Health-related quality of life of survivors of childhood acute lymphoblastic leukemia: a systematic review

Journal of Quality of Life Research

Authors: Vetsch J, Wakefield, C.E., Robertson E.G., Trahair T.N., Mateos M.K., Grootenhuis, M., Marshall G.M., Cohn R. J., Fardell J.E.

Corresponding Author:

Joanna E Fardell. Email: . Full postal address: Behavioural Sciences Unit, Kids Cancer Centre, Sydney Children’s Hospital, Level 1, High St, Randwick, NSW, AUSTRALIA, 2031. Ph: +612 9382 3114. Fax: +612 9382 1789.

Supplemental Table 1. HRQL outcomes by study

Authors/ Country / Quality scorea / Type of study / Number of participants
(males/ females) / Mean age at study,
min.max / Time since treatment
if not specified as other / Treatment / Control group / HRQL tool / Proxy or self-report / Overall HRQL, domains of HRQL
Apajasalo et al 1995 [46]
Finland / 0.95 / Cross-sectional / Total 168 (106 male, 62 female), 68 ALL / 23 years (range 16-35 years) / Median 12 years / n/a / 129 adults, aged 17-35 years, randomly selected from National population register, 69 women, 60 men / 15D / Self-report /
  • HRQL was stat. significantly better than controls probably not be clinically relevant
  • ALL survivors had better sleeping, depression, vitality, distress, elimination, and discomfort than controls
  • Leukemia survivors had better dimensions of breathing and discomfort than solid tumor survivors
  • Overall no difference between malignancies

Badr et al 2013 [30]
United States / 0.91 / Cross-sectional / 170 (88 male, 82 female), leukemia 55 / 17.7 years (SD=5.6; range=3.3-28.9) / Time since dx: 8.6 years (SD=4.0; range=1.4-16.7) / Not reported / Healthy population (n, not provided) / Pediatric Quality of Life (PedsQL 4.0) / Self-report /
  • HRQL lower in CNS tumors and lymphoma survivors compared to ALL and sarcoma
  • ALL survivors had lower overall scores compared to healthy population
  • ALL survivors had greater general and cognitive fatigue to healthy population
  • CNS tumors and lymphoma greater general fatigue and cancer worry than leukemia and sarcoma survivors.

Barr et al 1993 [54]
Canada / 0.68 / Cross-sectional / Total n=55 (sex not reported)
low risk n=25, out of them n=10 very long-term survivors (15-more than 25 years)
high risk survivors n=30 / n/a / Not reported / St. Jude Study protocol 8, L2 protocol from Memorial Sloan Kettering Cancer Centre, protocols 85-01, 87-01 from Dana Faber / No / Multi-attribute health status classification system / Physician, nurse proxy /
  • Low risk survivors, 60% had no morbidity, very little severe morbidity and no morbidity for self-care or pain
  • 20% had cognitive deficits
  • Very long-term survivors 50% had emotional and cognitive morbidity (data not shown)

Barr et al 2001 [55] Canada / 0.72 / Feasibility study / 197 (gender not reported), 95 ALL / Not reported / Not reported / Not reported / No / Health Utilities Index / Physician and parent proxy /
  • For ALL patients, unspecified major morbidity burdens were in attributes of emotion, cognition and pain.
  • ALL patients had reduced morbidity burden compared to Non-Hodgkins lymphoma.
  • Positive correlation between proxys.
  • Mean scores for HUI2 were sig lower for parents than physicians responses.

Baytan et al [31] Turkey / 0.81 / Cross-sectional / 50, 27 females, 23 males / 15.8 years (SD 1.8 years) / Not reported / BFM-9 Protocol / Age and gender matched siblings (n=50) / PedsQL / Self-report /
  • Survivors poorer overall, physical and psychosocial HRQL scores than siblings

Chiou et al 2010 [56]
Taiwan / 0.91 / Cross-sectional / 32 (17 male, 15 female) / 13.17 (SD=2.49)
/ Mean age off treatment
7.47 (SD=2.37) / Nationwide protocol depending on treatment year, TPOG ALL 93, TPOG ALL 97, and TPOG ALL 2002 / Community controls: 154 (47.4% male)
Community sample: 12.36 (SD=2.13)
Non-adult sibling controls: 30 (43.3% male)
Sibling sample: 13.45 (SD=3.18) / Child Health Questionnaire 50-item Parent Form (CHQ-PF 50) / Parent proxy /
  • Parents reported lower HRQL than that of the community control group in several subscales of HRHRQL including physical summary and psychosocial summary.
  • Survivors also had lower HRHRQL than their non-adult siblings across several subscales including physical summary and psychosocial summary

Chou et al 2009 [47] Taiwan / 0.91 / Pilot study / Total 98 (61 male, 37 female), ALL 49, 27 males, CNS 49, 34 males / 19.67 (sd=1.18; range=18-21) / Time since dx: 6.22 (1.03) / Not reported / No / Minneapolis-Manchester quality of life (MMQL) / Self-report /
  • Leukemia survivors scored higher on all quality of life scales including physical functioning and psychological functioning when compared to those who survived a brain tumour

Eiser et al 2003 [32]
UK / 0.91 / Cross-sectional / 68 mother-survivor dyads
ALL (n=45, 28 male)
CNS (n=23, 10 male) / ALL: 13.51 (3.15)
CNS: 13.74 (3.06) / ALL: 9.67 (3.36)
CNS: 7.23 (2.42) / MRC (Medical Research Council) or UKCCSG (United Kingdom Children’s Cancer Study Group) protocols / No / PedsQL / Self-report and parent proxy /
  • Survivors of ALL reported better health than CNS survivors
  • Survivors of ALL have better physical health than psychosocial health
  • Mothers reported worse proxy-HRQL than survivors, and physical health was higher than psychosocial health.
  • Moderate agreement in parent proxy reported HRQL and ALL survivors. Concordance was worse for physical health than psychosocial health.

Eiser et al 2004 [34]
UK / 0.68 / Cross-sectional / 64 (27 male, 37 female) patients
59 parents (58 mothers) 40 ALL, 24 CNS / ALL
13.45 (SD=2.91; range=9-21)
CNS tumours
14.46 (SD=2.60; range=8-19) / Not reported / Not reported / No / PedsQL / Self-report and parent proxy /
  • Survivors in ALL group reported higher HRQL than those in CNS group, for both self-report and parent proxy-report in physical, social, family and school domain
  • Parents proxy ratings correlated significantly with survivors self-ratings of HRQL.

Eiser et al 2005 [33]
UK / 0.91 / Cross-sectional / 77 (gender reported for diagnosis and tx)
, 57 ALL, ALL no GHT (n=14): (5 male, 9 female) ALL + GHT (n=6) / ALL no GHT: 13.39 (3.19)
ALL + GHT: 15.44 (3.19)
CNS no GHT: 13.90 (1.97)
CNS + GHT: 13.50 (3.56) / Time since dx:
ALL no GHT: 9.72 (3.50)
ALL + GHT: 10.93 (2.68)
CNS no GHT: 5.58 (1.49)
CNS + GHT: 7.75 (2.61) / Depending on treatment time UKALLX, UKALLXI / Norm population UK
(n, not provided) / PedsQL / Self-report and parent proxy /
  • ALL did have sig poorer overall HRQL compared to UK norm population, but not when considering physical health and psychosocial health separately.
  • ALL report higher HRQL than CNS tumour survivors.

Eiser, Greco et al 2004 [35]
UK / 0.91 / Cross-sectional / 77 (gender not reported), 49 ALL / ALL survivors: 14.14 years (SD=3.44; range=9-20)
CNS survivors: 14.33 years(SD=2.63; range=8-19) / In remission for at least 2 years (range=2-17) / Not reported / Norm population US
(n, not provided) / PedsQL; and semi-structured interview / Self-report and parent proxy /
  • ALL survivors did not differ compared with norm population
  • ALL survivors reported better HRQL than CNS survivors on all subscales (physical, emotional, social, school functioning, well-being

Essig et al 2012 [62]
Switzerland / 1 / Cross-sectional / 457 (229 male, 228 female) / n/a / n/a / Combinatinofo chemo and radio and BMT / Population norm
Taken from German Federal Health Survey (N=6964) / Short Form-36 / Self-report /
  • Compared with German population norm, survivors scores on HRQL were similar or higher, regardless of relapse status (all within 1 SD of norm)for overall HRQL and subdomains.

Fluchel et al 2008 [58]
Uruguay / 1 / Cross-sectional / 95 (47 male, 48 female), 49 ALL / 13.6 years (SD=4.26; range=7-27) / Free of disease for at least 2 years after completion of therapy / Combination of chemo, radio and surgery. / 96 (33.3% male)
Mean age=12.2 (SD=2.70; range=8-17) / Health Utilities Index / Self-report and parents, physicians, and teachers proxy /
  • ALL survivors have lower a mean HRQL utility score than control subjects
  • The mean score for survivors of ALL is higher than the score for survivors of brain tumors in overall HRQL, emotion and cognition
  • 71.4% of ALL survivors reported HRQL scores representing moderate or severe overall disability

Follin et al 2010 [48]
Sweden / 0.95 / Non-randomized (GH vs non-GH) prospective study - baseline and follow-up / 29 (17 male, 12 female) / 25 years (range=
19-31) / Not reported / protocols of the Nordic countries and of the Swedish Child Leukemia Group / Patients matched with a control subject: age, sex, residence (rural vs. non rural), and smoking habits (n=29) / Symptom checklist-90 / Self-report /
  • No sig differences in HRQL scores in GH or non GH treated groups before or after 5 and 8 years
  • No differences between ALL (GH and non-GH) vs. controls at baseline or after 5 and 8 years.

Gordijn et al 2013 [59]
Netherlands / 1 / Cross-sectional / 62 (31 male, 31 female) / 9.7 years (SD=3.2; range=5-17) / 36 months (range=22-62) / ALL-9 and ALL-10 protocols / Dutch norm
(parent reports n=353, child reports n=466) / Child Health Questionnaire (CHQ) / Self-report and parent proxy /
  • ALL had poorer physical HRQL than Dutch norm when parent proxy rated
  • ALL rated their psychosocial HRQL better compared to Dutch norm

Gunn et al 2013 [44]
Finland / 0.91 / Cross-sectional / 52 males, males only / 29 years (range 25-38) / 23 years (10-33) / Cyclophoshamide, testicular radiotherapy, central nervous system radiohterapy / Yes, age and gender matched controls without a history of cancer (n=56) / RAND-36 / Self-report /
  • ALL scored lower on physical functioning, role/emotional, emotional wellbeing, general health than controls
  • In comparison to standard population significantly worse on physical functioning and role/physical

Harila et al 2010 [43]
Finland / 1 / Cross-sectional / 74, (26 male, 48 female) / 24 years (range 17-37) / 20 years (range 10-32) / Several ALL protocols between 1972-1992, The Nordic protocols were used from 1992 / Yes, healthy young adults selected from population registry, age, gender, living area matched and Finnish population norms (n=146) / RAND-36 / Self-report /
  • ALL survivors scored statistically significantly better than the norms in all dimensions of RAND-36 except for the bodily pain subscale
  • ALL scored better than controls on the subscales of role limitations due to emotional problems, mental health and vitality, no difference between ALL and controls in general health
  • Irradiated group had higher scores (better HRQL)on the subscales of mental health, vitality compared to controls
  • No HRQL difference in irradiated non-irradiated group

Khan et al 2014 [45]
United States / 0.95 / Prospective cross-sectional / 162 (90 male, 72 female) for HRQL measure n=141 / 15.7 years (range 6.9-28.9) / 7.4 years (range 1.9-20.3) / Institutional protocols / No / SF-36 / Self-report /
  • 10% had poor HRQL on mental and physical component summary scale scores

Kunin-Batson et al 2014 [36]
United States / 1 / Prospective cross-sectional / 263 (120 female, 143 male) / 13.1 years (range 7.5-17.0) / Time since dx: 9 years (range 4.8-13.7) / COG legacy protocol 1922 and 1952 / Norm values (n=5972) / PedsQL 4.0 standard version / Self-report and parent-proxy /
  • Parent and child rating of overall HRQL rating lower than population norm data on psychosocial summary scale and school functioning subscale but not in the impaired range
  • Physical summary was similar to norm
  • Parent rating was also lower than norm for emotional functioning
  • No significant difference between parent and self-report except for the domains physical HRQL, parent rating was slightly lower than child self

Link et al 2006 [49]
Sweden / 0.86 / Cross-sectional / 44
(21 female, 23 male) / Median 24.8 years
range 19.8-31.3 / Median 16.7 years
(range 6.3-23.9) / Swedish child leukaemia group protocol until 1981, after common protocols of nordic countries / Yes, random selection of aged, gender and residence matched controls (n=44) / SCL-90, AGHDA / Self-report /
  • Survivors had same HRQL scores as control
  • Six out of 44 patients and four out of 44 controls, respectively, had an AGHDA score of 11
  • Emotional domain trend for being lower in ALL than controls

Meeske et al 2005 [50]
United States / 1 / Cross-sectional / 161, 74 male, 87 female / 18-41 years / 13.9 years (4-23 years) / n/a / United States norm
(n, not reported) / RAND SF-36 / Self-report, interview by telephone /
  • Across all domains fatigued survivor scores fell significantly below normative values
  • Non-fatigued survivors were higher than the scores of the peers in vitality, role function-emotional mental health, social functioning and mcs
  • HRQL scores were lowest for survivors who were both fatigued and depressed compared to only depressed or only fatigued

Moe et al 1997 [51]
Norway / 0.80 / Cross-sectional / 94 (52 male, 42 female) / Mean year of birth =1973 / 15-20 years post initial diagnosis / 126 IDM and 6 HDM (132=86.3%) and other (not receiving national treatment protocol=21=13.7%) / 90 controls (either siblings or first cousin)
53 males (58.9%); average year of birth is also 1973 / SF-12 / Self-report /
  • ALL survivors and controls were not sig different
  • Only the somatization score on the GHQ involving items closely related to fatigue demonstrated a significantly higher score for the ALL survivors

Nayiager et al 2016 [52]
Canada / 1 / Cross-sectional / 75 (41 males, 34 females) / 10-26 years, median 15 years / Time since diagnosis: 10-26 years (median 15 years) / DFCI protocols / Candian aged 16-37 (n=2432) and US aged 18-44 (n=4048) general population / HUI2 and HUI3 / Self-report /
  • Overall HRQL similar as Canadian and US general population
  • One survivor reported HRQl worse than death
  • Appreciable burden of morbidity for domains emotion and pain

Ramchandren et al 2009 [38]
United States / 0.86 / Cross-sectional / 37 (gender not reported) / 14.4 years (SD=2.8) / 7.4 years (SD 3.2) / n/a / Norm values
(n not reported) / PedsQL 4.0 Generic Core Scales / Self-report /
  • No impaired HRQL compared to norms

Reinfjell et al 2007 [37]
Norway / 0.86 / Cross-sectional study / 40 ALL (21 girls, 19 boys), 42 healthy controls, 36 mothers and 21 fathers / 11.8 years (range 8.5-15.4) / Time since dx: 7.9 years (range 4.2-12.5) / Nordic protocol / Healthy controls, similar age and gender distribution (n=42) / PedsQL 4.0 Generic core Scales / Parent proxy and self-report /
  • Children treated for ALL had lower scores than healthy controls overall, psychosocial and parent proxy report
  • Parent proxy also showed lower scores for emotional function subscale
  • Mother proxy was lower for social function subscale and father for school function. All showed lower scores in psychosocial health scale overall compared to physical functioning scale

Sadighi et al 2014 [41]
United States / 0.91 / Cross-sectional / 162 (65 female, 82 male) / 15.7 years (range 6.9-29.0) / 7.4 years (range 1.9-20.3) / Institutional protocols / No / SF-36 / Self-report /
  • 11/162 had impaired HRQL
  • Overall HRQL was within normal range

Shimoda et al 2008 [53]
Brazil / 0.91 / Cross-sectional / 138 (75 male, 63 female) 31 ALL / 22.8 years (13.4-40.2) / n/a / n/a / Other diagnostic groups other countries utility scores
(Central America, n=175-197)
(Uruguay, n=92-95)
(Canada, n=84) / HUI / Self-report /
  • 5.1% of survivors reported their overall health as poor or fair
  • More than one-third of the 138 consecutive survivors who participated reported some cognitive disability or pain. Approximately one-quarter reported problems with vision, speech, or emotion

van Litsenburg et al 2013 [57]
Netherlands / 0.91 / Cross-sectional / 33 / 9.3 (SD 3.3) / 1.5 years (0.5-3.9) / n/a / Reference population (1435 parent-proxy scores of children aged 4-13 years) / HUI3 / Parent proxy /
  • 61% had perfect health
  • 21 % had three or more affected attribute
  • Over 90 % of participants had no impairment on the attributes vision, ambulation, hearing, and dexterity
  • No stat. significant difference on overall HRQL score to reference population
  • ALL children had lower scores on dexterity and cognition

Wright et al 2003 [60]
United States / 1 / Cross-sectional / 62 ALL / 12.1 years (7.0-18.90 / 5.4 years (1.0-13.6) / DFCI 85-01, 87-01, 91-01, 95-01) / 71 healthy subjects, difference in height and weight to ALL / HUI2 and HUI3 / Parent proxy and self-report /
  • No difference between proxy and self-report in ALL and healthy controls
  • Lower overall HUI2/3, lower emotion, cognition, pain in ALL compared to healthy subjects

Wright et al 2005 [61]
United States / 1 / Cross-sectional / 99 (44 females, 55 males), 77 HUI, 71 of comparison group / 12.1 years (5.1-25.2) / 4.7 years (1.0-13.6) / DFCI 85-01, 87-01, 91-01, 95-01) / 71 healthy subjects / HUI2 and HUI3 / Parent proxy and self-report /
  • Lower overall and pain in HUI2/3 in ALL compared to healthy subject
  • Lower emotion, cognition in HUI3 in ALL than comparison group

Zeltzer et al [42]
United States / 1 / Cross-sectional / 7147, ALL 2090 / 32 years (18-54) / Survival time: 23 years (15-34) / n/a / Siblings (n=388) age and gender specific population norms / SF-36 / Self-report /
  • ALL survivors and siblings scored higher than norms in mental health, lower on all other aspects of HRQL (except for pain and mental component summary)
  • ALL survivors and siblings mean did not differ on mental score
  • General health subscale in ALL survivors was lower than in siblings
  • ALL survivors had poorer outcomes than controls on physical function, role physical, general health, vitality, role emotional and social function as well as physical component

aQuality score calculated by total sum divided by total possible sum; total sum=number of yes*2+number of partials*1, total possible sum=28-number of n/a*2

Abbreviations: ALL, Acute lymphoblastic leukemia; CHQ, Child health questionnaire; CHQ-PF50, Child health questionnaire parent-form 50; GH, Growth Hormone; HRQL, Health related quality of life; HUI, Health Utilities Index; PedsQL, Pediatric quality of life inventory.

Note: aReported on leukemia, which was not further specified and remains unclear if AML was included as well