Articles

Hospital contact for mental disorders in survivors of

childhood cancer and their siblings in Denmark:
a population-based cohort study
Lasse Wegener Lund, Jeanette F Winther, Susanne O Dalton, Luise Cederkvist, Pia Jeppesen, Isabelle Deltour, Marie Hargreave, Susanne K Kjr,
Allan Jensen, Catherine Rechnitzer, Klaus K Andersen, Kjeld Schmiegelow, Christoer Johansen

Summary
Background Survivors of childhood cancer are known to be at risk for long-term physical and mental eects. Lancet Oncol 2013; 14: 97180
However, little is known about how cancers can aect mental health in the siblings of these patients. We aimed to Published Online
assess the long-term risks of mental disorders in survivors of childhood cancer and their siblings. August 14, 2013
http://dx.doi.org/10.1016/
S1470-2045(13)70351-6
Methods Hospital contact for mental disorders was assessed in a population-based cohort of 7085 Danish children
Survivorship (L W Lund MD,
treated for cancer by contemporary protocols between 1975 and 2010 and in their 13 105 siblings by use of data J F Winther DMSc,
from the Danish Psychiatric Central Research Registry. Hazard ratios (HRs) for rst hospital contact were S O Dalton PhD,
calculated using a Cox proportional hazards model. We compared these sibling and survivor cohorts with two Prof C Johansen DMSc),
Statistics, Bioinformatics and
population-based cohorts who were not childhood cancer survivors or siblings of survivors.
Registry (L Cederkvist MSc(Eng),
K K Andersen PhD), and Virus,
Findings Survivors of childhood cancer were at increased risk of hospital contact for mental disorders, with HRs of Lifestyle and Genes
150 (95% CI 132169) for males and 126 (110144) for females. Children younger than 10 years at diagnosis (M Hargreave MSc,
Prof S K Kjr DMSc,
had the highest risk, and increased risks were seen in survivors of CNS tumours, haematological malignancies,
A Jensen PhD), Danish Cancer
and solid tumours. Survivors had higher risk of neurodevelopmental, emotional, and behavioural disorders than Society Research Centre,
population-based comparisons and siblings, and male survivors had higher risk for unipolar depression. Overall, Copenhagen, Denmark;
siblings had no excess risk for mental disorders. However, our data suggest that siblings who were young at the Paediatrics and Adolescent
Medicine, Juliane Marie Centre
time of cancer diagnosis of the survivor were at increased risk for mental disorders, whereas those older than
(L W Lund, C Rechnitzer DMSc,
15 years at diagnosis were at a lower risk than the general population. Prof K Schmiegelow DMSc), and
Department of Oncology,
Interpretation Childhood cancer survivors should be followed up for mental late eects, especially those diagnosed Finsencenteret
(Prof C Johansen), University
in young age. Further, clinicians should also be aware that siblings who were young at the time of cancer diagnosis Hospital Rigshospitalet,
might be at increased risk for mental health disorders. Copenhagen, Denmark;
Department of Child and
Funding Danish Childhood Cancer Foundation, Danish Agency for Science, Technology and Innovation, Danish Adolescent Psychiatry,
University Hospital Glostrup,
Cancer Society, Gangsted Rasmussen Foundation, Rosalie Petersen Foundation, University Hospital Glostrup, Denmark
Rigshospitalets Fund for Cancer Rehabilitation, and the Otto Christensen Foundation. (P Jeppesen PhD); and Section
of Environment and Radiation,
Introduction only 4% of 3083 adult siblings of survivors reported International Agency for
Research on Cancer, Lyon,
Survivors of childhood cancer are at increased risk not symptoms of distress.7 Nonetheless, siblings are often France (I Deltour PhD)
only for somatic late eects related to the cancer and its used as comparisons in studies of psychosocial late eects Correspondence to:
treatment,1 but also for depression, anxiety, and antisocial in childhood cancer survivors.8 Dr Lasse Wegener Lund, Danish
behaviour.2,3 In the only previous nationwide population- In our study, we increased both the number of patients Cancer Society Research Centre,
based cohort study of mental health problems in Danish and the duration of follow-up from our previous study4 Survivorship,
Strandboulevarden 49, DK2100
survivors of childhood cancer, in which 3710 survivors from 3710 to 7085 childhood cancer survivorsto address Copenhagen, Denmark
were included and follow-up ended in 1994, no increased how contemporary intensive treatment aects the risk of wegener@cancer.dk
risk of hospitalisation for mental disorders was seen, later hospital contact for a mental disorder. We also
except in survivors of CNS tumours.4 explored the risks for mental disorder in the rst
Siblings of patients with childhood cancer can experience nationwide population-based cohort of 13 105 siblings of
psychological stress after an event, which can be viewed as paediatric cancer survivors. We compare each of these
independent of social and genetic predisposition.5 This two cohorts with two population-based cohorts who were
stress could be for reasons such as worries about whether not childhood cancer survivors and did not have siblings
their sibling will survive, worries about their parents, and diagnosed with cancer as a child.
changes in family roles and functioning. In a cohort study
of 2645 adult survivors of childhood cancer and 500 adult Methods
siblings, 15% of siblings reported depression, exceeding Study design and participants
the 8% prevalence in survivors.6 However, this nding was We used a matched cohort design to compare survivors
countered by the results of a cross-sectional study where of childhood cancer (survivor cohort) with an

www.thelancet.com/oncology Vol 14 September 2013 971

 Articles
age-matched and sex-matched population-based
comparison group who did not have a cancer diagnosis
as a child (survivor comparisons). We also identied all
siblings in each group and compared those who had a
brother of sister who were childhood cancer survivors
(sibling cohort) with siblings in the comparison group
who did not have brothers or sisters with cancer as a
child (sibling comparisons).
From the nationwide Danish Cancer Registry,9 we
identied 7573 children diagnosed with cancer between
Jan 1, 1975, and Dec 15, 2009. Their cancers were grouped
into 12 diagnostic groups according to the International
Classication of Childhood Cancer,10 and three main
diagnostic groups were formed: haematological malig-
nancies, CNS tumours, and solid tumours.
To examine the eect of signicant scarring or
amputation, we identied a subgroup of survivors of
solid tumours primarily located in the extremities
(malignant bone tumours and soft-tissue sarcomas)
and survivors of solid tumours primarily located in the
abdomen (sympathetic nervous system, kidney, and
liver). Further, survivors of haematological cancers who
underwent haemopoietic stem-cell transplantation
were identied using a Danish patient database.
We obtained approval from the Danish Data
Protection Agency (journal number 2009-41-3408) and
the National Board of Health (journal number 7-505-29-
See Online for appendix 1248/2). Since the study is based on record linkage and
we had no direct contact with patients or siblings, no
approval from the Committee on Health Research
Ethics was needed.
Procedures
Information on death and emigration was obtained
from the Central Population Registry (established April,
1968, and which has personal identication numbers
for all citizens), which allowed for linkage of registries.11
The Family Database within the Central Population
Registry is administered by the National Board of
Health and holds information on rst-degree relatives,
with 987% of mothers and 957% of fathers identiable
for children born in Denmark after 1960.12 We restricted
the childhood cancer cohort to individuals listed in this
database (survivor cohort; n=7235) and identied their
siblings (sibling cohort; n=13 479) and parents
(n=14 367). Siblings were grouped according to the
cancer type of the survivor.
For each child treated for cancer, we identied
20 survivor comparisons (born the same day according
to the Family Database), who were free of childhood
cancer at the date of diagnosis of the survivor
(n=144 700). We identied the parents of the survivor
comparisons and thereby their siblings (n=260 400).
Members of all four cohorts and their parents were
linked to the nationwide Danish Psychiatric Central
Research Registry, which contains dates and complete
discharge diagnoses for all inpatient contacts to Danish
972
psychiatric departments since April, 1969, and all
outpatient contacts since 1995.13 Discharge diagnoses
recorded in the registry are made by the treating
physicians, most of whom are psychiatrists. The
psychiatric diagnostic framework in Denmark changed
in 1994 from the International Classication of Diseases
version 8 to version 10.14,15 Since the 1990s, fewer
hospital beds have been available and more people have
been treated as an outpatient only.13 We therefore chose
to include both inpatient and outpatient contacts during
the period 19952011. All diagnoses of mental disorders
from 1975 to 2011 were categorised into two main
groups: psychotic disorders, consisting of the
subcategories of organic psychosis, schizophrenia and
other psychoses, and bipolar depression; and non-
psychotic disorders, including other aective disorders
(mainly unipolar depression), anxiety, personality
disorder, and two groups we dened for this study:
neurodevelopmental and other non-psychotic organic
disorders and emotional and behavioural disorders.
The latter group consisted of mental and behavioural
disorders related to psychoactive substance misuse,
diagnoses of emotional and behavioural disorder
specic to childhood and adolescence (except for
attention decit hyperactivity disorder, which was
categorised in the group of neurobehavioural disorders),
and emotional and behavioural reactions and
syndromes (appendix).
Multiple diagnoses in the same person were recorded,
but only the rst contact within each main diagnostic
group (or subgroups within main groups) was counted.
If a person had had a contact for a psychotic disorder,
any subsequent non-psychotic disorder was
disregarded.
We excluded families in which two or more children
had had cancer because they presumably had
particularly high levels of psychosocial stress (17
survivors and 44 siblings). We also excluded people
with whom there was no risk time (63 children who
died on the day of cancer diagnosis and 207 siblings
who died or emigrated before the date of cancer
diagnosis of the survivor), and those who had had a
psychiatric hospital contact 5 years before the cancer
diagnosis of the survivor (70 survivors and 123 siblings),
leaving 7085 survivors (82 331 person-years of follow-
up) and 13 105 siblings (225 793 person-years of follow-
up) for analysis. Similar exclusion criteria for the
comparison cohorts resulted in 140 534 survivor
comparisons (2 508 513 person-years of follow-up) and
251 578 sibling comparisons (4 307 009 person-years of
follow-up).
Statistical analysis
We applied the Cox proportional hazards model to
estimate the hazard ratio (HR) with 95% CIs for a rst
hospital contact for mental disorders for childhood
cancer survivors and their siblings by comparing each
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Childhood cancer survivors Siblings of childhood cancer survivors

Number of At least one Crude rate* Number of At least one Crude rate*
survivors (%) hospital contact survivors (%) hospital contact
Total 7085 (100%) 494 597 13 105 (100%) 1066 470
Sex
Male 4014 (57%) 275 595 6671 (51%) 503 437
Female 3071 (43%) 219 601 6434 (49%) 563 505
Age in years at cancer diagnosis||
Born after diagnosis** 2571 (20%) 175 427
04 2198 (31%) 140 552 1854 (14%) 151 471
59 1294 (18%) 95 626 2326 (18%) 232 566
1014 1338 (19%) 104 661 2338 (18%) 205 484
1519 2255 (32%) 155 593 4016 (31%) 303 441
Calendar period of diagnosis
197579 953 (13%) 56 363 1810 (14%) 162 292
198089 1921 (27%) 148 491 3688 (28%) 370 241
199099 2072 (29%) 183 738 3874 (30%) 366 364
200009 (30%) 107 928 3733 (29%) 168 736
Type of cancer (ICCC-1 group)
Leukaemia (I) 1707 (24%) 101 558 3187 (24%) 281 504
Lymphoma (II) 904 (13%) 55 485 1672 (13%) 154 519
CNS tumours (III) 1774 (25%) 158 788 3377 (26%) 273 469
Tumours of the sympathetic nervous 317 (5%) 10 358 637 (5%) 44 371
system (IV)
Retinoblastomas (V) 136 (2%) 9 362 241 (2%) 19 444
Renal tumours (VI) 257 (4%) 25 627 501 (4%) 47 504
Hepatic tumours (VII) 66 (1%) 5 1251 136 (1%) 8 396
Malignant bone tumours (VIII) 347 (5%) 13 472 627 (5%) 47 422
Soft-tissue sarcomas (IX) 404 (6%) 21 462 745 (6%) 54 442
Germ-cell, trophoblastic, and other gonadal 503 (7%) 43 585 860 (7%) 74 488
tumours (X)
Carcinomas and other malignant epithelial 580 (8%) 44 548 954 (7%) 56 372
neoplasms (XI)
Other and unspecied malignant 90 (1%) 10 1189 168 (1%) 9 440
neoplasms (XII)
Major cancer groups
Haematological malignancies (I,II) 2611 (37%) 156 530 4859 (37%) 435 509
Patients treated with haemopoietic stem-cell 237 (3%) 16 751 452 (4%) 41 626
transplantation
CNS tumours (III) 1774 (25%) 158 788 3377 (26%) 273 469
Solid tumours (IVXI)|||| 2610 (37%) 170 526 4701 (36%) 349 430
Solid tumours in extremities (VIII+IX) 751 (11%) 34 466 1372 (11%) 101 432
Solid tumours in abdomen (IV, VI, VII) 640 (9%) 40 557 1274 (10%) 99 426

*Crude rate of hospital contact for a mental disorder per 1000 person-years at risk. Equivalent to a cumulative rate of the entire study period of 059%. Corresponding
number of hospital contacts in the population comparison group was 5749 in 1 433 264 person-years, resulting in a crude rate for hospital contact of 401 contacts per
1000 person-years and a cumulative rate of 040%. Cumulative rate 044%; number of hospital contacts in comparisons 9928 in 2 225 466 person-years; crude rate:
448 hospital contacts; cumulative rate 045%. Cumulative rate: 060%; number of hospital contacts in comparisons 5187 in 1 075 249 person-years; crude rate
483 hospital contacts; cumulative rate 048%. Cumulative rate: 051%; number of hospital contacts in comparisons 10 547 in 2 081 543 person-years; crude rate
506 hospital contacts; cumulative rate 051%. ||Attained age of sibling at diagnosis of survivor applied. **Siblings born after cancer diagnosis. Siblings older than 20 years
also included. 75% of this category were 24 years old or younger at diagnosis. Siblings grouped according to calendar period of cancer diagnosis of survivor. According to
the International Classication of Childhood Cancer, rst edition (ICCC-1).10 Siblings grouped according to type of cancer of survivor child. ||||Other and unspecied
malignant neoplasms (XII) not included.

Table 1: Characteristics of childhood cancer survivors and their siblings, and observed hospital contacts for mental disorder

cohort with a population-based cohort using the cancer type and sex, because the age-specic incidence
statistical software R, version 2.14.0.16 With age as the for conditions such as schizophrenia is dierent in
underlying time scale, we did separate analyses for males and females.

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Males Females
Number* HR (95% CI) HRadj (95% CI) Number* HR (95% CI) HRadj (95% CI)
Survivors of childhood cancer
All psychiatric disorders 275 150 (132169) 140 (124158) 219 126 (110144) 120 (105137)
All psychotic disorders 58 144 (111187) 139 (107181) 31 135 (095194) 133 (093191)
Organic psychosis 17 180 (110293) NA 10 380 (197735) NA
Schizophrenia and other psychoses 37 133 (095184) 127 (092177) 16 104 (063172) NA
Bipolar depression 7 161 (075343) NA 7 131 (062279) NA
All non-psychotic disorders 256 155 (137176) 145 (128164) 207 124 (108143) 118 (103136)
Unipolar depression 59 166 (128215) 155 (119201) 58 101 (078131) 095 (073124)
Anxiety 23 093 (061141) NA 42 115 (084156) 109 (080148)
Personality disorder 30 101 (070146) 093 (077113) 40 092 (067126) 089 (065122)
Neurodevelopmental and other non-psychotic organic disorders 97 198 (161243) 177 (144217) 46 248 (183335) 229 (169309)
Emotional and behavioural disorders 153 158 (134186) 150 (127176) 128 127 (107152) 121 (102145)
Siblings
All psychiatric disorders 503 099 (091108) 101 (092110) 563 101 (093110) 103 (094112)
All psychotic disorders 88 088 (071109) 089 (072111) 61 088 (068114) 089 (069115)
Organic psychosis 19 074 (047116) NA 9 117 (060229) NA
Schizophrenia and other psychoses 64 097 (075124) 098 (076126) 28 081 (058112) 082 (059113)
Bipolar depression 10 094 (050178) NA 15 095 (056159) NA
All non-psychotic disorders 456 098 (089108) 100 (091109) 546 102 (094112) 104 (095113)
Unipolar depression 102 110 (090134) 111 (091136) 180 101 (087118) 103 (088119)
Anxiety 57 092 (070120) 093 (073121) 105 092 (076112) 093 (077113)
Personality disorder 70 091 (072116) 092 (073117) 156 113 (097133) 115 (098135)
Neurodevelopmental and other non-psychotic organic disorders 122 083 (069099) 107 (095120) 66 097 (076124) 099 (077127)
Emotional and behavioural disorders 291 105 (094118) 091 (069119) 340 105 (094117) 106 (095118)

HR=hazard ratio. NA=not applicable (only risk estimates for disorders with more than 30 observed numbers could be meaningfully adjusted). *Multiple diagnoses in the same person were recorded, but only the
rst hospital contact within each main diagnostic group (or subgroups within main groups) was counted. If a person had had a hospital contact for a psychotic disorder, any subsequent non-psychotic disorder
was disregarded. Adjusted for calendar period (197580 as reference) and for hospital contact for mental disorder in a parent or sibling 5 years before cancer diagnosis (yes/no). Since age at cancer diagnosis was
only applicable in survivors and their siblings, it was not included in the multivariate model.

Table 2: Univariate and multivariate hazard ratio for hospital contact for any mental disorder and for main diagnostic groups and subgroups

Members of all cohorts were followed up from the
date of cancer diagnosis or inclusion of the survivor, or
date of birth for siblings who were born after cancer
diagnosis, whichever occurred last. Survivor
comparisons and sibling comparisons entered the risk
set at the date of cancer diagnosis of the survivor to
whom they were matched. Follow-up ended at the
date of rst hospital contact, emigration, death, or the
end of the study period (Oct 15, 2011), whichever
occurred rst.
To exclude people with a previous psychiatric hospital
contact and to identify those with a family history of
mental disorders, all cohort members and their parents
were checked in the psychiatric registry for entries in
the 5 years before the inclusion date. Thus, follow-up
for mental disorders started in 1975, 5 years after the
rst complete year of registration in 1970.
For survivors (and their siblings) of haematological
malignancies, CNS tumours, and solid tumours,
HRs were calculated for all categories of mental
disorders. Owing to the studys lack of power, and to
reduce multiple testing, only risk estimates for hospital
contact for any mental disorder were calculated
for patients in each of the 12 diagnostic cancer groups,
for those with solid tumours in the extremities
or abdomen, and for patients who received haemo-
poietic stem-cell transplantation, and their respective
siblings.
Multivariate analyses were adjusted for: decade of
diagnosis and inclusion of the survivor to adjust for
changes over time in diagnostic procedures, anticancer
treatment, and number of psychiatric hospital contacts;
and for hospital contact for mental disorder in a parent
or sibling up until 5 years before entry (yes or no). Only
outcomes with more than 30 events could be
meaningfully adjusted.
To compare our results with those of previous studies,
we did two subanalyses: a stratied Cox model, to give a
risk estimate for overall hospital contact in survivors for
both sexes combined; and a direct comparison between
survivors and siblings, with siblings entering the risk
set at the date of cancer diagnosis of their brother or
sister or their date of birth, whichever occurred last. To
assess whether the registration of outpatient contacts

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A
Mental disorders Males: HR (95% CI) Females: HR (95% CI)

All mental disorders 137 (111169) 120 (094154)

All psychotic disorders 153 (099237) 203 (118348)
Organic psychosis 148 (061363) 472 (165135)
Schizophrenia 147 (086251) 165 (081336)
Bipolar depression 295 (106816) 227 (071731)
All non-psychotic disorders 138 (111172) 115 (088149)
Unipolar depression 201 (136299) 087 (052146)
Anxiety 099 (049200) 134 (081222)
Personality disorders 100 (053187) 094 (053167)
Neurodevelopmental disorders 093 (059146) 145 (074282)
Emotional and behavioural disorders 158 (120207) 110 (078154)

All mental disorders 211 (171261) 143 (112183)

All psychotic disorders 175 (109281) 139 (069282)
Organic psychosis 390 (195779) 926 (341251)
Schizophrenia 114 (056231) 054 (013220)
Bipolar depression 074 (010536) 055 (008395)
All non-psychotic disorders 225 (181280) 142 (110183)
Unipolar depression 165 (094287) 101 (061166)
Anxiety 175 (122251) 061 (027138)
Personality disorders 111 (055224) 069 (034139)
Neurodevelopmental disorders 421 (311569) 628 (418943)
Emotional and behavioural disorders 1 84 (135250) 148 (107203)

All mental disorders 121 (097149) 116 (093145)

All psychotic disorders 119 (075189) 093 (048180)
Organic psychosis 081 (026254) 085 (012619)
Schizophrenia 134 (080225) 091 (040206)
Bipolar depression 126 (031518) 141 (044448)
All non-psychotic disorders 124 (099155) 117 (094146)
Unipolar depression 133 (084210) 108 (073160)
Anxiety 029 (009092) 130 (082206)
Personality disorders 099 (056177) 106 (068166)
Neurodevelopmental disorders 157 (106234) 095 (045202)
Emotional and behavioural disorders 1 41 (107185) 128 (098168)

0 1 2 3 4 5 0 1 2 3 4 5

Figure 1: First hospital contact for mental disorders in survivors of childhood cancer, with population comparisons
Survivors diagnosed with cancer in one of the three main diagnostic groups: (A) haematological cancers, (B) CNS tumours, and (C) solid tumours. HR=hazard ratio.

changed the risk estimates, we did a sensitivity analysis Results

including only inpatient contacts throughout the period
of follow-up from 1975 to 2011.
Excess absolute risks are the dierences in crude
rates of a rst hospital contact for any mental disorder
per 1000 person-years at risk between survivors or
siblings, and their respective comparisons. Excess
absolute risks are reported separately for the period
recording only inpatient contacts (19751994) and in the
period also recording outpatient contacts (19952009).17
Role of the funding source
The sponsor of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report. The corresponding author had
full access to all the data in the study and had
nal responsibility for the decision to submit for
publication.
Baseline patient characteristics are shown in table 1.
The excess absolute risk for hospital contact for mental
disorders was 092 contacts per 1000 person-years for
male survivors of childhood cancer (95% CI 030154)
and 084 for females (024146) in the period with
only inpatient contacts (19751994). The excess absolute
risk during 19952009 was 225 contacts per 1000
person-years for males (95% CI 145304) and 126 for
females (026226) including both inpatient and
outpatient contacts. This would translate into an excess
of roughly one survivor with an inpatient contact, and
one female and two male survivors having an inpatient
or outpatient contact in the last period, for every
100 survivors followed-up for 10 years. The follow-up
extended to 37 years, with a median of 882
(IQR 2411925) years for childhood cancer survivors
and 1732 (2992625) years for comparisons.

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A
Childhood cancer survivors Siblings of childhood cancer patients
4

171 (132221)
167 (130214)
166 (133208)
HR for hospital contact for any

144 (109191)

159 (130195)
3

128 (093177)

127 (097166)

131 (106161)

124 (097157)
117 (094145)

122 (101146)
111 (089138)
mental disorder

112 (093134)
100 (078128)

097 (074111)

079 (067094)
085 (071103)

083 (071097)
2

Male survivors (p=031) Female survivors (p=0043) Brothers (p=00045) Sisters (p<00001)
0
04 59 1014 1519 Born after cancer diagnosis Born before cancer diagnosis
04 59 1014 >15
Age at cancer diagnosis (years) Attained age of sibling at cancer diagnosis of survivor (years)

B
Childhood cancer survivors Siblings of childhood cancer patients
4
148 (108202)
153 (113207)
HR for hospital contact for any

155 (104190)
154 (123191)

3
135 (104175)
133 (103173)

123 (093163)

113 (089143)

123 (105145)
mental disorder

111 (096127)
109 (096125)
094 (078114)

095 (078115)
089 (073109)
083 (068102)

083 (068101)
2

Male survivors (p=084) Female survivors (p=056) Brothers (p=028) Sisters (p=00023)
0
04 59 1014 1519 04 59 1014 1519

Time since cancer diagnosis (years) Time since cancer diagnosis of survivor (years)

Figure 2: First hospital contact for overall mental disorders in survivors of childhood cancer and their siblings according to age at cancer diagnosis (A) and
time since diagnosis as a time varying variable (B), with respective population comparisons
HR=hazard ratio. Data are HR (95% CI).

With the population-based comparisons as reference, males and 141 (089224) for females (gure 3). With
we noted a HR for a rst hospital contact in male population comparisons as referents, survivors who
survivors of 150 (95% CI 132169) and of 126 had received haematopoietic stem-cell transplantation
(110144) in females (table 2). The HR for all mental were at increased risk for hospital contact (HR 151,
disorders for male survivors of CNS tumours was 211 077293 in males and 156, 073333 in females),
(171261), and for females was 143 (112183; which was similar to the total group of leukaemia
gure 1). Also, survivors of haematological malignancies survivors (152, 116198 in males and 131, 097177
(HR 137 for male and 120 for female survivors) and in females).
solid tumours (121 for male and 116 for female) were Survivors of any type of cancer were at increased risk
at an increased risk (gure 1). Children with any cancer for hospital contact for emotional and behavioural
diagnosed before 10 years of age were at the highest disorders, and most survivors also presented for
risk for hospital contact for mental disorders (gure 2); neurodevelopmental and other non-psychotic organic
a similar result was obtained for survivors of disorders (gure 1). Survivors of CNS tumours were
haematological cancers and CNS tumours (data not also at increased risk for organic psychosis, and male
shown). No dierence in risk estimates was observed survivors of any cancer for unipolar depression.
with time since diagnosis (gure 2). Adjustment for previous hospital contacts in the
For survivors of solid tumours in the extremities, the family and calendar period of the cancer treatment as a
HRs for overall mental disorder were 116 (95% CI proxy for anticancer treatment intensity did not
074181) for males and 088 (052149) for females, substantially change the risk estimates, mainly because
whereas risks for hospital contact in survivors of solid the eect on the risk was similar in survivors, siblings,
tumours in the abdomen were 152 (098236) for and their respective comparisons (table 2).

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A Cancer type Male survivors: HR (95% CI) Female survivors: HR (95% CI)

Leukaemia 152 (116198) 131 (097177)

Lymphoma 120 (085168) 105 (067165)
CNS tumour 211 (171261) 143 (112183)
Neuroblastoma 098 (041238) 097 (040236)
Retinoblastoma 106 (043260) 077 (028208)
Renal tumour 144 (078264) 194 (113333)
Hepatic tumour 652 (256166) 0
Bone tumour 143 (071288) 069 (029168)
Soft-tissue sarcoma 102 (057182) 104 (053202)
Germ -cell tumour 144 (100207) 148 (083264)
Carcinoma 070 (037131) 119 (084168)
Other 266 (106665) 196 (079487)
Solid tumour in the extremity 116 (074181) 088 (052149)
Solid tumour in the abdomen 152 (098236) 141 (089224)
Haemopoietic stem-cell transplantation 151 (077293) 156 (073333)

B Cancer type Brothers: HR (95% CI) Sisters: HR (95% CI)

Leukaemia 109 (092130) 109 (092128)

Lymphoma 107 (084137) 118 (095146)
CNS tumour 101 (084120) 101 (084120)
Neuroblastoma 073 (046117) 094 (064140)
Retinoblastoma 091 (045184) 091 (045184)
Renal tumour 127 (087186) 093 (059148)
Hepatic tumour 079 (029215) 085 (031231)
Bone tumour 082 (053125) 095 (064142)
Soft-tissue sarcoma 090 (061133) 097 (066142)
Germ-cell tumour 096 (068136) 107 (078147)
Carcinoma 071 (048105) 078 (054113)
Other 109 (048248) 060 (019189)
Solid tumour in the extremity 086 (065115) 095 (072126)
Solid tumour in the abdomen 097 (073129) 093 (070124)
Haemopoietic stem-cell transplantation 103 (063171) 125 (083188)

0 1 2 3 4 5 0 1 2 3 4 5

Figure 3: First hospital contact for any mental disorder in (A) survivors of childhood cancer and (B) their siblings according to cancer type, with population comparisons
HR=hazard ratio.

In the analyses of both sexes combined, the HR for
any hospital contact in survivors was 138 (95% CI
126151). When survivors were compared directly with
their siblings, the risk estimates slightly decreased
(131, 113151 for males and 113, 097133 for
females). In the sensitivity analysis of only inpatient
contacts, the HR was 151 (124184) for male survivors
and 136 (108172) for female survivors.
Overall, no increased risk for hospital contact was
noted for brothers (HR 099, 95% CI 091108) or
sisters (101, 093110) of survivors, or for any specic
psychiatric subtype (table 2). Separate analyses
according to cancer diagnosis of the survivor did not
change these results (gure 3).
However, age of the sibling at the time of cancer
diagnosis of the survivor modied the risk for mental
disorders. Siblings of each sex who had been young at
the time of diagnosis were at increased risk for hospital
contact (gure 2). The highest risk was that of sisters
who were not yet born at the time of cancer diagnosis,
whereas siblings aged 15 years or more at diagnosis
were at lower risk than the general population (gure 2).
Young age at diagnosis was associated with an increased
risk for hospital contact for behavioural and emotional
disorders (test for trend p<00001 for brothers and
00018 for sisters; data not shown), and in sisters for
schizophrenia (p=00034), unipolar depression
(p<00001), and anxiety (p=0011). In sisters, the risk
for hospital contact increased with longer time since
cancer diagnosis (p=00023; gure 2).
Discussion
We found a signicantly increased risk for mental
disorders that needed hospital contact in survivors of
childhood cancer. In our previous, much smaller study
of children in whom cancer was diagnosed between
1943 and 1991, only those treated for a CNS tumour
were at increased risk.4 In the study reported here,
survivors of all types of cancer were at increased risk of
hospital contact for mental disorders. Survivors were at
increased risk for neurodevelopmental and other non-
psychotic organic disorders as well as for emotional
and behavioural disorders, and male survivors were at
increased risk for unipolar depression. This rst
population-based cohort of siblings of children with
cancer showed no overall increased risk of hospital
contact for a mental disorder (panel). However, siblings
who had been very young at the time of their brother or
sisters cancer diagnosis seemed to have an increased
risk for mental disorder.

www.thelancet.com/oncology Vol 14 September 2013 977

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Panel: Research in context
Systematic review
We have previously published a systematic review of
psychosocial late eects of childhood cancer24 searching the
online databases PubMed, Embase, and PsycINFO using the
terms childhood, child, paediatric, adolescent, did not have greater use of antidepressant or anxiolytic
survivor, cancer, malignant, neoplasm, late eect, medicine.22 The CCSS also reported that survivors who
psychosocial, psychological, social, and quality of life had undergone amputation had a normal health-related
and the following MeSH terms: infant, child, quality of life,8 as did a Dutch study of 353 childhood
adolescent, neoplasm, psychology, sociology, and cancer survivors.23 Whether these dierences reect
quality of life. We excluded publications not written in
English, studies with fewer than 100 cases, and included
only papers published after 1994. To decrease selection
bias, we excluded studies with a response rate below 60%.
We updated the search in May, 2013, and added the term
sibling. In the latest systematic review of psychosocial late
eects in siblings of childhood cancer we read all references.
Most previous studies on childhood cancer survivors are
based on self-reported data and have a low participation
rate. Further, studies of childhood cancer survivors
predominantly use siblings as comparisons. Only a few
smaller studies, mainly using cross-sectional design and
based on self-reporting, have looked at mental health of
siblings of survivors.
Interpretation
Survivors of childhood cancer had increased numbers of
hospital contacts for neurodevelopmental, emotional, and
behavioural disorders, especially if young at cancer diagnosis,
and male survivors of all types of childhood cancer are at risk
for depression. We propose that childhood cancer survivors
should be followed up for mental late eects, especially those
diagnosed in young age. Overall, siblings are at no increased
risk for mental disorders. However, siblings who were young
at the time of the cancer diagnosis are at increased risk for
mental disorder, whereas those over 15 years at diagnosis are
at a lower risk than the general population.
Our results indicate that, although cancer treatment
protocols have changed considerably over the past
decades, contemporary protocols remain harmful. After
1992, almost no Danish children with acute lymphoblastic
leukaemia underwent cranial irradiation, due to
improvements in systemic and intrathecal chemotherapy
and the sequelae of irradiation.18 Nonetheless, intrathecal
chemotherapy has been associated with depression,2
corticosteroids with short-term neurological and
behavioural side eects including psychosis,19 and
methotrexate with leukoencephalopathy, memory loss,
and dementia. However, these results are based on few
cases,20 and studies in children treated by contemporary
protocols including detailed information on anticancer
therapy are needed to identify the treatments responsible.
Survivors of solid tumours who were likely to undergo
amputation or be severely scarred, such as those with
978
sarcomas in the extremities, were at lower risk for
mental disorders than survivors of other solid tumours.
This nding contrasts with that of the North American
Childhood Cancer Survivor Study (CCSS), in which
scarred or disgured survivors of childhood cancer
were at increased risk for self-reported depression21 but
national diversity in health-care structures, insurance,
or the possibilities for rehabilitation of childhood
cancer survivors is unclear.24
Previous publications from CCSS also indicated that
childhood cancer survivors were at increased self-
reported risk for depression2,3 and for antisocial
behaviour as reported by their parents.2 However,
whether the participating survivors were representative
of the total cohort and whether the full picture was
captured by self-reporting is unclear.24
Siblings of children with cancer were at no overall
increased risk for hospital contact for a mental disorder.
Furthermore, we found no increased risk among the
siblings of children with cancer forms associated with
more psychosocial problems, such as CNS tumours.
Our nding that siblings who were particularly young
at the time of cancer diagnosis were at increased risk
for hospital contact for mental disorders might be
explained not only by the psychological stress resulting
in emotional distress, but also in altered patterns of
interpersonal interaction with parents or of altered
emotional or cognitive processing style25 and is in
accordance with the eect of parental death on risk for
hospitalisation for depression.26
Children who were not yet born when cancer was
diagnosed in their sibling were at the highest risk for
mental disorders. This nding is in line with that of
CCSS, which noted an increased self-reporting of
distress in siblings not yet born at cancer diagnosis.7
Our results could be explained by changes in brain
development in accordance with studies nding high
levels of maternal stress hormones in utero to be
associated with increased risk for depression and
schizophrenia.27 In our study, siblings older than
15 years at cancer diagnosis were at lower risk for
hospital contact for a mental disorder than the
population cohort. Qualitative studies of these siblings,
however, are needed. Further, the risk for mental
disorders increased with longer time since cancer
diagnosis in sisters, indicating a long-term eect of this
stressful event.
The strengths of this nationwide population-based
cohort study using the two oldest registries in the world
for cancer9 and psychiatric hospital contact13 are that it
had negligible bias and almost complete inclusion and
follow-up. Although our registry-based data are not
www.thelancet.com/oncology Vol 14 September 2013

subject to the biases associated with participation,
response, and self-reporting,24 surveillance bias might
explain the increased risk for hospital contact for
mental disorders in childhood cancer survivors.
Nevertheless, we found no overall increased risk for
siblings, who might also be closely monitored by their
parents and the Danish health-care system (which is
free of charge) because of increased awareness and
concern.
By analysing hospital contacts we only identied
individuals with the most serious disorders, thereby
only showing a small increased risk in absolute
numbers. The total burden of mental disorders is
probably larger.
We used cancer diagnosis as a proxy for treatment,
and were not able to include detailed treatment
information. However, studies from both CCSS, with
treatment data available for children treated between
1970 and 1986, and from a Canadian population-based
study of children treated more recently,28 have only
been able to identify a few treatments (such as
intrathecal administration of chemotherapy2) as risk
factors for adverse mental late eects. Treatment
intensity23,29 and duration of therapy3 have not been
associated with psychosocial late eects.24
The validity of the registration in the Danish
Psychiatric Central Research Registry of diagnoses of
schizophrenia, single episode depression, dementia,
and autism has been shown in several studies with
good results.13 However, we acknowledge that the
diagnoses in the two diagnostic groups of mental
disorders dened for this study (neurodevelopmental
and other non-psychotic organic disorders, and
emotional and behavioural disorders) could have been
grouped in other ways, and that these particular
diagnostic groups contain conditions with dierent
age-specic incidence and proposed pathogeneses.
However, this misclassication of mental disorders
would be expected to be similar in children with cancer
and in their comparisons, limiting the chance of bias.
In conclusion, survivors of all major diagnostic
childhood cancer groups are at increased risk for
mental disorders that are severe enough to require
treatment, and although the excess risk is small, the
burden of mental late eects is probably larger than our
results indicate. These results are important for
childhood cancer survivors and their families, and we
propose that survivors should be monitored for mental
disorders in survivorship clinics. Clinicians and parents
should also be aware that siblings who are young at the
time of cancer diagnosis might be at increased risk for
mental health problems.
Contributors
LWL is the principal investigator, and contributed to the study
conception and design, the collection and assembly of data, and data
analyses and interpretation. He has written all drafts and gures. JFW,
SOD, LC, PJ, ID, MH, AJ, CR, KKA, KS, and CJ contributed to the data
www.thelancet.com/oncology Vol 14 September 2013
Articles
analyses and interpretation. SOD, ID, CR, KS, and CJ contributed to
the study conception and design. LC, ID, and SKK contributed to the
collection and assembly of data. All authors have contributed to
writing the manuscript and approved of the nal version.
Conicts of interest
We declare that we have no conicts of interest.
Acknowledgments
This study was supported by the Danish Childhood Cancer
Foundation, the Danish Agency for Science, Technology and
Innovation, the Danish Cancer Society, the Gangsted Rasmussen
Foundation, the Rosalie Petersen Foundation, the University Hospital
Rigshospitalets Fund for Cancer Rehabilitation, and the Otto
Christensen Foundation. We thank Visti Birk Larsen for impeccable
data management, and Soe Licht and Thorgerdur Gudmundsdottir
for inspiring discussions.
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