Health-Related Quality of Life of Adolescent and Young Adult-Aged Childhood Cancer Survivors in a South African Cohort: A Pilot Study Using the Minneapolis-Manchester Quality of Life Instrument

Abstract

Purpose:

We investigated the health-related quality of life (HRQoL) of an adolescent and young adult (AYA)-aged South African childhood cancer survivor (CCS) cohort.

Methods:

Participants completed the Minneapolis-Manchester Quality of Life adolescent and adult forms. The overall Cronbach’s alpha coefficients were 0.81 (adolescent form) and 0.92 (adult form). The scale-level content validity indexes were acceptable (0.88 and 0.89 for the adolescent and adult forms, respectively). The total domain and overall HRQoL scores were calculated.

Results:

Sixty-two survivors completed the adolescent form and 30 completed the adult form. The median age was 17.5 years (range 13–34 years), and the median time from diagnosis was 12 years (male:female ratio 1:1.2). Risk factors for poor physical functioning included age at study visit (p = 0.015), solid tumor diagnosis (p = 0.012), radiotherapy (p = 0.021), and surgery (p = 0.006). Six or more late effects impacted most domains negatively; severe late effects (p = 0.020) decreased physical functioning. Lower socioeconomic status was associated with poorer physical (p = 0.006) and cognitive (p = 0.047) functioning. The adult form cohort had poorer psychological (p = 0.014) and social functioning (p = 0.005) and body image (p = 0.016) than the adolescent form cohort.

Conclusion:

Older age, radiotherapy, surgery, solid tumor diagnosis, and the number and severity of late effects negatively influenced HRQoL in AYA-aged CCSs. A long-term follow-up (LTFU) risk stratification system should include HRQoL status to assist with holistic LTFU care.

Introduction

Childhood cancer survivors (CCSs) have a high cumulative incidence of developing a chronic health condition,¹ which may negatively influence their health-related quality of life (HRQoL).^2,3 HRQoL refers to the impact of an individual’s health status on their perceived physical, mental, emotional, and social functioning and their life satisfaction.^4,5 Studies have reported conflicting results, ranging from poorer to no differences to improved HRQoL in CCSs compared with healthy controls.^6–9 Factors associated with a poorer HRQoL include female sex, older age, time since diagnosis, low socioeconomic status, lower educational attainment, and unemployment.^6,10 Additional risk factors are radiotherapy and the presence of late effects.^2,11 Survivors of certain types of cancer (brain and bone tumors, leukemia, and neuroblastoma) and those with relapsed disease may have poorer HRQoL, but the findings are contradictory.^2,8,12 Adolescent and young adult (AYA)-aged survivors may be more vulnerable due to their unique physical, psychological, and social developmental phase, the evolution of their identities and independence, changing interpersonal relationships, and other needs.^13,14

The measurement of HRQoL offers several challenges, such as heterogeneity in the nature of the different tools. CCSs and their caregivers have contradictory views regarding their HRQoL, and few instruments are suitable for younger children.^3,15 Generic HRQoL measures for survivors and those receiving treatment include the SF-36 Health Survey (SF-36),¹⁶ the Pediatric Quality of Life Inventory (PedsQL),¹⁷ the Medical Outcome Study Scale (MOS-24),¹⁸ and the KIDSCREEN-27 and -52.^19,20 Disease-specific measures for HRQoL include the PEDQOL,²¹ the PedsQL 3.0 Cancer module,²² used for children up to 18 years receiving cancer treatment and for survivors, and the Health Utilities Index.²³

The self-report Minneapolis-Manchester Quality of Life (MMQL) youth, adolescent, and adult forms^24–26 were developed specifically for survivors of childhood cancer instead of those actively receiving treatments, based on patient, parent, nurse, and doctor experiences. The forms include evaluation of body image, relationships, and cognitive functioning that are not usually included in the more commonly used measures and exclude cancer treatment symptoms. They share age-appropriate common domains to facilitate longitudinal assessments. Groups in Sweden, the United Kingdom, Korea, and Japan have validated local versions.^27–30 We selected the MMQL adolescent and adult forms for this study as they are cancer survivor specific, short, and easy to administer, and the forms are suited for longitudinal assessments across different age groups.

Limited information about the HRQoL for long-term adolescent and AYA-aged CCSs residing in low- and middle-income countries (LMICs) is available. Most study cohorts include patients receiving cancer treatment^31–33 or survivors not yet five years after treatment completion.^34,35 One South African study documented a lower (intermediate) functioning level as measured by the PedsQL tool for inpatients receiving treatment.³⁶ We conducted this pilot study among a cohort of long-term AYA-aged CCSs from a single center in South Africa to investigate the feasibility of assessing HRQoL in LMICs and to plan a more robust follow-up project.

Materials and Methods

This cross-sectional study was conducted from 2020 to 2021 at Tygerberg Hospital, a tertiary academic hospital in Cape Town, South Africa. Contactable CCSs on the Tygerberg Hospital childhood cancer tumor registry, diagnosed between 1983 and 2015, were invited to participate in a prospective survivorship study to document medical and psychological late effects. The inclusion criteria were a childhood cancer diagnosis and at least five years of survival after diagnosis. An exclusion criterion was a Langerhans cell histiocytosis diagnosis. Demographic and clinical information and socioeconomic status were extracted from the registry and patient folders. Diagnoses were classified as hematological malignancies (leukemia and lymphoma) or solid tumors. The authors classified chemotherapy intensity as low (including those who had no chemotherapy) or high.³⁷ CCSs’ socioeconomic status was classified according to the local hospital classification system: fully subsidized service (unemployed families), partially subsidized (< $4615 single income or $6593 family income per year), moderate income ($4615 – $6593 single income or $16,482 – $23,075 family income per year), and high income (>$16,482 single income or $23,075 family income per year).³⁸ An in-person long-term follow-up (LTFU) assessment was guided by the Children’s Oncology Group LTFU guidelines version 4.³⁹ The number of identified late effects were recorded, and the severity was classified as Grades 1 and 2 (mild to moderate) and Grades 3 and 4 (severe), according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.⁴⁰

The authors used two MMQL forms with permission from the original developer, who approved minor adaptations (ethnic group options, school levels, and types of tertiary education institutions) to reflect the local context (Supplementary Table S1). Formal validation of the forms was beyond the scope of this study. To assess the relevance of the forms to a South African cohort, 14 pediatric oncologists rated each item as ‘not relevant,’ ‘somewhat relevant,’ ‘relevant,’ or ‘very relevant’ (scored 1–4, respectively). The item-level content validity score for each item was determined by dividing the number of oncologists who rated an item as “3” or “4” by the number of respondents (14). The item-level content validity score ranged from 0.5 (not acceptable) for one item to 0.85 or more (acceptable) for 38 (67.9%) items. The scale-level content validity index was the average of all the item-level content validity indexes. The scale-level content validity indexes were acceptable (0.88 and 0.89 for the adolescent and adult forms, respectively).⁴¹ The English forms were translated into the other two local languages (Afrikaans and isiXhosa) utilizing the standard forward-backward methodology by the Stellenbosch University language center.

The age inclusion criterion for the HRQoL assessment study was 13–39 years. Participants completed either the 46-item MMQL adolescent form (13–20 years) or the 44-item adult form (21–55 years). Both forms shared the following domains: physical, psychological, social, and cognitive functioning, body image, and outlook on life. (Table 1) Some items were similar but appeared in different domains. Twelve items pertaining to body development, school, dating, and family relationships appeared only in the adolescent form. Ten items were unique to the adult form. The first section in the adolescent form requested additional demographic information, including the participants’ and their parents’ educational level, living arrangements, and the number of siblings. The MMQL forms do not restrict responses to a specific time period.

Table 1.

Overlap of Items of the Adolescent and Adult Minneapolis-Manchester Quality of Life Forms

Domain description and responses	Adolescent form	Adult form
General information	Date of birth	—
	Sex	—
	Ethnic group	—
	Highest grade/level of schooling completed?	—
	What is the marital status of your parents?	—
	Mother/stepmother’s education level?	—
	Father/stepfather’s education level?	—
	Living arrangements (with parents/partner/married/alone/at tertiary institution?)	—
	How many brothers and sisters do you have?	—
Physical functioning	How much of the time can you keep up with others/friends your age in sports or games?/I keep up with my friends in sports
	I have a lot of energy (very true, true, untrue, somewhat untrue, very untrue)
	I have lots of energy for running/sports (very true, true, untrue, somewhat untrue, very untrue)
	I cannot do many activities because of my health (very true, true, untrue, somewhat untrue, very untrue)
	I cannot do activities because of my arms/legs (very true, true, untrue, somewhat untrue, very untrue)
	In games and sports, I like watching rather than taking part (very true, true, untrue, somewhat untrue, very untrue)
	Feels strong and healthy (never, occasionally, some of the time, most of the time, all of the time)
	Feels tired during the day (never, occasionally, some of the time, most of the time, all of the time)	—
	I need time out to rest during the day (very true, true, untrue, somewhat untrue, very untrue)	—
Psychological functioning (how people describe themselves)(Never, occasionally, some of the time, most of the time, all of the time)	Sad
	Lonely
	Frightened
	Anxious/nervous
	Worried about dying
	Worried about my health
	Worried about things in general
	Angry	—
	Inferior to other people	—
Body image	How satisfied are you with your weight? (extremely or somewhat satisfied or dissatisfied)
	How happy are you with the way you look? (extremely or somewhat satisfied or dissatisfied)
	I like my body the way it is (extremely or somewhat satisfied or dissatisfied)
	How do you feel about your body development right now? (extremely or somewhat satisfied or dissatisfied)	I can always look good if I try (very true of me, somewhat true of me, not true or false of me, not very true of me, not at all true of me)
	I am uncomfortable with the way my body is developing (strongly agree, somewhat agree, do not agree/disagree, somewhat disagree, strongly disagree)	I wish I were in a better physical condition (strongly agree, somewhat agree, do not agree/disagree, somewhat disagree, strongly disagree)
	When others look at me they think I am underdeveloped (strongly agree, somewhat agree, do not agree/disagree, somewhat disagree, strongly disagree)	—
Social functioning (how people describe themselves)(Very true of me, somewhat true of me, not true or false of me, not very true of me, not at all true of me)	People like to be with me
	I have a lot in common with my friends
	I get along well with people my own age
	I have many close friends
	I have similar hobbies/interests to people my own age
	Being together with other people gives me a good feeling
Cognitive functioning	How much difficulty do you have concentrating at school/work? (none, a little, some, quite a lot, a whole lot)
	How much difficulty do you have concentrating at other times? (all of the time, most of the time, sometimes, occasionally, never)
	How often is homework/study hard for you? (all of the time, most of the time, sometimes, occasionally, never)
	How much difficulty do you have remembering things? (none, a little, some, quite a lot, a whole lot)
	Do you have difficulty concentrating at work/school? (all of the time, most of the time, sometimes, occasionally, never)
	How much difficulty do you have with reading/writing? (none, a little, some, quite a lot, a whole lot)
	How much difficulty do you have with math/calculations? (none, a little, some, quite a lot, a whole lot)
	How often do you need more help with schoolwork than others in your class? (all of the time, most of the time, sometimes, occasionally, never)	—
	How much difficulty do you have with your schoolwork compared to others in your class? (none, a little, some, quite a lot, a whole lot)	—
Intimate relationships (how people describe themselves)(Very true of me, somewhat true of me, not true or false of me, not very true of me, not at all true of me)	I find it difficult to make friends
	I feel left out in groups of people my own age
	I find it easy to have an intimate relationship
	I am confident when I am with people of the opposite sex	—
Outlook on life(strongly agree, somewhat agree, do not agree/disagree, somewhat disagree, strongly disagree)	I am happy with the way things are
	I am happy with life in general
	I am satisfied with my current life situation
	—	I am happy with the state of my health
	—	I am a healthy person

The original scoring system was retained. Items were scored from one to five (the highest level of HRQoL). Each domain’s total scores were divided by the number of items in the specific domain to obtain the domain-specific score. The overall HRQoL score was calculated by adding all the item scores and dividing this sum by the number of items in the form. The overall Cronbach’s alpha coefficients were 0.81 (adolescent form) and 0.92 (adult form). The Cronbach’s alpha coefficients for each domain in both forms are depicted in Table 2. Three coefficients were poor: physical functioning (0.581) and intimate relations (0.508) in the adolescent and psychological functioning (0.572) in the adult form, and the body image coefficient (0.658) in the adolescent form was questionable.

Table 2.

Cronbach’s Alpha Coefficients for the Minneapolis-Manchester Quality of Life Adolescent and Adult Forms

	Adolescent form	Adult form
	n = 62	n = 30
	Cronbach’s alpha coefficient	Cronbach’s alpha coefficient
Physical functioning	0.581	0.817
Cognitive functioning	0.775	0.809
Psychological functioning	0.723	0.586
Body image	0.658	0.813
Social functioning	0.771	0.795
Intimate relations	0.508	—
Outlook on life	0.836	0.738
Overall HRQoL	0.814	0.921

HRQoL, health-related quality of life.

Investigators explained the questionnaire completion process during the in-person LTFU visits. During the COVID pandemic, when in-person research visits were prohibited, the MMQL forms were verbatim converted to an online format with telephonic explanations by the investigators. There were no refusals to participate. The Health Research Ethics Committee of Stellenbosch University approved the study, and participants provided informed consent before enrollment.

Statistical analyses

Basic descriptive statistical analyses using Stata version 17 statistical software described demographic and medical data. Cronbach’s coefficient was used to estimate the internal consistency reliability. Spearman correlation was employed for all continuous variables: age at diagnosis, age at study visit, the time since diagnosis, the number and severity of cancer-related late effects, and number of siblings. Chi-square and Fisher’s exact tests were used to compare the recruited cohort to the remaining cohort. Mann–Whitney tests and t-tests were used to compare the different domains’ mean scores for the adolescent and adult MMQL form groups. The Mann–Whitney test was used to compare domain data that were not normally distributed (body image and outlook on life domains). Univariate linear regression analysis (with age at the study visit as a significant risk factor for most domains kept constant) was used to investigate predictors of poor HRQoL for all categorical variables: sex, socioeconomic classification, cancer diagnosis, treatment modalities (chemotherapy intensity, radiotherapy, and surgery), and the number and severity of late effects. As brain tumor survivors reportedly have worse HRQoL, a subanalysis was done to compare their results to the rest of the cohort. A p value of <0.05 was considered statistically significant.

Results

The Tygerberg Childhood Tumor Registry contained 1518 survivors diagnosed between 1983 and 2015. Of these, 797 (52.5%) were alive but only 644 (80.8%) had all medical and contact information available (Fig. 1). In the 13–20 years adolescent group (149/644; 23.1%), 62 survivors (41.6%) were contactable and all participated. In the young adult group (21–39 years) (361/644; 56.1%), only 30 (8.3%) were contactable and participated. Most (47/62; 75.8%) of the adolescent group were receiving LTFU care as opposed to only 13.3% (4/30) of the young adult group after being discharged from LTFU care after 5 years as per the previous local practice or getting lost to follow-up. One participant in the adolescent group died due to relapsed disease after the study completion. Six survivors in each group (12/92; 13%) were not yet receiving LTFU care. We excluded one 13-year-old CCS as he had completed the youth form instead of the adolescent form. Most (87/92; 94.6%) completed the forms during their LTFU visit, while seven (7.6%) completed them online. As these seven could not attend an in-person LTFU visit, their late effects were not assessed. Most (66/92; 71.7%) completed an Afrikaans form; 28.3% (26/92) completed an English form.

FIG. 1.

Flow chart for cohort recruitment procedure.

Characteristics of the study cohort and uncontactable survivors are summarized in Supplementary Table S2. The two groups had a similar median age at diagnosis (p = 0.248). They did not differ regarding radiotherapy (p = 0.115), but the study cohort comprised more females (p = 0.047) and had a shorter follow-up period since diagnosis (p < 0.001). The study cohort received chemotherapy (p < 0.001) more frequently and surgery less often (p = 0.025). The adolescent participants and nonparticipants were only similar regarding sex (p = 0.491) and radiotherapy received (p = 0.651). (Supplementary Table S3) The adult participants and nonparticipants had no significant differences in age at diagnosis (p = 0.299) and surgery (p = 0.068) and radiotherapy (p = 0.269) received.

The study cohort comprised 51 (55.4%) females and 41 (44.6%) males. (Table 3) The majority were fully subsidized patients (34/92; 37%). Most survived hematological malignancies (54/92; 58.7%); therefore, most were treated with chemotherapy only (38/92; 41.3%). The total cohort’s median age at completion of the forms was 17.5 years [interquartile range (IQR) 14–24.5 years; range 13–34 years]. The median time since diagnosis was 12 years (IQR 8.5–16 years; range 5–31 years). Survivors had a median of three late effects (IQR 1–6). The most common late effects were metabolic/nutritional (43/85; 50.6%), gastrointestinal (27/85; 31.8%), and hematological (26/85; 30.6%) disorders.

Table 3.

Demographic and Medical Characteristics of the Total Cohort

Characteristic	n = 92	n	%
Sex	Male	41	44.6
	Female	51	55.4
Language	English	26	28.3
	Afrikaans	66	71.7
Age at diagnosis (years)	Mean (min-max)	6.0	0–15
	Median (IQR)	5	3–9
Age at study visit (years)	Mean (min-max)	19.2	13–34
	Median (IQR)	17.5	14–24.5
Period since diagnosis	Mean (min-max)	12.7	5–31
	Median (IQR)	12	8.5–16
Diagnosis	Brain tumor	8	8.7
	Leukemia	34	37.0
	Lymphoma	20	21.7
	Neuroblastoma	1	1.1
	Osteosarcoma	5	5.4
	Germ cell tumors	3	3.3
	Other	4	4.4
	Renal tumor	10	10.9
	Retinoblastoma	1	1.1
	Rhabdomyosarcoma	6	6.5
Diagnosis group	Solid tumors	38	41.3
	Hematological malignancies	54	58.7
Treatment modality	No treatment	1	1.1
	Chemotherapy only	38	41.3
	Surgery only	1	1.1
	Chemotherapy and surgery	24	26.1
	Chemotherapy and radiotherapy	14	15.2
	Chemotherapy, surgery, and radiotherapy	11	12.0
	Other	3	3.3
Socioeconomic status at study visit	Fully subsidized (H0)	34	37.0
	Partially subsidized (H1)	20	21.7
	Moderate income (H2)	7	7.6
	High income (H3)	2	2.2
	Medical insurance	29	31.5
Number of late effects^an = 85	Mean (min-max)	4.6	0–22
	Median (IQR)	3	1–6
Identified late effects	Hematological disorders	26	30.6
	Cardiac disorders	11	13.0
	Ear disorders	9	10.6
	Endocrine disorders	15	17.7
	Eye disorders	5	5.9
	Gastrointestinal disorders	27	31.8
	Infections	4	4.7
	Investigation disorders	14	16.5
	Metabolism and nutritional disorders	43	50.6
	Musculoskeletal disorders	17	20.0
	Neurocognitive disorders	16	18.8
	Pregnancy, puerperium, and perinatal conditions	1	1.2
	Psychiatric disorders	11	12.9
	Reproductive system and breast disorders	5	5.9
	Renal disorders	6	7.1
	Respiratory, thoracic, and mediastinal disorders	12	14.1
	Skin lesions	5	5.9
	Subsequent malignancy	2	2.4
	Vascular disorders	6	7.1
	Miscellaneous disorders	24	28.2

^aSeven (7.6%) participants did not have late effect assessments.

IQR, interquartile range.

Two participants had missing items [n = 4 (body image one item; outlook on life three items) and n = 1 (cognitive functioning), respectively] and were excluded from the calculation of total HRQoL. The mean score for the overall HRQoL was 3.8 [standard deviation (SD) 0.5]. (Table 4) The outlook on life (mean 4.2; SD 0.9) and social functioning (mean 4.1; SD 0.8) domains had the highest total scores, and the physical functioning domain had the lowest score (mean 3.6; SD 0.7).

Table 4.

Comparison of Mean Scores for the Adolescent and Adult Minneapolis-Manchester Quality of Life Forms Using Single t-Tests

	Combined cohort		Adolescent form cohort		Adult form cohort
	n = 92		n = 62		n = 30
	Mean (range)	SD	Mean (range)	SD	Mean (range)	SD	p value
Physical functioning	3.6 (2.1–4.9)	0.7	3.6 (2.1–4.8)	0.6	3.8 (2.3–4.9)	0.8	0.161
Cognitive functioning	3.7 (1.4–5)	0.7	3.7 (1.7–5)	0.7	3.8 (1.4–5)	0.8	0.459
Psychological functioning	3.8 (1.9–5)	0.6	3.9 (1.9–5)	0.6	3.6 (2.1–4.6)	0.5	0.014
Body image^a	3.9 (1.5–5)	0.8	4.0 (1.5–5)^b(1)	0.7	3.6 (1.8–5)	0.9	0.016
Social functioning^a	4.1 (1.3–5)	0.8	4.2 (1.3–5)^b(1)	0.8	3.8 (2–5)	0.8	0.005
Intimate relations	—	—	3.9 (2–5)	0.8	—	—	—
Outlook on life^a	4.2 (1–5)	0.9	4.2 (1–5)^b(3)	0.9	4.0 (1–5)	0.9	0.107
Overall HRQoL	3.8 (1.9–4.8)	0.5	3.9 (2.6–4.8)	0.4	3.7 (1.9–4.8)	0.6	0.185

Mann–Whitney test used.

Missing items (number).

SD, standard deviation; HRQoL, health-related quality of life.

The adolescent and adult cohorts differed significantly in three domains. The adult cohort had significantly poorer psychological (p = 0.014) and social functioning (p = 0.005) and inferior body image (p = 0.016). (Table 4) Spearman correlation analysis identified the age at the study visit to be significantly associated with poorer psychological (ρ −0.262; p = 0.016) and social functioning (ρ −0.241; p = 0.027) and with a negative body image (ρ −0.272; p = 0.013) and a poorer outlook on life (ρ −0.307; p = 0.005; Table 5). The number of late effects was associated with poorer physical (ρ −0.341; p = 0.002) and social functioning (ρ −0.263; p = 0.016), a negative body image (ρ −0.231; p = 0.035), a poorer outlook on life (ρ −0.299; p = 0.006), and a poorer overall HRQoL (ρ −0.326; p = 0.003).

Table 5.

Spearman Correlation of All Continuous Variables

	Physical functioning	Cognitive functioning	Psychological functioning	Body image	Social functioning	Outlook on life	Overall HRQoL
Age at diagnosis
Spearman correlation	−0.073	0.033	−0.126	−0.163	−0.122	−0.093	−0.090
p value	0.509	0.762	0.250	0.139	0.267	0.401	0.420
Age at study visit
Spearman correlation	−0.050	0.204	−0.262	−0.272	−0.241	−0.307	−0.177
p value	0.649	0.061	0.016	0.013	0.027	0.005	0.110
Period since diagnosis
Spearman correlation	0.018	0.186	−0.139	−0.072	−0.106	−0.158	−0.074
p value	0.873	0.089	0.206	0.516	0.338	0.152	0.507
Late effects
Spearman correlation	−0.341	−0.050	−0.164	−0.231	−0.263	−0.299	−0.326
p value	0.002	0.651	0.135	0.035	0.016	0.006	0.003

HRQoL, health-related quality of life.

On univariate linear regression analysis, younger age was associated with poorer physical functioning [β1 −0.7; 95% confidence interval (CI) −1.3 to −0.1; p = 0.015; (Table 6)]. Female sex as a risk factor for poorer psychological functioning (β1 −0.2; 95% CI −0.5–0.005; p = 0.054) almost reached statistical significance while this sex was associated with a better outlook on life (β1 0.3; 95% CI 0.1–0.8; p = 0.023). The lowest socioeconomic status was significantly associated with poorer cognitive functioning (β1 −0.4; 95% CI −0.7 to −0.005; p = 0.047) and the moderate-income category with poorer physical functioning (β1 −0.5; 95% CI −0.8 to −0.1; p = 0.006). A higher number of siblings were significantly associated with poorer social functioning (β1 −0.5; 95% CI −0.9 to −0.1; p = 0.019). Having divorced or separated parents was associated with poorer social functioning (β1 −0.5; 95% CI −1.0 to −0.1; p = 0.023), a poorer outlook on life (β1 −0.6; 95% CI −1.1 to −0.04; p = 0.035), and overall HRQoL (β1 −0.3; 95% CI -0.5 to −0.1; p = 0.009).

Table 6.

Univariate Linear Regression Analysis of Risk Factors Associated with Poor Health-Related Quality of Life

	Physical functioning [β1^a(95%CI)]	Cognitive functioning [β1(95%CI)]	Psychological functioning [β1(95%CI)]	Body image [β1(95%CI)]	Social functioning [β1(95%CI)]	Outlook on life [β1(95%CI)]	Overall HRQoL [β1(95%CI)]
MMQL forms
Adult form (21–55 years)	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Adolescent form (13–20 years)	−0.7 (−1.3 to −0.1)	0.4 (−0.2 to 1.1)	0.1 (−0.4 to 0.6)	−0.1 (−0.8 to 0.6)	0.3 (−0.4 to 1.0)	0.5 (−1.3 to 0.3)	0.1 (−0.5 to 0.3)
p value	0.015	0.159	0.694	0.764	0.426	0.186	0.643
Sex
Male	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Female	−0.1 (−0.4 to 0.2)	0.2 (−0.1 to 0.5)	−0.2(−0.5 to 0.005)	−0.1 (−0.5 to 0.2)	0.2 (−0.2 to 0.5)	0.3 (0.1 to 0.8)	0.02 (−0.2 to 0.2)
p value	0.623	0.274	0.054	0.428	0.360	0.023	0.821
Period since diagnosis
5–15 years	Reference	Reference	Reference	Reference	Reference	Reference	Reference
16+ years	0.1 (−0.4 to 0.6)	0.3 (−0.2 to 0.8)	0.05 (−0.4 to 0.5)	0.01 (−0.5 to 0.6)	0.1 (−0.5 to 0.6)	0.02 (−0.6 to 0.7)	0.1 (−0.2 to 0.4)
p value	0.701	0.177	0.826	0.960	0.832	0.943	0.579
Socioeconomic classification
High income (H3 and private)	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Fully subsidized (H0)	−0.3 (−0.6 to 0.1)	−0.4(−0.7 to −0.005)	−0.1 (−0.4 to 0.2)	−0.04 (−0.4 to 0.4)	−0.1 (−0.5 to 0.4)	0.4 (−0.04 to 0.9)	−0.1 (−0.4 to 0.1)
p value	0.118	0.047	0.509	0.859	0.780	0.076	0.361
Partially subsidized and moderate income (H1 and H2)	−0.5 (−0.8 to −0.1)	−0.01 (−0.4 to 0.3)	−0.2 (−0.5 to 0.1)	−0.3 (−0.7 to 0.1)	0.02 (−0.4 to 0.4)	−0.02 (−0.5 to 0.4)	−0.2 (−0.4 to 0.1)
p value	0.006	0.942	0.166	0.113	0.911	0.936	0.119
Diagnosis group
Hematological malignancies	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Solid tumors	−0.3 (−0.6 to −0.1)	−0.2 (−0.5 to 0.1)	0.1 (−0.2 to 0.3)	0.1 (−0.3 to 0.4)	0.3 (−0.1 to 0.6)	0.03 (−0.3 to 0.4)	−0.03 (−0.2 to 0.2)
p value	0.012	0.280	0.490	0.731	0.135	0.865	0.755
Brain tumors versus other diagnoses
Other tumors	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Brain tumors	−0.7 (−1.2 to −0.2)	−0.5 (−1.0 to 0.03)	0.2 (−0.2 to 0.6)	−0.04 (−0.6 to 0.5)	−0.1 (−0.7 to 0.5)	−0.4 (−1.0 to 0.3)	−0.2 (−0.6 to 0.2)
p value	0.003	0.064	0.348	0.879	0.830	0.283	0.264
Chemotherapy intensity
Low intensity	Reference	Reference	Reference	Reference	Reference	Reference	Reference
High intensity	−0.1 (−0.4 to 0.2)	0.1 (−0.2 to 0.4)	0.04 (−0.2 to 0.3)	−0.2 (−0.5 to 0.1)	−0.1 (−0.5 to 0.2)	0.1 (−0.3 to 0.5)	−0.05 (−0.3 to 0.2)
p value	0.418	0.550	0.755	0.257	0.422	0.734	0.656
Radiotherapy
Not received	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Received	−0.4 (−0.6 to −0.1)	−0.4 (−0.7 to −0.1)	−0.1 (−0.3 to 0.2)	−0.2 (−0.5 to 0.2)	0.1 (−0.3 to 0.4)	−0.4 (−0.8 to −0.01)	−0.2 (−0.4 to 0.01)
p value	0.021	0.018	0.591	0.349	0.694	0.043	0.056
Surgery
Not received	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Received	−0.4 (−0.6 to −0.1)	−0.2 (−0.5 to 0.1)	0.1 (−0.2 to 0.3)	0.1 (−0.2 to 0.4)	0.2 (−0.2 to 0.5)	0.2 (−0.2 to 0.6)	−0.04 (−0.2 to 0.2)
p value	0.006	0.291	0.590	0.526	0.290	0.350	0.683
Number of late effects
0–5	Reference	Reference	Reference	Reference	Reference	Reference	Reference
≥6	−0.6 (−0.8 to −0.3)	−0.4 (−0.8 to −0.1)	−0.2 (−0.5 to 0.01)	−0.4 (−0.7 to −0.01)	−0.1 (−0.4 to 0.3)	−0.4 (−0.8 to −0.02)	−0.4 (−0.6 to −0.2)
p value	<0.001	0.009	0.062	0.043	0.750	0.038	0.001
Late effects severity
Grades 1 and 2	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Grades 3 and 4	−0.4 (−0.7 to −0.1)	−0.1 (−0.4 to 0.3)	−0.1 (−0.4 to 0.2)	−0.2 (−0.6 to 0.2)	0.03 (−0.4 to 0.4)	−0.4 (−0.9 to 0.03)	−0.2 (−0.4 to 0.1)
p value	0.020	0.731	0.540	0.239	0.898	0.068	0.188
Adolescent form (13–20 years)
Parental marital status
Married and living together	Reference	Reference	Reference	Reference	Reference	Reference	Reference
Separated or divorced	−0.2 (−0.6 to 0.1)	−0.3 (−0.6 to 0.1)	−0.2 (−0.5 to 0.1)	−0.3 (−0.7 to 0.1)	−0.5 (−1.0 to −0.1)	−0.6 (−1.1 to −0.04)	−0.3 (−0.5 to −0.1)
p value	0.111	0.170	0.226	0.159	0.023	0.035	0.009
Total siblings
0–2 siblings	Reference	Reference	Reference	Reference	Reference	Reference	Reference
≥3 siblings	−0.2 (−0.5 to 0.1)	0.2 (−0.2 to 0.5)	−0.05 (−0.4 to 0.3)	−0.2 (−0.6 to 0.2)	−0.5 (−0.9 to −0.1)	−0.3 (−0.8 to 0.1)	−0.1 (−0.3 to 0.1)
p value	0.275	0.363	0.771	0.292	0.019	0.174	0.205

β1 coefficient.

CI, confidence interval; HRQoL, health-related quality of life; MMQL, Minneapolis-Manchester Quality of Life.

Solid tumor survivors had lower physical functioning (β1 −0.3; 95% CI -0.6 to −0.1; p = 0.012; Table 6). Compared with the rest of the cohort, brain tumor survivors had significantly worse physical functioning (β1 −0.7; 95% CI −1.2 to −0.2; p = 0.003). Radiotherapy was a risk factor for poorer physical (β1 −0.4; 95% CI −0.6 to −0.1; p = 0.021) and cognitive (β1 −0.4; 95% CI −0.7 to −0.1; p = 0.018) functioning and a poorer outlook on life (β1 −0.4; 95% CI −0.8 to −0.01; p = 0.043). Surgery was associated with poorer physical functioning (β1 −0.4; 95% CI −0.6 to −0.1; p < 0.006). The presence of six or more late effects affected the most domains negatively: poorer physical functioning (β1 −0.6; 95% CI −0.8 to −0.3; p < 0.001), cognitive functioning (β1 −0.4; 95% CI −0.8 to −0.1; p = 0.009), body image (β1 −0.4; 95% CI −0.7 to −0.01; p = 0.043), outlook on life (β1 −0.4; 95% CI −0.8 to −0.02; p = 0.038), and overall HRQoL (β1 −0.4; 95% CI −0.6 to −0.2; p = 0.001). More severe late effects impacted physical functioning (β1 −0.4; 95% CI −0.7 to −0.1; p < 0.02), as expected.

Discussion

In summary, we identified subsets of AYA-aged CCSs in a South African cohort with poorer HRQoL: older survivors; those treated for solid tumors, radiotherapy, and surgery; and those with a higher number and severity of late effects. Socioeconomic status may play a role as two lower strata were significant risk factors for poorer cognitive and physical functioning. It is important to screen CCSs for HRQoL problems to provide adequate support.

Unfortunately, very few studies from LMICs were available for comparison and none from Africa. Yağci-Küpeli et al. reported low physical and school performance scores using PedsQL 4.0 for a Turkish cohort of CCSs at various times after treatment completion, mostly less than five years.⁴² Rajagopal et al. found lower HRQoL in a Malaysian cohort of short-term brain tumor survivors⁴³ using the PedsQL 3.0 Cancer module compared to cohorts in high-income countries (HICs), as did Fawzy et al. in a mixed cohort of Egyptian patients and survivors (PedsQL 3.0 Cancer module.)³⁴ Coça et al. documented an improvement in HRQoL in Brazilian survivors up to 18 years of age (PedsQL 3.0 and 4.0 Cancer modules) 1 year after treatment, although the HRQoL was still inferior to that of healthy peers.³⁵

The HRQoL for long-term survivors in LMICs may be poorer compared with survivors in HICs, but the information is lacking. Adolescents in Argentina receiving cancer treatment or within one month of treatment completion reported better HRQoL (PedsQL) than their Swedish counterparts, while younger children under 13 years reported worse HRQoL.³³ Looking at other chronic health conditions, poorer HRQoL was reported for children with cerebral palsy (CP) living in LMICs using several measures (Child Health Questionnaire Parent Form, PedQL 3.0 CP module and 4.0, CP Quality of Life Questionnaire for Children, Lifestyle Assessment Questionnaire CP) versus those residing in HICs.⁴⁴ The health life expectancy at birth, an estimate of the number of healthy life years and quality of life, for the general population in LMICs is also significantly lower compared with HICs.⁴⁵ A similar trend may thus apply to CCSs living in LMICs.

There is a need for documentation of HRQoL in long-term CCSs residing in resource-constrained settings as they may experience more financial, psychosocial, and other challenges⁴⁶ associated with poor HRQoL.⁴⁷ Many may not have had access to modern therapies that could reduce the risk of late effects, and they do not have adequate access to care, which may lead to worse HRQoL outcomes.⁴⁸ It is, therefore, imperative that health care workers identify already vulnerable CCSs in these higher-risk settings with a worse HRQoL to support them in achieving optimal life satisfaction. Nongovernment organizations in LMICs can be vital in improving access to survivorship care.⁴⁹

Our adolescent form cohort had only a slightly lower mean overall HRQoL score (3.9) than the original MMQL cohort from the United States (3.96) (p = 0.430),²⁵ as did the local adult cohort (3.7 vs. 3.73, respectively) (p = 0.809)²⁶ (Supplementary Table S4). The local adult form cohort had lower scores for all domains except the body image and outlook on life domains compared with the original adult cohort scores.²⁶ In our cohort, the physical functioning domain was the most affected, which is similar to reports from Switzerland (SF-36), Turkey, and Egypt.^11,34,42

Adult survivors in our cohort had lower scores than adolescent survivors in three domains. This correlates with other reports which indicated that older age and longer follow-up time were risk factors for reduced HRQoL.⁵⁰ The risk of chronic health conditions and their functional limitations increase significantly over time,¹ which may explain this observation. Providing basic training in coping skills might lead to improved HRQoL for some young adult survivors.⁵¹

Similar to other studies, a solid tumor diagnosis^11,33 and radiotherapy^11,52 significantly impacted HRQoL. As expected, brain tumor survivors in our study had a lower mean score for physical functioning compared to other survivors. This group of survivors needs more intensive follow-up care, multidisciplinary support, and early intervention to potentially improve their HRQoL.

Several studies have reported the relationship between lower socioeconomic status and poorer overall HRQoL, which is confirmed in this study for only two domains (physical and cognitive functioning), which is difficult to explain.^9,53–55 This finding should be investigated further in the planned larger follow-up study. Fawzy et al. noted an inverse association between family size and HRQoL, confirmed in our adolescent cohort.³⁴ Parents’ marital status (being divorced or separated) also impacted HRQoL among adolescents negatively. Larger family sizes and separated parents may be associated with fewer financial and emotional resources, leading to less support for the survivor.⁵⁶

Other reports documented a negative impact of higher intensity treatment on HRQoL.^34,50,57,58 We could not confirm this, likely due to the small sample size. Nathan et al. reported no association between treatment intensity and HRQoL (SF-36) for survivors of Wilms tumor and neuroblastoma.⁵³ They, therefore, recommended HRQoL screening for all CCSs regardless of treatment intensity. A possible explanation could be the predominance of lower-stage disease in the cohort.

We documented that the number of late effects was a significant risk factor, not the mere presence of it. Fardell et al. recently reported a similar finding, but late effects were identified by parents.⁵⁹ In contrast, in our study, late effects were more reliably determined through an in-person LTFU assessment by a physician. This is an important finding as it could assist in identifying CCSs at a higher risk of developing a poor HRQoL during LTFU for further referral and support. The severity of late effects and their correlation with HRQoL have not been studied, as well as other risk factors. Similar to our findings, a Dutch study confirmed that CCSs with a more than 20-year follow-up period with CTCAE (version 3.0) Grades 3 and 4 severe late effects displayed significantly worse physical functioning and general health perception.⁶⁰ Schulte et al. recently developed and validated a prediction model for a decline in HRQoL in CCSs and documented the association of modified CTCAE (version 4.03) Grades 2 to 4 chronic health conditions with declining HRQoL in a large cohort in the United States.⁵⁴

Risk stratification systems are currently used to guide the frequency and intensity of LTFU for CCSs.^39,61–63 This study supports the recommendation that these guidelines include screening for HRQoL. Combining the presence of psychological distress, HRQoL, the number and severity of late effects, and other identified risk factors⁵² with the current stratification systems to develop a score-based risk-stratification system may be considered. This way, LTFU risk-based care may improve to be more holistic, with timely identification of CCSs requiring additional support.⁸

Limitations

Despite limitations, this single-center study reports important information regarding HRQoL in CCSs living in a resource-constrained country. The MMQL forms have not been validated in South Africa. A similar study will be done in the future with the inclusion of a healthy cohort to obtain normative data for South Africa and to establish validity in the local context. The cohort size was relatively small due to COVID-19 pandemic restrictions. The results were not generalizable as the adolescent and adult participants and nonparticipants were not comparable. Most adult participants were not in an LTFU care program, which could have negatively impacted their health status and HRQoL. Their self-reported HRQoL may have been poorer because the study was conducted during the pandemic, when participants may have experienced more psychological distress, isolation, and challenges at work or school. Participants may have responded differently to the paper and online formats. Adolescents may have reported a better HRQoL because they thought that the results would be shared with their families. We did not evaluate ethnicity and culture, which may have influenced results. There may be a culture of reluctance to admit experiencing difficulty. This study did not include a control cohort; therefore, CCSs’ HRQoL could not be compared to that of local healthy peers.

Conclusions

Older age, solid tumor diagnosis, radiotherapy, surgery, and the number and severity of late effects negatively influenced HRQoL in this South African cohort. The adult form cohort had a nonsignificant lower score for overall HRQoL than the original United States cohort. HRQoL must be monitored in vulnerable CCSs in LMICs to support those in need. LTFU risk stratification systems should include HRQoL assessment to assist with more holistic LTFU planning and care.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Health Research Ethics Committee of the Faculty of Medicine and Health Sciences of Stellenbosch University (May 28, 2019; S18/03/062).

Footnotes

Acknowledgment

The authors thank Mrs. R Nortje who assisted with the study procedures.

Authors’ Contributions

A.V.Z. (lead), M.K. (equal), and P.C.R. (equal) contributed to the study’s conception and design. Material preparation and data collection were performed by A.V.Z., and S.N. performed the data analysis. A.V.Z. wrote the first draft of the article, and all authors commented on previous versions of the article. All authors read and approved the final article.

Author Disclosure Statement

The authors have no relevant financial or nonfinancial interests to disclose.

Disclaimer

The content of any publications from any studies during this degree is solely the responsibility of the authors and does not necessarily represent the official views of the South African Medical Research Council.

Funding Information

The degree from which this study emanated was funded by the South African Medical Research Council under the Bongani Mayosi National Health Scholars Program (Grant number 57041).

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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