Long-Term Psychosocial Well-Being and Quality of Life Among Childhood Cancer Survivors Who Developed a Subsequent Malignant Neoplasm

Abstract

Childhood cancer survivors (CCS) are at increased risk of subsequent malignant neoplasms (SMNs). However, the impact of SMNs on long-term psychosocial functioning is unknown. In a cohort of 322 young adult CCS, survivors who developed a SMN (n = 43, 13.4%) did not report a significantly higher burden of fatigue, insomnia, depression, anxiety, or impaired quality of life on average 8 years after SMN diagnosis. They, however, endorsed significantly greater body image concerns. Our findings indicate that CCS with an SMN do not significantly differ from those without regarding most psychosocial outcomes in young adulthood, although clinicians may be vigilant for greater body image dissatisfaction.

Introduction

Childhood cancer survivors (CCS) are at higher risk of impaired psychosocial outcomes, such as depression, anxiety, and suicidal behavior, as a result of cancer diagnosis, treatment, and medical late effects.¹ Moreover, fatigue and sleep disruption are common among CCS in long-term survivorship² and lead to impaired neurocognitive function.³ In addition, treatment-related disfigurement and persisting hair loss are prevalent in CCS and negatively influence their emotional functioning and quality of life (QOL).⁴

Recognized as a late complication, subsequent malignant neoplasms (SMNs) are common among survivors with a 30-year cumulative incidence of 9.1% for nonmelanoma skin cancer and 7.9% for other SMNs.⁵ Increased risk of SMNs is attributable to the cancer treatments (e.g., radiation therapy, alkylating, and anthracycline chemotherapies), and genetic susceptibility.⁶ Emerging evidence reveals that cancer diagnosis during young adulthood, a challenging life period, has lasting impact on psychosocial well-being.⁷ As a second cancer diagnosis likely occurred in young adulthood, it is largely unknown how SMNs influence CCS' long-term psychosocial functioning. To address this, we assessed the long-term psychosocial outcomes and QOL in survivors with and without a history of SMN.

Materials and Methods

Study population

Project REACH (Research Evaluating After Cancer Health) is a longitudinal cohort recruiting cancer survivors seen at long-term follow-up clinics at a single cancer center.⁸ Participants who were diagnosed with pediatric cancer < age 21, ≥2 years postdiagnosis, ≥1 year posttreatment, and able to complete study forms independently in English were eligible for enrolment. We invited 747 eligible survivors for participation during 2007–2013 and 601 (80%) agreed by completing a baseline survey.

During 2016–2018, 489 adults were asked to complete a follow-up survey of psychosocial outcomes. Surveys were mailed to participants or provided in-person at the time of survivorship clinic visit, and 322 CCS who completed the survey were included in this study. The majority of participants were 18–29 years of age (60%) and mean age at survey was 29.87 ± 9.54 years. The nonresponders (n = 167, 35%) were comparable, except for fewer females (41% vs. 54%) and of those underwent radiotherapy (53% vs. 65%), to the included participants. This study was approved by the cancer center's Institutional Review Board.

Ascertainment of SMNs

The survey asked participants to list all prior cancer diagnoses. Participants who reported more than one type of cancer were considered as potential SMNs and their medical records were reviewed to confirm the diagnoses. Three individuals who reported SMNs were not confirmed and therefore not classified as SMNs. Based on the treatment intensity and survival rate,⁹ we grouped nonmelanoma skin cancer or thyroid cancer as the only SMN as “low-risk” SMNs, whereas other SMNs as “high-risk” SMNs. Survivors reporting no SMNs or reported but not confirmed by record review (n = 3) served as the reference group.

Measures of psychosocial outcomes

Participants were assessed for psychosocial and QOL outcomes as follows. To compare the estimates across outcomes, all scores (Supplementary Table S1) were converted to z-scores for analysis.

(1)

Fatigue: The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)¹⁰ is a 13-item self-report inventory widely used in studies of cancer-related fatigue.¹¹ The FACIT-F inquires about fatigue over the prior week. The total score ranges from 0 to 52, with a higher score indicating less fatigue.

(2)

Sleep quality: The Pittsburgh Sleep Quality Index (PSQI)² is a commonly used 19-item self-report measure of sleep quality and disturbances over the past 1 month. Participants were asked to report their bed time, wake time, and total hours of actual sleep. The total score is calculated by totaling the seven component scores (range 0–21), with a higher score suggesting poorer sleep quality. The PSQI has been used previously in adult survivor of childhood cancer populations.²

(3)

QOL: The Short-Form 12¹² (SF-12) is a 12-item measure of health-related QOL, validated across both general and multiple patient populations, including cancer survivors.¹³ The SF-12 asks respondents to rate their current functioning and responses are used to generate scores reflecting physical and emotional health and well-being. We calculated physical component summary and mental component summary following standard SF-12 scoring procedures. The scores are standardized t-scores with a mean of 50 and a standard deviation (SD) of 10. A higher score indicates better functioning.

(4)

Depression and anxiety: The Brief Symptom Inventory-18 (BSI-18) is a widely used, well-validated brief measure of psychological distress that has been used extensively in oncology populations.¹⁴ The 18 items form a Global Severity Index reflecting general psychological distress as well as three subscales, including somatization, depression, and anxiety. As depression and anxiety are the most common mental conditions in cancer survivors,¹⁵ we calculated gender-specific t-scores for depression and anxiety, with a higher score indicating greater symptom.

(5)

Body image: This was evaluated using four items originally from the Body Image Scale and subsequently included in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQBR-23).¹⁶ The items inquire about body dissatisfaction in general (i.e., not specific to a cancer type), including difficulty in looking at one's self naked, feeling less feminine/masculine, and physically less attractive as a result of the disease or treatment. Following recommended scoring procedures,¹⁷ we calculated a total score (range 0–100), with a higher score indicating less dissatisfaction.

Statistical analysis

We compared demographic and clinical characteristics of survivors with and without SMNs, using t-test or chi-squared test. Using linear regression, we derived coefficients (β) and 95% confidence intervals (CIs) of psychosocial outcomes among survivors with SMNs with adjustment for sex, age, and calendar period at diagnosis of first malignancy, age at survey, educational level, household income, cohabitation status, type of first malignancy, surgery, chemotherapy, and radiation therapy for first malignancy. For consistency, the sign of the regression coefficients for fatigue, physical and mental health, and body image were reversed so that across all outcomes a positive estimate indicates higher symptom burden. To shed light on the differential influence of SMNs by prognosis and treatment intensity, subgroup analyses were further performed for high-risk versus low-risk SMNs.

Results

Participants were diagnosed with pediatric cancers at a mean age of 9.11 ± SD 5.81 years. At the follow-up by young adulthood (mean age 29.87 ± 9.54 years), 43 survivors (13.4%) developed 60 confirmed SMNs (Table 1). SMNs occurred most commonly when survivors were aged 18–29 years (44%), or 30–39 years (35%), and the most common SMNs were thyroid (n = 14), nonmelanoma skin (n = 11), and breast cancers (n = 10). Compared to survivors without SMNs (i.e., reference group), survivors with SMNs were older at the survey, more likely to be female, had higher educational attainment and household income, and were more likely married/living as married (p < 0.05). Their first malignancies were more likely to be lymphoma or sarcoma and treated by radiation therapy (p < 0.05).

Table 1.

Characteristics Between Childhood Cancer Survivors With and Without Subsequent Malignant Neoplasms

	Survivors without SMNs	Survivors with SMNs	p
Total number	279	43
Age at survey, year	28.38 (8.01)	39.49 (12.71)	<0.001
18–29	181 (64.87)	13 (30.23)	<0.001
30–39	73 (26.16)	6 (13.95)
40+	25 (8.96)	24 (55.81)
Sex
Female	141 (50.54)	33 (76.74)	0.001
Male	138 (49.46)	10 (23.26)
Educational level
High school and below	50 (17.92)	9 (20.93)	0.004
College	195 (69.89)	21 (48.84)
Postgraduate	34 (12.19)	13 (30.23)
Household income
<$50,000	68 (24.37)	9 (20.93)	0.004
$50,000–$99,999	83 (29.75)	10 (23.26)
≥$100,000	101 (36.20)	19 (44.19)
Unknown	27 (9.68)	5 (11.63)
Marital status
No	210 (75.27)	26 (60.47)	0.041
Yes	69 (24.73)	17 (39.53)
First malignancy
Age at diagnosis, year	8.91 (5.79)	10.40 (5.81)	0.123
Time from first malignancy to survey, years	19.47 (8.00)	29.09 (11.29)	<0.001
Type of cancer
Brain	111 (39.78)	5 (11.63)	0.001
Leukemia	59 (21.15)	7 (16.28)
Lymphoma	36 (12.90)	16 (37.21)
Neuroblastoma	21 (7.53)	3 (6.98)
Sarcoma	26 (9.32)	8 (18.60)
Other	26 (9.32)	4 (9.30)
Chemotherapy
No	75 (26.88)	11 (25.58)	0.858
Yes	204 (73.12)	32 (74.42)
Radiation therapy
No	109 (39.07)	4 (9.30)	<0.001
Yes, but no to brain	50 (17.92)	23 (53.49)
Yes, to brain	120 (43.01)	16 (37.21)
Surgery
No	102 (36.56)	12 (27.91)	0.269
Yes	177 (63.44)	31 (72.09)
Subsequent malignancies
Age at diagnosis, year	—	29.78 (13.13)
18–29	—	19 (44.19)
30–39	—	15 (34.88)
40+	—	9 (20.93)
Time from SMN to survey,^a years	—	7.96 (8.29)
With multi-SMNs	—	11 (25.58)
Number of SMNs	—	60
Type of cancer
Brain	—	8 (13.33)
Breast	—	10 (16.67)
Head and neck	—	3 (5.00)
Melanoma	—	4 (6.67)
Nonmelanoma skin	—	11 (18.33)
Soft tissue sarcoma	—	5 (8.33)
Thyroid	—	14 (23.33)
Other	—	5 (8.33)

Values are shown as n (%) or mean (SD).

For individuals with multi-SMNs, the last SMN was used to calculate the time to survey.

SD, standard deviation; SMNs, subsequent malignancy neoplasms.

Psychosocial outcomes were assessed on average 20.75 ± 9.10 years after first cancer diagnosis in all survivors and 7.96 ± 8.29 years after SMN diagnosis in survivors with SMNs. Compared to the reference group, SMN was not significantly associated with a higher burden of fatigue, insomnia, depression, or anxiety symptoms, or impaired QOL in physical or mental health (Fig. 1). Post hoc analysis with 100,000 simulations indicated a 14% chance to detect significant effects of SMN when β = 0.14 (e.g., depression) given this sample size. However, survivors with SMNs reported a higher level of body image concerns (z-score: 0.64 ± 1.30 vs. −0.09 ± 0.91; β = 0.40, 95% CI: 0.04–0.76).

FIG. 1.

Long-term psychosocial well-being and quality of life among childhood cancer survivors with SMNs compared to survivors without SMNs. Survivors with nonmelanoma skin cancer or thyroid cancer as the only SMN were grouped as low-risk SMNs (n = 16), whereas other SMNs were classified as high-risk SMNs (n = 27). Models were adjusted for sex, age, and calendar period at diagnosis of first malignancy, age at survey, educational level, household income, cohabitation status, type of first malignancy, surgery, chemotherapy, and radiation therapy for first malignancy. To be in line with other endpoints, all symptom scores were converted to z-scores (i.e., mean = 0 and standard deviation = 1) and the coefficient signs were reversed for fatigue, physical and mental health, and body image, meaning positive β indicates higher symptom burden. CI, confidence interval; HRCOL, health-related quality of life; Ref., reference; SMNs, subsequent malignant neoplasms.

When analyses examined survivors with high-risk (n = 27) and low-risk SMNs (n = 16) separately, the survivors with high-risk SMNs tended to have greater symptom burdens of all psychosocial outcomes than the reference group, although body image concern was the only association that reached statistical significance (β = 0.52, 95% CI: 0.08–0.96). Psychosocial outcomes were statistically comparable between survivors with low-risk SMNs (n = 16) and the reference group (p > 0.05).

Discussion

The present study is one of the firsts to address the impact of SMNs across a wide variety of long-term psychosocial functioning and QOL concerns in young adult survivors of childhood cancer. Compared to survivors without SMNs, survivors with SMNs did not report significantly greater fatigue, insomnia, depression, or anxiety symptoms, or impaired QOL in physical or mental health on average 8 years after SMN diagnosis. However, survivors with SMNs endorsed higher level of body image concerns.

A previous report suggested that SMN or relapse is not an important predictor for somatic symptoms and depression/anxiety in survivors of adolescent cancers (age at diagnosis 11–21 years).¹⁸ Our findings extended the knowledge to that, in survivors of cancers predominately diagnosed in early childhood, SMNs were not significantly associated with poor psychosocial outcomes and QOL. Larger cohorts are, however, needed to confirm or refute the nonsignificantly positive associations of SMNs with depression and fatigue symptoms, and impaired mental health QOL (β = 0.14, 0.14, and 0.15, respectively).

Body image is important for adolescents and young adults to develop self-identity and intimate relationships. However, childhood cancer and its treatment may drastically and permanently affect physical appearance from young ages.¹⁹ CCS are more likely to report body image dissatisfaction after careful adjustment for risk factors, including age, cancer type, and treatment of the first malignancy.²⁰ Our finding adds to the knowledge that survivors with SMNs have even greater body image concerns during young adulthood. It is possible that the negative perceptions of body image are attributable to scarring or disfigurement due to the therapy directed toward SMNs. Because body image concerns may be associated with increased psychological symptom burden,²¹ clinicians caring for survivors should be aware of the risk for body image dissatisfaction in young adult survivors with a history of SMN, and consider interventions to support this vulnerable population.

It has been recognized that adults diagnosed with poor prognosis cancers experience elevated risk of mental disorders, while those diagnosed with less aggressive cancers do not.²² While our data did not show that high-risk SMNs had a statistically significant impact on psychosocial outcomes beyond body image, the nonsignificant elevation in survivors with high-risk SMN across all outcomes indicates a differential impact of SMNs depending on cancer types and that should be investigated further in large-scale cohorts.

Our study benefitted from surveying a wide range of psychosocial outcomes with standardized measures,^23,24 and confirming SMN diagnoses by reviewing medical records, which minimizes misclassifications. Study limitations include a cohort from a single institution which may limit generalizability. CCS of brain tumor were overrepresented in our cohort due to a pediatric neuro-oncology clinic at our center. We, however, performed an additional analysis by excluding CCS of brain tumor as the first malignancy and yielded largely similar results (data not shown). In addition, our survey method may miss survivors who are most socially disadvantaged or suffering severe mental disorders; and using a single psychosocial assessment, typically several years after SMN diagnosis does not allow for assessing immediate and temporal impacts of SMNs.

Although we verified self-reported SMNs, underreport (if any) may lead to misclassification of SMNs and attenuated associations. However, the sensitivity of self-reported cancers is usually deemed high.²⁵ Although 35% of survivors did not respond to the follow-up survey, the baseline characteristics were largely similar between them and included survivors. Importantly, on average 30 years after the childhood cancer diagnosis, the prevalence of SMNs in our data is comparable with the literature (13% vs. 10%).⁵ Finally, there is a chance that our finding on body image is due to multiple testing (Type 1 error), which is to be confirmed in independent cohorts.

Conclusions

Our findings suggest that CCS with SMNs are not at significantly increased risk of poor psychosocial outcomes in young adulthood. Future studies with larger cohorts are needed to confirm these findings. A greater concern for body image was, however, noted among CCS with SMNs. Clinicians should be vigilant for body image dissatisfaction in CCS with a history of SMN.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

Project REACH was supported by the Swim Across America foundation. This work was also supported by the Erik and Edith Fernström Foundation (2019-00410) and Swedish Research Council (2018-00648) to D.L.

Supplementary Material

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Supplementary Material

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