symptoms, n Yes 67 124 43.2% 90.3% 85.2% 0.304 
 No 88 1,149     
Self-report symptomsSensitivitySpecificityAccuracyKappa
 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 1,244     
Prolonged pain in arms, legs, or back, n Yes 28 285 42.4% 78.9% 77.2% 0.076 
 No 38 1,066     
Abnormal sensation in arms, legs, or back, n Yes 19 126 29.2% 90.7% 87.8% 0.125 
 No 46 1,222     
Having ≥2 symptoms Yes 29 162 43.9% 88.1% 86.1% 0.169 
 No 37 1,200     
 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 1,251     
Weakness or inability to move legs, n Yes 45 45 38.1% 96.5% 91.7% 0.389 
 No 73 1,254     
≥2 of 5 symptoms Yes 59 132 49.6% 89.9% 86.6% 0.310 
 No 60 1,177     
 Both PSN and PMNa (n = 30)     
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 1,273     
Prolonged pain in arms, legs, or back, n Yes 16 297 53.3% 78.6% 78.1% 0.057 
 No 14 1,090     
Abnormal sensation in arms, legs, or back, n Yes 12 133 40.0% 90.4% 89.3% 0.106 
 No 18 1,250     
Weakness or inability to move arm(s), n Yes 16 71 53.3% 94.9% 94.0% 0.250 
 No 14 1,315     
Weakness or inability to move legs, n Yes 17 73 58.6% 94.7% 94.0% 0.263 
 No 12 1,315     
≥2 of 5 symptoms, n Yes 21 170 70.0% 87.8% 87.5% 0.160 
 No 1,228     
 Either PSN or PMNb (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 1,183     
Prolonged pain in arms, legs, or back, n Yes 70 243 45.2% 80.7% 76.9% 0.179 
 No 85 1,019     
Abnormal sensation in arms, legs, or back, n Yes 43 102 28.1% 91.9% 85.0% 0.205 
 No 110 1,158     
Weakness or inability to move arm(s), n Yes 47 40 30.5% 96.8% 89.6% 0.338 
 No 107 1,222     
Weakness or inability to move legs, n Yes 50 40 32.7% 96.8% 89.9% 0.360 
 No 103 1,224     
≥2 of 5 symptoms, n Yes 67 124 43.2% 90.3% 85.2% 0.304 
 No 88 1,149     

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

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

Table 3B.

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

Self-report symptomsSensitivitySpecificityAccuracyKappa
 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 1,306     
Prolonged pain in arms, legs, or back, n Yes 27 234 44.3% 83.4% 81.8% 0.108 
 No 34 1,178     
Abnormal sensation in arms, legs, or back, n Yes 15 125 25.4% 91.1% 88.5% 0.100 
 No 44 1,286     
≥2 of 5 symptoms, n Yes 20 157 32.8% 89.0% 86.7% 0.114 
 No 41 1,270     
 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 1,361     
Weakness or inability to move legs, n Yes 28 45 35.4% 96.8% 93.5% 0.334 
 No 51 1,348     
≥2 of 5 symptoms, n Yes 40 137 48.2% 90.2% 87.9% 0.251 
 No 43 1,268     
 Both PSN and PMNa (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 1,340     
Prolonged pain in arms, legs, or back, n Yes 12 249 40.0% 92.3% 91.8% 0.058 
 No 11 1,201     
Abnormal sensation in arms, legs, or back, n Yes 131 42.9% 91.0% 90.3% 0.089 
 No 12 1,318     
Weakness or inability to move arm(s), n Yes 43 31.8% 97.0% 96.1% 0.177 
 No 15 1,407     
Weakness or inability to move legs, n Yes 11 62 52.4% 95.7% 95.1% 0.217 
 No 10 1,389     
≥2 of 5 symptoms, n Yes 13 164 56.5% 88.9% 88.3% 0.105 
 No 10 1,301     
 Either PSN or PMNb (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 1,269     
Prolonged pain in arms, legs, or back, n Yes 55 206 45.8% 84.8% 81.6% 0.199 
 No 65 1,147     
Abnormal sensation in arms, legs, or back, n Yes 32 108 27.1% 92.0% 86.8% 0.176 
 No 86 1,244     
Weakness or inability to move arm(s), n Yes 19 31 16.1% 97.7% 91.2% 0.187 
 No 99 1,323     
Weakness or inability to move legs, n Yes 33 40 28.2% 97.0% 91.6% 0.305 
 No 84 1,315     
≥2 of 5 symptoms, n Yes 47 130 38.8% 90.5% 86.3% 0.242 
 No 74 1,237     
Self-report symptomsSensitivitySpecificityAccuracyKappa
 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 1,306     
Prolonged pain in arms, legs, or back, n Yes 27 234 44.3% 83.4% 81.8% 0.108 
 No 34 1,178     
Abnormal sensation in arms, legs, or back, n Yes 15 125 25.4% 91.1% 88.5% 0.100 
 No 44 1,286     
≥2 of 5 symptoms, n Yes 20 157 32.8% 89.0% 86.7% 0.114 
 No 41 1,270     
 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 1,361     
Weakness or inability to move legs, n Yes 28 45 35.4% 96.8% 93.5% 0.334 
 No 51 1,348     
≥2 of 5 symptoms, n Yes 40 137 48.2% 90.2% 87.9% 0.251 
 No 43 1,268     
 Both PSN and PMNa (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 1,340     
Prolonged pain in arms, legs, or back, n Yes 12 249 40.0% 92.3% 91.8% 0.058 
 No 11 1,201     
Abnormal sensation in arms, legs, or back, n Yes 131 42.9% 91.0% 90.3% 0.089 
 No 12 1,318     
Weakness or inability to move arm(s), n Yes 43 31.8% 97.0% 96.1% 0.177 
 No 15 1,407     
Weakness or inability to move legs, n Yes 11 62 52.4% 95.7% 95.1% 0.217 
 No 10 1,389     
≥2 of 5 symptoms, n Yes 13 164 56.5% 88.9% 88.3% 0.105 
 No 10 1,301     
 Either PSN or PMNb (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 1,269     
Prolonged pain in arms, legs, or back, n Yes 55 206 45.8% 84.8% 81.6% 0.199 
 No 65 1,147     
Abnormal sensation in arms, legs, or back, n Yes 32 108 27.1% 92.0% 86.8% 0.176 
 No 86 1,244     
Weakness or inability to move arm(s), n Yes 19 31 16.1% 97.7% 91.2% 0.187 
 No 99 1,323     
Weakness or inability to move legs, n Yes 33 40 28.2% 97.0% 91.6% 0.305 
 No 84 1,315     
≥2 of 5 symptoms, n Yes 47 130 38.8% 90.5% 86.3% 0.242 
 No 74 1,237     

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

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

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 peripheral neuropathy and clinical peripheral neuropathy

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 peripheral neuropathy,a by sex.

Females (N = 1,436)Males (N = 1,497)
PRR (95% CI)PPRR (95% CI)P
Decreased sense of touch or feeling in hands, fingers, arms, or legs      
 Yes 6.43 (4.25–9.72) <0.001 6.06 (3.84–9.54) <0.001 
 No Ref  Ref  
Abnormal sensation in arms, legs, or back      
 Yes 4.10 (2.71–6.20) <0.001 3.73 (2.36–5.92) <0.001 
 No Ref  Ref  
Prolonged pain in arms, legs, or back      
 Yes 3.35 (2.36–4.76) <0.001 4.28 (2.87–6.38) <0.001 
 No Ref  Ref  
Weakness or inability to move arm(s)      
 Yes 12.36 (7.70–19.84) <0.001 7.12 (3.81–13.29) <0.001 
 No Ref  Ref  
Weakness or inability to move legs      
 Yes 14.19 (8.86–22.75) <0.001 12.06 (7.13–20.37) <0.001 
 No Ref  Ref  
≥2 of 5 symptoms, Na      
 Yes 6.54 (4.50–9.51) <0.001 5.24 (3.45–7.95) <0.001 
 No Ref  Ref  
Females (N = 1,436)Males (N = 1,497)
PRR (95% CI)PPRR (95% CI)P
Decreased sense of touch or feeling in hands, fingers, arms, or legs      
 Yes 6.43 (4.25–9.72) <0.001 6.06 (3.84–9.54) <0.001 
 No Ref  Ref  
Abnormal sensation in arms, legs, or back      
 Yes 4.10 (2.71–6.20) <0.001 3.73 (2.36–5.92) <0.001 
 No Ref  Ref  
Prolonged pain in arms, legs, or back      
 Yes 3.35 (2.36–4.76) <0.001 4.28 (2.87–6.38) <0.001 
 No Ref  Ref  
Weakness or inability to move arm(s)      
 Yes 12.36 (7.70–19.84) <0.001 7.12 (3.81–13.29) <0.001 
 No Ref  Ref  
Weakness or inability to move legs      
 Yes 14.19 (8.86–22.75) <0.001 12.06 (7.13–20.37) <0.001 
 No Ref  Ref  
≥2 of 5 symptoms, Na      
 Yes 6.54 (4.50–9.51) <0.001 5.24 (3.45–7.95) <0.001 
 No Ref  Ref  

Abbreviation: Ref, Reference.

aPeripheral neuropathy: 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.

Factors associated with misclassification of identifying self-reported neuropathy

The proportion of survivors classified incorrectly (false positives and false negatives) are shown in Supplementary Fig. S1 and Table 5,Table 5B. 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)aFN (N = 99)b
PRR (95% CI)PPRR (95% CI)P
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) <0.001 2.08 (1.09–3.95) 0.026 
 No Ref  Ref  
Full scale IQc 
 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, y 1 (0.98–1.03) 0.889 1.05 (1.02–1.09) 0.001 
Age at diagnosis, y 1.06 (1.02–1.11) 0.002 0.98 (0.93–1.03) 0.417 
FP (N = 91)aFN (N = 99)b
PRR (95% CI)PPRR (95% CI)P
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) <0.001 2.08 (1.09–3.95) 0.026 
 No Ref  Ref  
Full scale IQc 
 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, y 1 (0.98–1.03) 0.889 1.05 (1.02–1.09) 0.001 
Age at diagnosis, y 1.06 (1.02–1.11) 0.002 0.98 (0.93–1.03) 0.417 

Abbreviations: FP, false positive; FN, false negative.

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

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

cImpairment defined as z scores ≤−2.

Table 5B.

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

FP (N = 79)aFN (N = 81)b
PRRa (95% CI)PPRRb (95% CI)P
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) 0.00 (0.00) 
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) <0.001 1.8 (0.82–3.95) 0.141 
 No Ref  Ref  
Full scale IQc 
 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) <0.001 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  
Age at assessment, y 1.02 (0.99–1.04) 0.212 1.05 (1.01–1.08) 0.011 
Age at diagnosis, y 1 (0.96–1.04) 0.999 1 (0.95–1.06) 0.885 
FP (N = 79)aFN (N = 81)b
PRRa (95% CI)PPRRb (95% CI)P
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) 0.00 (0.00) 
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) <0.001 1.8 (0.82–3.95) 0.141 
 No Ref  Ref  
Full scale IQc 
 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) <0.001 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  
Age at assessment, y 1.02 (0.99–1.04) 0.212 1.05 (1.01–1.08) 0.011 
Age at diagnosis, y 1 (0.96–1.04) 0.999 1 (0.95–1.06) 0.885 

Abbreviation: NA, not applicable.

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

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

cImpairment defined as z scores ≤-2.

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 4 weeks. Factors associated with risk for being classified as not having neuropathy when neuropathy was clinically present was only older age at assessment.

This study provides a novel comparison of concordance between patient self-reported symptoms (by questionnaire) of peripheral neuropathy and clinically ascertained PMN and PSN 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 4 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 peripheral neuropathy. 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 questions that are too general, 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 with 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 comorbidities (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 for 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 patients with pediatric cancer, 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 peripheral neuropathy, 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 peripheral neuropathy when it is truly present. These results emphasize the need for the development of a comprehensive questionnaire to more accurately assess peripheral neuropathy among adult survivors of childhood cancer.

S. Hayek reports grants from NIH and American Lebanese Syrian Associated Charities (ALSAC) during the conduct of the study. R. Dhaduk reports grants from NIH and ALSAC during the conduct of the study. W.E. Evans reports grants from NCI during the conduct of the study; in addition, W.E. Evans serves as Chair of Scientific Advisory Board Princess Máxima Centre and is a board member of BioSkryb. K. Bjornard reports grants from NIH and other support from ALSAC during the conduct of the study. C.L. Wilson reports grants from NIH during the conduct of the study. L.L. Robison reports grants from NCI during the conduct of the study. K.R. Krull reports grants from NCI during the conduct of the study. K.K. Ness reports grants from NIH and other support from ALSAC during the conduct of the study. No disclosures were reported by the other authors.

S. Hayek: Conceptualization, formal analysis, methodology, writing–original draft, writing–review and editing. R. Dhaduk: Formal analysis, methodology, writing–review and editing. Y. Sapkota: Writing–review and editing. W.E. Evans: Conceptualization, writing–review and editing. B. Diouf: Conceptualization, writing–review and editing. K. Bjornard: Writing–review and editing. C.L. Wilson: Writing–review and editing. M.M. Hudson: Resources, funding acquisition, writing–review and editing. L.L. Robison: Resources, funding acquisition, writing–review and editing. R.B. Khan: Conceptualization, investigation, methodology, writing–review and editing. D.K. Srivastava: Conceptualization, formal analysis, methodology, writing–review and editing. K.R. Krull: Writing–review and editing. K.K. Ness: Conceptualization, formal analysis, validation, investigation, methodology, writing–review and editing.

This study was supported by research funding from the NCI (U01CA195547, to M.M. Hudson; P30CA021765, to Charles Roberts) and by the ALSAC.

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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