PERSPECTIVES

SCIENCE AND SOCIETY

Survivors of childhood and

adolescent cancer: life-long risks
and responsibilities
Leslie L.Robison and Melissa M.Hudson

Abstract | Survival rates for most paediatric cancers have improved at a remarkable
pace over the past four decades. In developed countries, cure is now the probable
outcome for most children and adolescents who are diagnosed with cancer: their
5year survival rate approaches 80%. However, the vast majority of these cancer
survivors will have at least one chronic health condition by 40years of age.
The burden of responsibility to understand the long-term morbidity and mortality
that is associated with currently successful treatments must be borne by many,
including the research and health care communities, survivor advocacy groups,
and governmental and policy-making entities.
Although cancer that occurs in individuals
who are 20years old represents only
1% of the annual cancer incidence in the
United States1, it is a distinct subgroup with
respect to cancer type, biological features,
response to treatment and long-term outcomes25 (FIG.1). It is estimated that in this
subgroup there are approximately 13,500
new cases per year in the United States
and the incidence has been increasing at
an average rate of 0.5% per year since 1975
(REF.1). Approximately 50% of childhood
and adolescent cancers are acute leukaemia
or cancers of the central nervous system.
Included in the remaining cases are diagnoses such as retinoblastoma, neuroblastoma,
Wilms tumour and hepatoblastoma, which
are primarily confined to the paediatric age
range and occur almost exclusively in the
first 5years of life. For paediatric cancers,
the highest age-specific incidence is
within the first year oflife.
Over the past 30years, the survival rate
in children and adolescents with cancer has
steadily improved (FIG.1) and the cancerspecific death rate has decreased by more
than 50%. Nonetheless, cancer still remains
the most common cause of disease-related
mortality in this age group. Currently, eight of

every ten children and adolescents who are

diagnosed with cancer will survive 5years
beyond their diagnosis1. The overwhelming majority of those who reach the 5year
milestone will become long-term survivors5.
The US National Cancer Institute (NCI)
Surveillance Epidemiology and End Results
(SEER) programme estimates that, as of
1January 2010, there were approximately
379,100 individuals living in the United
States who had been diagnosed with cancer
during childhood or adolescence5; this can
be compared with the estimate of 328,650
in 2005 (REF.6). Assuming constant rates
of incidence and survival post2009, the
prevalence of paediatric cancer survivors is
predicted to surpass 420,000by the end of
2013 and will approach 500,000by 2020. We
can currently estimate that approximately
one of every 750 individuals in the United
States is a survivor of childhood or adolescent cancer. This growing population reflects
a highly vulnerable group of individuals who
will probably experience adverse healthrelated and quality-of-life outcomes during
their subsequent lifetimes, as a result of their
curative cancer treatment 711. Extended surveillance of childhood and adolescent cancer
survivors has shown that they have a high

NATURE REVIEWS | CANCER

risk of early mortality from subsequent cancers (that is, cancer other than that originally
diagnosed), cardiac events and pulmonary
conditions12,13. This Science and Society article focuses on these adverse health-related
and quality-of-life issues and discusses how
these might be addressed by collaborative
research.
Risk of adverse health outcomes
To varying degrees, long-term survivors
of childhood cancer experience a range of
adverse outcomes12,1419 (FIG.2). Although
it is important to identify, quantify and
characterize exposure-specific risks, a
priority is to characterize those survivors
at the highest risk and to target them for
intervention-based strategies20. The aetiology and the associated morbidity of many
adverse outcomes that are experienced by
childhood cancer survivors may be multifactorial, involving combinations of factors
after treatment 21 (FIG.3). Factors that relate
to the primary malignancy, demographics,
pre-morbid conditions, underlying genetic
predisposition and health-related behaviours can modify the risks that are associated with treatment. Nonetheless, with the
exception of specific conditions (such as
mutations in relevant genes), it is typically
treatment-specific factors that determine the
risk of adverse late effects. Provided below
are selected examples of treatment-specific
adverse outcomes.

Radiation therapy. Radiation therapy has

been an essential form of treatment for
many childhood malignancies22,23. With
the increasing number of survivors and the
longer followup duration, knowledge
of the long-term adverse late effects that
are associated with radiation therapy has
greatly increased. There are several factors
that can influence radiation-associated
risks, including the radiation source, cumulative dose, volume and fractionation, as
well as demographic factors such as sex
and age at the time of radiation exposure24.
Organ-specific radiation exposure affects
the risk of organ-specific adverse outcomes,
typically in a dose-dependent manner 25.
Radiation-associated outcomes include
cardiovascular 2629, cerebrovascular 3032,
VOLUME 14 | JANUARY 2014 | 61

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES

Annual incidence rate per 105

3,000
2,500
2,000

300
250

100

200
150
100

Proportion surviving (%)

Incidence per 105

50
0
0

12 16 20

Age at cancer diagnosis

1,500
1,000

1%

500
0

90
2005

80

2000

1995

70

1990
19851989

60

19801984
19751979

50
0

10

20

30

40

50

60

70

80

90

Figure 1 | Age-specific cancer incidence rates and survival rates.

a | This graph highlights the small proportion of childhood and adolescent
cancer patients (only 1% of the annual cancer incidence in the United States)
in comparison to cancer rates across all age groups. b | This graph shows

endocrine3338, gastrointestinal39, reproductive15,4044, hepatic45, pulmonary 4649 and urinary tract 5052 dysfunction, musculoskeletal
growth impairment 5355, and neurocognitive, neurosensory and neurological deficits5661 (TABLE1). Cancer survivors whose
treatment included radiation therapy are at
risk of invasive and non-invasive secondary
neoplasms6276. Among childhood cancer
survivors, risks have been well-described
for cancers of the skin (predominantly
basal cell carcinoma)62,63,72,73, breast 69,77,78,
thyroid64,75,79, bone68 and brain70,80,81.
Increasingly, with extended followup from
larger paediatric cancer cohorts, data are
beginning to show radiation-associated
risks for subsequent neoplasms that involve
the colon and rectum67,71,76, the kidney 82
and the lung 83.
Chemotherapy. Specific classes of chemotherapeutic agents that are used in the
successful treatment of children and
adolescents with cancer 22,23 including
alkylating agents41,42,46,51,52,8487, anthracycline
antibiotics29,88,89, antimetabolites45,51,61,90,
corticosteroids60,90,91, epipodophyllotoxins86
and vinca alkaloids92,93 are associated
with a broad range of potential long-term
late effects (TABLE2). The risk for adverse
long-term outcomes that are associated
with chemotherapy is generally dependent on the cumulative dose, but it might
also depend on the scheduling and route
of administration, as well as the sex and
age of the patient. Beyond these factors,
there remains considerable inter-individual
variability in observed risk of therapyrelated late effects, which has been the

Age at cancer diagnosis

10

15

20

Survival from diagnosis (years)

improvements in overall survival, by year of cancer diagnosis, among cancer

patients who were diagnosed before the age ofNature
20years.
Data from the
Reviews | Cancer
Surveillance, Epidemiology, and End Results programme of the US National
Cancer Institute1.

focus of research that aims to characterize

and quantify the potential contribution of
genetic predisposition94.
Surgery. Surgical procedures that are carried out as part of the diagnosis or treatment of cancer in children and adolescents
can have long-term effects on health status
and quality of life95. Examples of long-term
effects of surgery include amputation and
limb-sparing procedures that can directly
affect physical function and mobility 18,96;
eye enucleation, which affects craniofacial
development 97; oophorectomy or orchi
ectomy, which affects reproduction41,42;
cystectomy, which affects bladder function52; nephrectomy, which subsequently
affects renal function51; splenectomy,
which affects risk of infection95; and neuro
surgical procedures that can result in
neurocognitive, neuroendocrine or motor
sensory deficits and in seizures, as well as
spinal cord injury that results in incontinence or sexual dysfunction58,98. Beyond the
functional implications of surgery, scarring
and disfigurement can also affect the quality
of life of survivors99.
Variable latency of late effects. Clinicians
who supervise the care of childhood cancer
survivors should be aware of the variable
latency that is associated with clinical manifestation of cancer treatment toxicities, as
well as patient and treatment factors that
modify risk. Some treatment effects present
soon after exposure and persist long term,
whereas others develop many years after
the completion of therapy. For example, the
sensorineural hearing loss that is associated

62 | JANUARY 2014 | VOLUME 14

with cisplatin treatment typically develops

soon after treatment (an acute toxicity)
and persists during long-term followup57.
Younger age at the time of treatment, higher
cumulative dose and combined-modality
therapy that includes ototoxic radiation,
increase the risk and severity of the hearing deficit. An appreciation of the natural
history of cisplatin-induced ototoxicity
has resulted in the proactive monitoring of
hearing during treatment and has facilitated
timely preventive and remedial interventions to optimize language development and
academic achievement among young cancer
survivors. By contrast, young women who
are treated with chest radiation for childhood cancer have an increased risk of breast
cancer with a median time to diagnosis of
1520years after the radiation; breast cancer
risk is increased as early as 8years after radiation exposure100. The dose and the volume
of breast tissue in the radiation treatment
field are important modifiers of risk, as are
other cancer treatments that may affect ovarian function. These data directly informed
the recommendations for the initiation of
breast cancer surveillance among young
women who are treated with chest radiation
for childhood cancer 100.
Evaluating evolving therapy
Paediatric cancer treatment approaches have
evolved over time in response to medical
advances in cancer biology, developmental
therapeutics, radiation technology, diagnostic imaging and supportive care.
Surprisingly, despite the many changes
that have been undertaken during the past
50years in efforts to improve the outcomes
www.nature.com/reviews/cancer

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
Growth and development
Skeletal maturation
Linear growth
Emotional and social maturation
Intellectual function
Sexual development
Psychosocial
Mental health
Education
Employment
Health insurance
Social interactions
Chronic symptoms
Physical and
body image

Childhood and
adolescent cancer

Carcinogenesis
Recurrent primary
cancer
Subsequent neoplasms

Organ function
Cardiac
Endocrine
GI and hepatic
Genitourinary
Musculoskeletal
Neurological
Pulmonary

Fertility and reproduction

Fertility
Health of ospring
Sexual functioning

Nature
Reviews
| Cancer
Figure 2 | Range of health-related and quality-of-life outcomes among
long-term
survivors
of
childhood and adolescent cancers. This figure shows some of the issues that are faced by survivors
of childhood and adolescent cancers. GI, gastrointestinal.

among children with cancer, the specific

drugs and treatment modalities that were
used in early clinical trials are still included
in contemporary treatment protocols22,23.
Initial paediatric-focused cancer therapy
trials aimed to prevent developmental
toxicities from affecting physical and intell
ectual growth and development. Subsequent
progress in cancer biology and therapeutics
has resulted in greater numbers of survivors
living into adulthood and has facilitated the
appreciation of the increased risk of organ
dysfunction and secondary carcinogenesis in
ageing survivors. These findings collectively
stimulated a reassessment of the short- and
long-term gains that are associated with the
use of intensive multimodality therapy in
young people, and this produced paradigm
shifts in the management of many paediatric
cancers. For example, cranial irradiation
was once lauded for its effectiveness in treating and preventing central nervous system
disease in children with acute lymphoblastic
leukaemia, but its use in frontline treatment
protocols is now limited101. In the case of
paediatric Hodgkins lymphoma treatment,
doses of anthracyclines, as well as the fields
and volumes of chest irradiation are proactively restricted to decrease the risk of both
cardiovascular injury and the development
of subsequent neoplasms especially breast
cancer among female survivors102.
These and similar modifications that
have been undertaken for other paediatric
malignancies have reduced the occurrence
of life-threatening complications that present during childhood and adolescence, but
their effects on ageing adults have not been

established. However, as outlined above,

contemporary therapy is still associated
with many life-altering toxicities that affect
neurocognitive, neurosensory, endocrine
and reproductive function810. Pre-emptive
screening and surveillance of at-risk treatment groups can facilitate the early detection of and timely intervention for these
common late effects. In general, the clinical
course of normal tissue injury during the
paediatric, adolescent and young adult age
range has been well-defined for many treatments. However, further research is needed
to improve our understanding of the effects
of ageing on the health of adults who are
treated for cancer during childhood (FIG.4)
Psychosocial and quality-of-life outcomes
Long-term survivors of childhood and
adolescent cancers are at risk of experiencing various psychological and social outcomes19,103105, which may result in decreased
overall quality of life. Studies of long-term
survivors have investigated the prevalence
of and risk factors associated with educational and occupational attainment 106109,
access to health insurance110,111, probability
of marriage112114, depression, anxiety
and somatic distress115117, post-traumatic
distress118,119, post-traumatic growth120,
fatigue121123 and pain124. To varying degrees,
the study of cancer- and treatment-related
factors has identified high-risk populations.
However, only limited data are available that
describe longitudinal changes, and predictors of change, for the psychosocial functioning of ageing survivors of childhood and
adolescent cancer 115,118.

NATURE REVIEWS | CANCER

Chronic health conditions, psychosocial

sequelae and chronic symptoms may ultimately reduce the quality of survival through
their effect on health and functional status711.
These outcomes can be substantially influenced by the developmental age at the time
of treatment, the presence of comorbid
conditions that precede cancer diagnosis, and
the survivors access to remedial and preventive services. For example, although younger
paediatric patients have higher risks of neuro
cognitive injury after central nervous systemdirected therapy 61, adolescent and young
adult cancer survivors have been identified
as a group that is particularly vulnerable to
adverse psychosocial outcomes11,125. To optimize health outcomes across the age range of
childhood cancer survivors, care providers
should consider the effects of both medical
and psychosocial sequelae on the general
health, mental health and function that is
appropriate for the developmental age of
the survivor, and they should help to facilitate
survivors access to remedial services.
Methodological and practical issues
A cancer survivor can be defined in various
ways, which range from when the diagnosis
is made to some post-diagnosis time point.
From a vital statistics perspective, a cancer
patient is considered to be a survivor starting at diagnosis, whereas researchers often
use a time from diagnosis definition, which
might be selected on the basis of the specific
research question that is being addressed; for
example, large cohorts, such as the Childhood
Cancer Survivor Study 126 and the British
Childhood Cancer Survivor Study 127, have
used 5years from diagnosis, others have used
3years post-diagnosis128, and some, such
as the Bone Marrow Transplant Survivor
Cohort, have applied alternative criteria
using survival of 2years from the time of
haematopoietic stem cell transplant10. The
major implication of differing definitions
directly relates to the generalizability of the
results and conclusions that are obtained from
a specific population. Thus, as the amount
of literature increases, it is important to consider how the source population was defined
when describing the status and risk profiles
for childhood cancer survivors. Beyond the
definition of a cancer survivor, there are
several research-related issues that need to
be considered when interpreting the cancer
survivorship literature, as these can all influence how results are interpreted and translated into clinical practice: the study design,
source and eligibility criteria for the study
population; the study sample size; partici
pation rates; completeness of followup;
VOLUME 14 | JANUARY 2014 | 63

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
Survivorship education or training
Survivorship experience
Practice style
Perceptions regarding preventive care
Access to survivorship resources
Knowledge or access to individual survivor health history
Age at treatment and
attained age
Sex, race or ethnicity
Familial or genetic factors
Pre- or co-morbid conditions
Health behaviours
Cognitive or developmental
status
Health knowledge
Health risk perceptions
Self-ecacy
Insurance or health care access

Provider

Patient

Cancer
treatmentassociated
morbidity
Health care
system

Cancer

Histology or
involved sites
Biology or response
Treatment
Surgery
Chemotherapy
Radiotherapy
Transplantation
Transfusion
Treatment events

Financing and payment policies

Organization and aliation of providers
Data systems and information sharing
Models of survivorship care
Insurance coverage and benets supporting survivorship care
(especially preventive and psychosocial services)
Community resources
Survivorship advocacy activity

Figure 3 | Inter-relationships. This figure shows patient-, cancer-, health care system- and providerrelated issues that affect cancer treatment-associated morbidity among the long-term survivors of
Nature Reviews | Cancer
childhood and adolescent cancer.

how treatment-related exposures were

assigned; ascertainment and characterization of outcomes; and the ability to consider
potential modifiers of risk129,130.
The implementation of research in ageing
survivor populations poses considerable
challenges for researchers who must explain
outcomes years after the discharge of patients
from paediatric cancer treatment centres.
Although challenging, crucial insights into
the occurrence of and risk factors for longterm adverse outcomes have been achieved
through clinical and epidemiological investigations, which have been carried out at various research venues. Without exception, any
observational study of long-term outcomes
of childhood cancer survivors has inherent
limitations that affect the interpretation and
the comparability of the research findings.
Nonetheless, the replication of findings
across various study populations, which
are subject to different study methodologies and designs, is indicative of a powerful scientific approach to establishing and
quantifyingrisk.
National registries and similar administrative sources can provide meaningful
information about causes of mortality after
childhood cancer, about health care use and
about medical events such as subsequent
neoplasms and pregnancy outcomes, but the
linkage of outcomes to patient-specific data,

especially the types and the doses of cancer

treatment modalities, is required to identify
groups who are at high risk for morbidity.
Several large-cohort studies have successfully
used survivor (or carer) reports of biomedical
and psychosocial outcomes to describe longterm survivor health126,127, but these studies
are limited by the potential for survivors to
misinterpret health events and the potential
bias introduced by their variable access to
health care and to screening for treatmentrelated toxicities. Ongoing cohort studies aim
to more accurately characterize the health
of long-term childhood cancer survivors
through systematic medical assessments that
are based on established cancer treatmentrelated toxicity profiles131,132. The St. Jude
Lifetime Cohort study identified a high
prevalence of undiagnosed disease among
1,713 adult (median age: 32years; age range:
1860years) survivors of childhood cancer
(median time from diagnosis: 25years; range:
1047years) who completed comprehensive
outpatient risk-based medical testing during a
23day period8. In this cohort, the estimated
cumulative prevalence of survivors who
would develop at least one chronic health
condition by 45years of age was 95.5%, and
that of survivors who would develop a serious
or disabling or life-threatening chronic condition by 45years of age was 80.5%8. From this
study, and other studies that report results

64 | JANUARY 2014 | VOLUME 14

from systematic health screening of adult

survivors of childhood cancer, it is concerning that there are high prevalences of health
conditions typically observed in much older
individuals, such as neurocognitive and
neurosensory deficits, cardiovascular disease
and pulmonary dysfunction8,133,134. These data
suggest accelerated or premature ageing as a
consequence of specific cytotoxic therapies
that are used to cure childhood cancer, and
this deserves further study. Although there
is compelling evidence for the contribution
of cancer treatment to organ dysfunction
that presents during childhood, other factors, including comorbid health problems,
health habits and natural organ senescence,
certainly modify the risk in ageing adults.
Research to identify treatment, psychosocial
and behavioural, genetic and demographic
predictors of adverse outcomes is crucial
to guide the screening and surveillance of
survivors as they age, and it is crucial for the
development of interventions to preserve
the health of survivors.
Translation of outcomes-based research
The ideal approach to childhood cancer
survivor care involves a risk-based model
that incorporates routine health care and a
personalized plan of surveillance and screening, as well as the management and prevention of late effects that are predisposed by
cancer and its treatment 95. Health outcomes
research among childhood cancer survivors
has yielded compelling data linking adverse
outcomes with specific treatment modalities,
and these data permit clinicians to identify
potentially at-risk survivors. Several groups
have used this evidence to inform clinical
practice guidelines that aim to facilitate the
early detection of cancer-treatment morbidity and the access of survivors to preventive
and remedial interventions that can preserve
health135138. A hybrid approach featuring
an evidence- and consensus-based design
has been used to develop guidelines that
are related to the long-term followup care
of childhood cancer survivors135138. This
approach has been considered reasonable
because of the strength of the evidence used
to support numerous cancer treatmentrelated adverse outcomes and because of the
crucial need for a resource for clinicians who
manage the care of medically vulnerable survivors. Because paediatric cancer survivors
are fairly rare in primary care practices, most
community providers lack knowledge about
the complications that may arise as a result
of treatment for paediatric malignancies, and
this may lead to their discomfort in supervising the care of survivors139 a problem
www.nature.com/reviews/cancer

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
that is made worse because many survivors
and their families may also lack this knowledge. Currently available clinical practice
guidelines provide information about the
potential risks of late effects that are associated with specific cancer treatment modalities, targeted health screening, suggested
methods of risk reduction and educational
resources to assist providers in coordinating
risk-based survivor care135138.
It should be noted that optimal healthscreening after treatment for childhood,
adolescent and young adult cancers has
not yet been defined. Although published
research on the risks of late effects provides
insights into who may potentially benefit
from screening and early detection after specific treatments, further research is required
to determine when to initiate screening, the
frequency of screening, the most efficacious
and cost-effective modality of screening, and
the overall risks, benefits and harms to the
health care system and the survivor. The
implementation of high-quality clinical
studies assessing the effect of screening on
the morbidity and the mortality that are
associated with specific late effects is often
precluded by the relatively small size of the
paediatric cancer survivor population (represented by heterogeneous histological subtypes and treatment approaches), the diverse
health risks that are associated with these
treatments, and the frequency and delayed
time to onset of many treatment complications. Notwithstanding these limitations, in
addition to standardizing followup care to
respond to the unique health care needs of
childhood cancer survivors, the currently
available clinical practice guidelines provide
an important platform for research to begin
to address knowledge gaps in the care of
childhood cancer survivors. In this regard,
recently published research has focused on
evaluating the benefit of specific diagnostic
studies in identifying late effects8,134,140,141.
Pertinent considerations in interpreting the
results of these studies include variability in
the age of the cancer patients at the time of
treatment, age at the time of screening, time
from cancer treatment and representativeness to source population. Collectively, these
studies show that screening identifies a substantial proportion of childhood cancer survivors who have previously unrecognized,
treatment-related health complications of
varying degrees of severity. Specifically, riskbased screening among participants in the
St. Jude Lifetime Cohort identified a high
prevalence of newly discovered neurocognitive and neurosensory deficits, heart valve
disorders and pulmonary dysfunction that

Table 1 | Selected examples of established radiation-associated late effects

Radiation
exposure

Established late effects

Refs

Cardiovascular

Cardiomyopathy
Carotid and subclavian artery disease
Coronary artery disease
Dysrhythmias and conduction disorders
Heart valve abnormalities
Pericardial fibrosis and pericarditis

2629

Central nervous
system

Neurocognitive deficits, including learning deficits and diminished

intelligence quotient, executive function, sustained attention,
memory processing speed and visualmotor integration
Cerebrovascular disease, including stroke, moyamoya and occlusive
cerebral vasculopathy
Clinical leukoencephalopathy, which causes spasticity, ataxia,
dysarthria, dysphagia, hemiparesis and seizures
Neurological and neurosensory deficits

3032,
5661

Endocrine

Pituitary dysfunction, including altered pubertal timing; growth

hormone, TSH, ACTH, LH and FSH deficiency; altered body
composition (reduced lean muscle mass, overweight and obesity);
and metabolic syndrome
Thyroid abnormalities, including hypothyroid, hyperthyroid and
thyroid nodules
Diabetes mellitus

3338

Gastrointestinal Oesophageal stricture

Chronic enterocolitis
Bowel obstruction
Gastrointestinal fistula or stricture

39

Reproductive
system
(females)

Uterine vascular insufficiency that predisposes to spontaneous

abortion, neonatal death, infants who have low birth weights, foetal
malposition and premature labour
Ovarian dysfunction that results in delayed or arrested puberty,
premature menopause and infertility

15,
4244

Reproductive
system (males)

Leydig cell dysfunction that results in delayed or arrested puberty

and androgen insufficiency
Germ cell failure, oligospermia, azoospermia and infertility

40,41

Hepatobiliary

Hepatic fibrosis
Cholelithiasis

45

Musculoskeletal Hypoplasia and fibrosis

Reduced or uneven growth (resulting in shortened trunk height,
limb length discrepancy and kyphoscoliosis)

5355

Pulmonary

Pulmonary fibrosis
Interstitial pneumonitis
Restrictive lung disease
Obstructive lung disease

4649

Urinary tract

Bladder fibrosis
Dysfunctional voiding
Vesicoureteral reflux
Hydronephrosis
Renal insufficiency
Hypertension

5052

Any organ
system

Subsequent neoplasms, including those of the skin (predominantly

basal cell carcinoma), breast, thyroid, bone and brain. Increasing
amounts of data indicate a risk of radiation-associated colorectal
cancers

6273,
75,76

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, leutinizing hormone;

TSH, thyroid-stimulating hormone.

may benefit from remedial and preventive

interventions to reduce future declines in
function8.
Until recently, national groups have
worked independently to develop clinical
practice guidelines, and this has resulted in
a variation in screening recommendations,

NATURE REVIEWS | CANCER

patient risk groups, diagnostic tests and

screening intervals135138. Recognizing the
inefficient use of resources that has resulted
from this non-integrated approach to
guideline development, the International
Late Effects of Childhood Cancer Guideline
Harmonization Group (IGHG) was formed
VOLUME 14 | JANUARY 2014 | 65

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
Table 2 | Selected examples of established chemotherapy-associated late effects
Class of
chemotherapy

Chemotherapeutic
agents

Established late effects

Alkylating agents

Busulfan, carboplatin,
carmustine,
chlorambucil, cisplatin,
cyclophosphamide,
ifosfamide, lomustine,
mechlorethamine,
melphalan,
procarbazine and
thiotepa; plus
the non-classical
alkylators dacarbazine
and temozolomide

Secondary myelodysplasia or acute

myeloid leukaemia
Gonadal dysfunction and infertility
Pulmonary fibrosis (after exposure to
busulfan, carmustine or lomustine)
Urinary tract abnormalities (after
exposure to cyclophosphamide or
ifosfamide)
Renal dysfunction (after exposure to
cisplatin, carboplatin and ifosfamide)
Ototoxicity (after exposure to cisplatin
or very high doses of carboplatin)
Dyslipidemia (after exposure to
cisplatin)

41,42,
46,51,
52,
8487

Anthracyclines

Daunorubicin,
doxorubicin,
epirubicin and
idarubicin

Left ventricular dysfunction

Cardiomyopathy
Dysrhythmias

29,88,
89

Corticosteroids

Dexamethasone and
prednisone

Reduced bone mineral density

Osteonecrosis
Cataracts

60,90,
91

Vinca alkaloids

Vincristine and
vinblastine

Peripheral sensory and motor

neuropathy

92,93

Antimetabolites

Methotrexate

Neurocognitive impairment
Leukoencephalopathy
Liver dysfunction
Renal toxicity
Decreased bone mineral density

45,51,
61,90

Epipodophyllotoxins Etoposide and

teniposide

in 2010 with the goal of establishing a common vision and an integrated strategy for
the surveillance of late effects in childhood,
adolescent and young adult cancer survivors
throughout the world142. This collaboration will provide a unique forum to address
knowledge gaps related to the care of cancer
survivors, and it will provide methods to
optimize the implementation of clinical
practice guidelines and their effect on the
quality of care given to childhood cancer
survivors.
Beyond the translation of research-based
knowledge into clinical care guidelines, it is
now important to focus greater attention on
translating knowledge from research to the
development and the testing of interventionbased approaches, which are designed to
avoid or ameliorate adverse outcomes. It is
hoped and expected that the future portfolio of intervention-based research will
encompass a wide range of approaches and
outcomes. Specific interventions may include
social, behavioural and/or pharmacological
approaches. Owing to the often multifactorial
nature of known or anticipated risk factors
for the majority of adverse outcomes (such
as cardiotoxic therapy, obesity, tobacco use
and risk for cardiac disease), interventions

Acute myeloid leukaemia

Refs

86

might be most effective when they use a

combination of approaches. Outcomes for
intervention research may relate to changes
in health behaviours such as diet, exercise
and tobacco use; health care practices such
as ongoing medical surveillance and compliance with recommended risk-based screening; prevention or amelioration of adverse
health outcomes such as cancer, congestive
heart failure, obesity, fatigue or hypertension; and promotion of positive social and
quality-of-life outcomes such as education,
employment, access to health insurance and
mentalhealth.
Future challenges
With the rapid increase in evidence regarding the health risks associated with survival
after successful treatment of paediatric or
adolescent cancer, medical and research
communities have the ongoing responsibility to critically evaluate the literature, define
the characteristics of populations at high risk
for morbidity and translate this evidence
to clinical practice guidelines for riskstratified followup care. The implementation and dissemination of outcomes and of
intervention-based research must consider
potential barriers that occur at the level of

66 | JANUARY 2014 | VOLUME 14

the survivor, the health care provider or the

health care environment, which affect
the access of survivors to quality care (FIG.3).
Survivor-related barriers. A lack of knowledge regarding cancer treatment history and
its associated long-term health risks143145 is an
important barrier to the participation of survivors in followup care. Paediatric late effects
programmes have aimed to remediate this
through longitudinal health counselling
and the provision of treatment summaries and
survivorship care plans146. The educational
process is complicated by the fact that the
transition of care typically occurs when survivors reach a developmental age at which
they may be more aware of cancer-related
health risks and personally responsible
for health behaviours. The published research
that relates to these initiatives is mostly limited to descriptive studies of clinic-based
interventions21,147,148. Few studies assess the
effect of clinic-based interventions on survivor health knowledge, health perceptions
or health behaviours, including their ongoing participation in care143,149,150. Despite the
absence of evidence to support specific bene
fits from the counselling and the resources
that are routinely provided in late effects
programmes, the consensus remains that
such interventions represent good clinical
care151. However, there is a crucial need for
future research to define effective and efficient methods of health risk counselling that
is developmentally and culturally appropriate
for the survivor population.
Provider-related barriers. Knowledge deficits among health care providers regarding
health issues that affect paediatric cancer
survivors can also pose barriers to the delivery of good survivorship care. Surprisingly,
a lack of familiarity with the recommended
screening for paediatric cancer treatment
toxicities is not limited to primary care
providers. In a study that evaluated preferences and knowledge gaps among paediatric
oncologists regarding the care of childhood
cancer survivors, only 33% of respondents
correctly answered vignette-based questions
about the surveillance recommendations
for breast cancer, cardiomyopathy and thyroid function152. These providers expressed
increasing discomfort in managing the care of
paediatric survivors who were 21years
of age, but a significant proportion (38%)
preferred to observe their survivors for
as long as possible. In a related study that
evaluated the same outcomes among family
physicians, only 2% of respondents correctly
answered the same vignette-based questions
www.nature.com/reviews/cancer

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
regarding surveillance139. The vast majority
(85%) of these family physicians preferred
to care for survivors in consultation with
clinicians from a cancer treatment centre or
a late effects programme. Access to clinical
care guidelines and the receipt of a patientspecific letter detailing surveillance recommendations were perceived by the physicians
to be the modalities that were most likely to
assist them in survivorship care. These
interventions were successfully implemented
in a model of shared care between Dutch
paediatric oncologists and family doctors153.
These studies highlight the need to increase
the amount of education and training
programmes related to survivorship care
for health professionals, improve the dissemination of clinical practice guidelines for
treating survivors of childhood cancer, and
evaluate methods to increase communication and collaboration among the oncology and primary care providers who share
survivorshipcare.
Barriers related to the health care environment. Potential barriers to good care of cancer survivors that are imposed by the health
care environment relate to the availability
of providers and survivorship resources,
specialized late effects clinics and operational models of survivorship care, which are
greatly influenced by provider and payer relationships and by health care policies. In the
United States, care given to cancer survivors
is generally a non-revenue-generating service
for providers because of limited or absent
reimbursement for substantial components
of the care154. This reality represents a considerable threat to the access of survivors

to specialized late effects clinics that have

multidisciplinary staff with expertise in late
effects, health screening and surveillance.
These programmes also focus on educating
survivors, on promoting the access of survivors to resources that remediate or prevent
treatment-related toxicities, and on facilitating communication and care transitions
with community providers. The care of
most paediatric cancer survivors is eventually passed to community providers because
specialized paediatric late effects programmes are not universally available, and
when they are available they usually have
institutional age limitations that preclude
followup beyond adolescence155. This transition of care can be complicated by suboptimal communication among members
of the treating oncology team and primary
care providers who lack awareness about
the unique health risks associated with the
treatment of cancer during childhood and
with screening and surveillance recommendations. Various models of survivorship
care have been implemented to facilitate care
transitions and to ensure that the health
care needs of childhood cancer survivors
are optimally addressed156. Among these, a
shared-care model that uses a risk-stratified
approach based on treatment intensity, or
risk for late effects, has been favoured by
late effects specialists because this model
promotes ongoing communication across
the range of cancer care and takes advantage
of the expertise of the oncology team and
the primary care provider during delivery
of care156. Research is required to delineate
the essential elements of survivorship care
and flexible models of care delivery that can

1.00

Cancer survivor
General population

Cumulative incidence

0.75

Excess lifetime
morbidity associated
with cancer and therapy

0.50

Advanced onset of
morbidity associated
with cancer and therapy

0.25

?
0.00
0

10

20

Known
late eects

30

40

50

Age (years)

Emerging
late eects

60

70

Unknown
late eects

Figure 4 | A theoretical framework. This figure shows the gaps in knowledge regarding the long-term
outcomes among ageing childhood and adolescent cancer survivors.
Nature Reviews | Cancer
NATURE REVIEWS | CANCER

increase the access of survivors to interventions that proactively address cancer-related

morbidity.
Insurance and policy barriers. In countries
such as the United States, where governmentbased health care is not provided, lack of
health insurance or health policy exclusions
and restrictions represent a considerable barrier to the care of cancer survivors, which
may disproportionately affect individuals
who have a racial or ethnic minority status or
a low socioeconomic status. National health
legislation such as the US Patient Protection
and Affordability Act provides many policy
changes to ensure that paediatric cancer
survivors have access to appropriate health
care services157. This legislation provides
mechanisms to increase the level of access to
components of survivorship care, but additional measures will be required to achieve
the goal of high quality, comprehensive and
coordinated survivorship care. To realize this
goal, health care policy change is needed to
define the essential metrics of quality care
that should be accessible to all survivors, and
it is needed to improve provider reimbursement for comprehensive-care coordination
that includes assessment for medical and
psychosocial sequelae, delivery of interventions to remediate or prevent treatment complications, counselling regarding methods of
risk reduction, and referral to resources that
help to address medical, psychosocial and
practicalneeds.
Conclusions
Although the many individuals who have had
a role in achieving the remarkable increase
in the survival rates of childhood and adolescent cancers should be gratified, with success
also comes responsibility. Simply focusing on
the cure of the cancer cannot be an acceptable objective when considering the life-long
risk of developing treatment-related complications that survivors experience. Because of
the young age of these cancer survivors, and
thus their potential longevity, the delayed
consequences of therapy will probably have a
greater effect on their lives, their families and
on society atlarge, than the acute complication of the cytotoxic and surgical therapies
that they have already experienced. Thus,
there is a role not only for researchers and
health care providers but also for survivors
and their families, governing bodies and
advocacy groups in helping to understand
and overcome the barriers that prevent survivors from receiving optimal care to minimize adverse health-related outcomes and to
maximize quality-of-life outcomes.
VOLUME 14 | JANUARY 2014 | 67

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
Leslie L.Robison and Melissa M.Hudson are at the
Department of Epidemiology and Cancer Control,
St. Jude Childrens Research Hospital,
262 Danny Thomas Place, Memphis,
Tennessee 38105, USA.
Melissa M.Hudson is also at the Department of
Oncology, St. Jude Childrens Research Hospital,
262 Danny Thomas Place, Memphis,
Tennessee 38105, USA.
Correspondence to L.L.R.
e-mail: les.robison@stjude.org
doi:10.1038/nrc3634
Published online 5 December 2013
1. Howlader,N. etal. (eds) SEER Cancer Statistics Review,
19752010. National Cancer Institute. Bethesda, MD
[online] http://seer.cancer.gov/csr/1975_2010/
(2013).
2. Gajjar,A. etal. Childrens Oncology Groups 2013
blueprint for research: central nervous system
tumors. Pediatr. Blood Cancer 60, 10221026
(2013).
3. Norris,R.E. & Adamson,P.C. Challenges and
opportunities in childhood cancer drug development.
Nature Rev. Cancer 12, 776782 (2012).
4. Pui,C.H., Carroll,W.L., Meshinchi,S. & Arceci,R.J.
Biology, risk stratification, and therapy of pediatric
acute leukemias: an update. J.Clin. Oncol. 29,
551565 (2011).
5. Smith,M.A. etal. Outcomes for children and
adolescents with cancer: challenges for the twentyfirst century. J.Clin. Oncol. 28, 26252634
(2010).
6. Mariotto,A.B. etal. Long-term survivors of childhood
cancers in the United States. Cancer Epidemiol.
Biomarkers Prev. 18, 10331040 (2009).
7. Hudson,M.M. etal. Health status of adult long-term
survivors of childhood cancer: a report from the
Childhood Cancer Survivor Study. JAMA 290,
15831592 (2003).
8. Hudson,M.M. etal. Clinical ascertainment of health
outcomes among adults treated for childhood cancer.
JAMA 309, 23712381 (2013).
9. Oeffinger,K.C. etal. Chronic health conditions in
adult survivors of childhood cancer. N.Engl. J.Med.
355, 15721582 (2006).
10. Sun,C.L. etal. Prevalence and predictors of chronic
health conditions after hematopoietic cell
transplantation: a report from the Bone Marrow
Transplant Survivor Study. Blood 116, 31293139,
(2010).
11. Tai,E. etal. Health status of adolescent and young
adult cancer survivors. Cancer 118, 48844891
(2012).
12. Armstrong,G.T., Pan,Z., Ness,K.K.,Srivastava,D. &
Robison,L.L. Temporal trends in cause-specific late
mortality among 5year survivors of childhood cancer.
J.Clin. Oncol. 28, 12241231 (2010).
13. Mertens,A.C. etal. Cause-specific late mortality
among 5year survivors of childhood cancer: the
Childhood Cancer Survivor Study. J.Natl Cancer Inst.
100, 13681379 (2008).
14. Diller,L. etal. Chronic disease in the Childhood Cancer
Survivor Study cohort: a review of published findings.
J.Clin. Oncol. 27, 23392355 (2009).
15. Green,D.M. etal. Fertility of female survivors of
childhood cancer: a report from the childhood cancer
survivor study. J.Clin. Oncol. 27, 26772685
(2009).
16. Gurney,J.G. etal. Social outcomes in the Childhood
Cancer Survivor Study cohort. J.Clin. Oncol. 27,
23902395 (2009).
17. Meadows,A.T. etal. Second neoplasms in survivors of
childhood cancer: findings from the Childhood Cancer
Survivor Study cohort. J.Clin. Oncol. 27, 23562362
(2009).
18. Ness,K.K. etal. Physical performance limitations in
the Childhood Cancer Survivor Study cohort. J.Clin.
Oncol. 27, 23822389 (2009).
19. Zeltzer,L.K. etal. Psychological status in childhood
cancer survivors: a report from the Childhood Cancer
Survivor Study. J.Clin. Oncol. 27, 23962404 (2009).
20. Hudson,M.M. etal. High-risk populations identified
in Childhood Cancer Survivor Study investigations:
implications for risk-based surveillance. J.Clin. Oncol.
27, 24052414 (2009).

21. Hudson,M.M. A model for care across the cancer

continuum. Cancer 104, 26382642 (2005).
22. Green,D.M. etal. Relevance of historical therapeutic
approaches to the contemporary treatment of
pediatric solid tumors. Pediatr. Blood Cancer 60,
10831094 (2013).
23. Hudson,M.M. etal. Lessons from the past:
opportunities to improve childhood cancer survivor
care through outcomes investigations of historical
therapeutic approaches for pediatric hematological
malignancies. Pediatr. Blood Cancer 58, 334343
(2012).
24. Armstrong,G.T., Stovall,M. & Robison,L.L. Longterm effects of radiation exposure among adult
survivors of childhood cancer: results from the
childhood cancer survivor study. Radiat. Res. 174,
840850 (2010).
25. van Dijk,I.W. etal. Dose-effect relationships for
adverse events after cranial radiation therapy in longterm childhood cancer survivors. Int. J.Radiat. Oncol.
Biol. Phys. 85, 768775 (2013).
26. Galper,S.L. etal. Clinically significant cardiac disease
in patients with Hodgkin lymphoma treated with
mediastinal irradiation. Blood 117, 412418 (2011).
27. Schellong,G. etal. Late valvular and other cardiac
diseases after different doses of mediastinal
radiotherapy for Hodgkin disease in children and
adolescents: report from the longitudinal GPOH
followup project of the German-Austrian DALHD
studies. Pediatr. Blood Cancer 55, 11451152 (2010).
28. Tukenova,M. etal. Role of cancer treatment in longterm overall and cardiovascular mortality after
childhood cancer. J.Clin. Oncol. 28, 13081315
(2010).
29. van der Pal,H.J. etal. High risk of symptomatic
cardiac events in childhood cancer survivors.
J.Clin. Oncol. 30, 14291437 (2012).
30. Bowers,D.C. etal. Late-occurring stroke among longterm survivors of childhood leukemia and brain
tumors: a report from the Childhood Cancer Survivor
Study. J.Clin. Oncol. 24, 52775282 (2006).
31. Bowers,D.C. etal. Stroke as a late treatment effect of
Hodgkins Disease: a report from the Childhood Cancer
Survivor Study. J.Clin. Oncol. 23, 65086515 (2005).
32. Morris,B. etal. Cerebrovascular disease in childhood
cancer survivors: A Childrens Oncology Group Report.
Neurology 73, 19061913 (2009).
33. Chemaitilly,W. & Sklar,C.A. Endocrine complications
in long-term survivors of childhood cancers. Endocr.
Relat. Cancer 17, R141R159 (2010).
34. de Vathaire,F. etal. Radiation dose to the pancreas
and risk of diabetes mellitus in childhood cancer
survivors: a retrospective cohort study. Lancet Oncol.
13, 10021010 (2012).
35. Laughton,S.J. etal. Endocrine outcomes for children
with embryonal brain tumors after risk-adapted
craniospinal and conformal primary-site irradiation and
high-dose chemotherapy with stem-cell rescue on the
SJMB96 trial. J.Clin. Oncol. 26, 11121118 (2008).
36. Meacham,L.R. etal. Diabetes mellitus in long-term
survivors of childhood cancer. Increased risk
associated with radiation therapy: a report for the
childhood cancer survivor study. Arch. Intern. Med.
169, 13811388 (2009).
37. Merchant,T.E. etal. Growth hormone secretion after
conformal radiation therapy in pediatric patients with
localized brain tumors. J.Clin. Oncol. 29, 47764780
(2011).
38. Patterson,B.C., Truxillo,L., Wasilewski-Masker,K.,
Mertens,A.C. & Meacham,L.R. Adrenal function
testing in pediatric cancer survivors. Pediatr. Blood
Cancer 53, 13021307 (2009).
39. Goldsby,R. etal. Survivors of childhood cancer have
increased risk of gastrointestinal complications later in
life. Gastroenterology 140, 14641471, e1 (2011).
40. Green,D.M. etal. Fertility of male survivors of
childhood cancer: a report from the Childhood Cancer
Survivor Study. J.Clin. Oncol. 28, 332339 (2010).
41. Kenney,L.B. etal. Male reproductive health after
childhood, adolescent, and young adult cancers: a
report from the Childrens Oncology Group. J.Clin.
Oncol. 30, 34083416 (2012).
42. Metzger,M.L. etal. Female reproductive health after
childhood, adolescent, and young adult cancers:
guidelines for the assessment and management of
female reproductive complications. J.Clin. Oncol. 31,
12391247 (2013).
43. Signorello,L.B. etal. Female survivors of childhood
cancer: preterm birth and low birth weight among
their children. J.Natl Cancer Inst. 98, 14531461
(2006).

68 | JANUARY 2014 | VOLUME 14

44. Signorello,L.B. etal. Stillbirth and neonatal death in

relation to radiation exposure before conception: a
retrospective cohort study. Lancet 376, 624630
(2010).
45. Castellino,S. etal. Hepato-biliary late effects in
survivors of childhood and adolescent cancer: a report
from the Childrens Oncology Group. Pediatr. Blood
Cancer 54, 663669 (2010).
46. Huang,T.T. etal. Pulmonary outcomes in survivors of
childhood cancer: a systematic review. Chest 140,
881901 (2011).
47. Mertens,A.C. etal. Pulmonary complications in
survivors of childhood and adolescent cancer. A report
from the Childhood Cancer Survivor Study. Cancer 95,
24312441 (2002).
48. Motosue,M.S. etal. Pulmonary function after whole
lung irradiation in pediatric patients with solid
malignancies. Cancer 118, 14501456 (2012).
49. Mulder,R.L. etal. Pulmonary function impairment
measured by pulmonary function tests in long-term
survivors of childhood cancer. Thorax 66, 10651071
(2011).
50. Dawson,L.A. etal. Radiation-associated kidney injury.
Int. J.Radiat. Oncol. Biol. Phys. 76, S108S115
(2010).
51. Jones,D.P., Spunt,S.L., Green,D. &
Springate,J.E. Renal late effects in patients treated
for cancer in childhood: a report from the Childrens
Oncology Group. Pediatr. Blood Cancer 51,
724731 (2008).
52. Ritchey,M., Ferrer,F., Shearer,P. & Spunt,S.L. Late
effects on the urinary bladder in patients treated for
cancer in childhood: a report from the Childrens
Oncology Group. Pediatr. Blood Cancer 52, 439446
(2009).
53. Estilo,C.L. etal. Effects of therapy on dentofacial
development in long-term survivors of head and neck
rhabdomyosarcoma: the memorial sloan-kettering
cancer center experience. J.Pediatr. Hematol. Oncol.
25, 215222 (2003).
54. Merchant,T.E. etal. Differential attenuation of
clavicle growth after asymmetric mantle radiotherapy.
Int. J.Radiat. Oncol. Biol. Phys. 59, 556561 (2004).
55. Paulino,A.C. Late effects of radiotherapy for pediatric
extremity sarcomas. Int. J.Radiat. Oncol. Biol. Phys.
60, 265274 (2004).
56. Goldsby,R.E. etal. Late-occurring neurologic
sequelae in adult survivors of childhood acute
lymphoblastic leukemia: a report from the Childhood
Cancer Survivor Study. J.Clin. Oncol. 28, 324331
(2010).
57. Grewal,S. etal. Auditory late effects of childhood
cancer therapy: a report from the Childrens Oncology
Group. Pediatrics 125, e938e950 (2010).
58. Packer,R.J. etal. Long-term neurologic and
neurosensory sequelae in adult survivors of a
childhood brain tumor: childhood cancer survivor
study. J.Clin. Oncol. 21, 32553261 (2003).
59. Whelan,K. etal. Auditory complications in childhood
cancer survivors: a report from the childhood cancer
survivor study. Pediatr. Blood Cancer 57, 126134
(2011).
60. Whelan,K.F. etal. Ocular late effects in childhood and
adolescent cancer survivors: a report from the
childhood cancer survivor study. Pediatr. Blood Cancer
54, 103109 (2010).
61. Winick,N. Neurocognitive outcome in survivors of
pediatric cancer. Curr. Opin. Pediatr. 23, 2733
(2011).
62. Armstrong,G.T. etal. Occurrence of multiple
subsequent neoplasms in long-term survivors of
childhood cancer: a report from the childhood cancer
survivor study. J.Clin. Oncol. 29, 30563064
(2011).
63. Bassal,M. etal. Risk of selected subsequent
carcinomas in survivors of childhood cancer: a report
from the Childhood Cancer Survivor Study. J.Clin.
Oncol. 24, 476483 (2006).
64. Bhatti,P. etal. Risk of second primary thyroid
cancer after radiotherapy for a childhood cancer in a
large cohort study: an update from the childhood
cancer survivor study. Radiat. Res. 174, 741752
(2010).
65. Boukheris,H. etal. Risk of salivary gland cancer after
childhood cancer: a report from the Childhood Cancer
Survivor Study. Int. J.Radiat. Oncol. Biol. Phys. 85,
776783 (2013).
66. Friedman,D.L. etal. Subsequent neoplasms in 5year
survivors of childhood cancer: the Childhood Cancer
Survivor Study. J.Natl Cancer Inst. 102, 10831095
(2010).

www.nature.com/reviews/cancer
2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
67. Henderson,T.O. etal. Secondary gastrointestinal
cancer in childhood cancer survivors: a cohort study.
Ann. Intern. Med. 156, 757766 (2012).
68. Henderson,T.O. etal. Risk factors associated with
secondary sarcomas in childhood cancer survivors: a
report from the childhood cancer survivor study. Int.
J.Radiat. Oncol. Biol. Phys. 84, 224230 (2012).
69. Inskip,P.D. etal. Radiation dose and breast cancer
risk in the childhood cancer survivor study. J.Clin.
Oncol. 27, 39013907 (2009).
70. Neglia,J.P. etal. New primary neoplasms of the
central nervous system in survivors of childhood
cancer: a report from the Childhood Cancer Survivor
Study. J.Natl Cancer Inst. 98, 15281537 (2006).
71. Nottage,K. etal. Secondary colorectal carcinoma after
childhood cancer. J.Clin. Oncol. 30, 25522558
(2012).
72. Pappo,A.S. etal. Melanoma as a subsequent
neoplasm in adult survivors of childhood cancer: a
report from the childhood cancer survivor study.
Pediatr. Blood Cancer 60, 461466 (2013).
73. Perkins,J.L. etal. Nonmelanoma skin cancer in
survivors of childhood and adolescent cancer: a report
from the childhood cancer survivor study. J.Clin.
Oncol. 23, 37333741 (2005).
74. Reulen,R.C. etal. Long-term risks of subsequent
primary neoplasms among survivors of childhood
cancer. JAMA 305, 23112319 (2011).
75. Ronckers,C.M. etal. Thyroid cancer in childhood
cancer survivors: a detailed evaluation of radiation
dose response and its modifiers. Radiat. Res. 166,
618628 (2006).
76. Tukenova,M. etal. Second malignant neoplasms in
digestive organs after childhood cancer: a cohortnested case-control study. Int. J.Radiat. Oncol. Biol.
Phys. 82, e383e390 (2012).
77. De Bruin,M.L. etal. Breast cancer risk in female
survivors of Hodgkins lymphoma: lower risk after
smaller radiation volumes. J.Clin. Oncol. 27,
42394246 (2009).
78. Swerdlow,A.J. etal. Breast cancer risk after
supradiaphragmatic radiotherapy for Hodgkins
lymphoma in England and Wales: a National Cohort
Study. J.Clin. Oncol. 30, 27452752 (2012).
79. Sigurdson,A.J. etal. Primary thyroid cancer after a
first tumour in childhood (the Childhood Cancer
Survivor Study): a nested case-control study. Lancet
365, 20142023 (2005).
80. Bowers,D.C. etal. Subsequent neoplasms of the CNS
among survivors of childhood cancer: a systematic
review. Lancet Oncol. 14, e321e328 (2013).
81. Taylor,A.J. etal. Population-based risks of CNS
tumors in survivors of childhood cancer: the British
Childhood Cancer Survivor Study. J.Clin. Oncol. 28,
52875293 (2010).
82. Wilson,C.L. etal. Renal carcinoma after childhood
cancer: a report from the childhood cancer survivor
study. J.Natl Cancer Inst. 105, 504508 (2013).
83. Ibrahim,E.M. etal. Increased risk of second lung
cancer in Hodgkins lymphoma survivors: a metaanalysis. Lung 191, 117134 (2013).
84. Brock,P.R. etal. Platinum-induced ototoxicity in
children: a consensus review on mechanisms,
predisposition, and protection, including a new
International Society of Pediatric Oncology Boston
ototoxicity scale. J.Clin. Oncol. 30, 24082417
(2012).
85. Feldman,D.R., Schaffer,W.L. & Steingart,R.M. Late
cardiovascular toxicity following chemotherapy for
germ cell tumors. J.Natl Compr. Canc. Netw. 10,
537544 (2012).
86. Hijiya,N., Ness,K.K., Ribeiro,R.C. & Hudson,M.M.
Acute leukemia as a secondary malignancy in children
and adolescents: current findings and issues. Cancer
115, 2335 (2009).
87. Skinner,R. Nephrotoxicity what do we know and
what dont we know? J.Pediatr. Hematol. Oncol. 33,
128134 (2011).
88. Lipshultz,S.E. etal. Chronic progressive cardiac
dysfunction years after doxorubicin therapy for
childhood acute lymphoblastic leukemia. J.Clin.
Oncol. 23, 26292636 (2005).
89. Mulrooney,D.A. etal. Cardiac outcomes in a cohort
of adult survivors of childhood and adolescent
cancer: retrospective analysis of the Childhood
Cancer Survivor Study cohort. BMJ 339, b4606
(2009).
90. Wasilewski-Masker,K. etal. Bone mineral density
deficits in survivors of childhood cancer: long-term
followup guidelines and review of the literature.
Pediatrics 121, e705e713 (2008).

91. Kadan-Lottick,N.S. etal. Osteonecrosis in adult

survivors of childhood cancer: a report from the
childhood cancer survivor study. J.Clin. Oncol. 26,
30383045 (2008).
92. Jain,P. etal. Vincristine-induced neuropathy in
childhood ALL (acute lymphoblastic leukemia)
survivors: prevalence and electrophysiological
characteristics. J.Child Neurol. http://dx.doi.
org/10.1177/0883073813491829 (2013).
93. Ness,K.K. etal. Chemotherapy-related neuropathic
symptoms and functional impairment in adult
survivors of extracranial solid tumors of childhood:
results from the st. Jude lifetime cohort study. Arch.
Phys. Med. Rehabil. 94, 14511457 (2013).
94. Bhatia,S. Role of genetic susceptibility in
development of treatment-related adverse outcomes
in cancer survivors. Cancer Epidemiol. Biomarkers
Prev. 20, 20482067 (2011).
95. Oeffinger,K.C. & Hudson,M.M. Long-term
complications following childhood and adolescent
cancer: foundations for providing risk-based health care
for survivors. CA Cancer J.Clin. 54, 208236 (2004).
96. Barr,R.D. & Wunder,J.S. Bone and soft tissue
sarcomas are often curable but at what cost?: a call
to arms (and legs). Cancer 115, 40464054 (2009).
97. Lin,H.Y. & Liao,S.L. Orbital development in
survivors of retinoblastoma treated by enucleation
with hydroxyapatite implant. Br. J.Ophthalmol. 95,
630633 (2011).
98. Turner,C.D. etal. Medical, psychological, cognitive
and educational late-effects in pediatric low-grade
glioma survivors treated with surgery only. Pediatr.
Blood Cancer 53, 417423 (2009).
99. Kinahan,K.E. etal. Scarring, disfigurement, and
quality of life in long-term survivors of childhood
cancer: a report from the Childhood Cancer Survivor
study. J.Clin. Oncol. 30, 24662474 (2012).
100. Henderson,T.O. etal. Systematic review: surveillance
for breast cancer in women treated with chest
radiation for childhood, adolescent, or young adult
cancer. Ann. Intern. Med. 152, 444455 (2010).
101. Pui,C.H. Prophylactic cranial irradiation: going,
going, gone. Lancet Oncol. 10, 932933 (2009).
102. Hodgson,D.C., Hudson,M.M. & Constine,L.S.
Pediatric hodgkin lymphoma: maximizing efficacy and
minimizing toxicity. Semin. Radiat. Oncol. 17,
230242 (2007).
103. Lund,L.W., Schmiegelow,K., Rechnitzer,C. &
Johansen,C. A systematic review of studies on
psychosocial late effects of childhood cancer:
structures of society and methodological pitfalls may
challenge the conclusions. Pediatr. Blood Cancer 56,
532543 (2011).
104. Nathan,P.C. etal. Guidelines for identification of,
advocacy for, and intervention in neurocognitive
problems in survivors of childhood cancer: a report
from the Childrens Oncology Group. Arch. Pediatr.
Adolesc. Med. 161, 798806 (2007).
105. Wakefield,C.E. etal. The psychosocial impact of
completing childhood cancer treatment: a systematic
review of the literature. J.Pediatr. Psychol. 35,
262274 (2010).
106. Kirchhoff,A.C. etal. Occupational outcomes of adult
childhood cancer survivors: a report from the
childhood cancer survivor study. Cancer 117,
30333044 (2011).
107. Kuehni,C.E. etal. Educational achievement in Swiss
childhood cancer survivors compared with the general
population. Cancer 118, 14391449 (2012).
108. Lancashire,E.R. etal. Educational attainment among
adult survivors of childhood cancer in Great Britain: a
population-based cohort study. J.Natl Cancer Inst.
102, 254270 (2010).
109. Mitby,P.A. etal. Utilization of special education
services and educational attainment among long-term
survivors of childhood cancer: a report from the
Childhood Cancer Survivor Study. Cancer 97,
11151126 (2003).
110. Kirchhoff,A.C. etal. Employer-sponsored health
insurance coverage limitations: results from the
Childhood Cancer Survivor Study. Support Care
Cancer 21, 377383 (2013).
111. Park,E.R. etal. Health insurance coverage in
survivors of childhood cancer: the Childhood Cancer
Survivor Study. J.Clin. Oncol. 23, 91879197
(2005).
112. Frobisher,C., Lancashire,E.R., Winter,D.L.,
Jenkinson,H.C. & Hawkins,M.M. Long-term
population-based marriage rates among adult
survivors of childhood cancer in Britain. Int. J.Cancer
121, 846855 (2007).

NATURE REVIEWS | CANCER

113. Frobisher,C. etal. Long-term population-based

divorce rates among adult survivors of childhood
cancer in Britain. Pediatr. Blood Cancer 54, 116122
(2010).
114. Janson,C. etal. Predictors of marriage and divorce
in adult survivors of childhood cancers: a report from
the Childhood Cancer Survivor Study. Cancer
Epidemiol. Biomarkers Prev. 18, 26262635
(2009).
115. Brinkman,T.M. etal. Longitudinal patterns of
psychological distress in adult survivors of childhood
cancer. Br. J.Cancer 109, 13731381 (2013).
116. Zebrack,B.J. etal. Psychological outcomes in longterm survivors of childhood brain cancer: a report
from the Childhood Cancer Survivor Study. J.Clin.
Oncol. 22, 9991006 (2004).
117. Zebrack,B.J. etal. Psychological outcomes in longterm survivors of childhood leukemia, Hodgkins
disease, and non-Hodgkins lymphoma: a report from
the Childhood Cancer Survivor Study. Pediatrics 110,
4252 (2002).
118. Kwak,M. etal. Trajectories of psychological distress in
adolescent and young adult patients with cancer: a
1year longitudinal study. J.Clin. Oncol. 31,
21602166 (2013).
119. Stuber,M.L. etal. Prevalence and predictors of
posttraumatic stress disorder in adult survivors of
childhood cancer. Pediatrics 125, e1124e1134
(2010).
120. Zebrack,B.J. etal. Perceived positive impact of
cancer among long-term survivors of childhood cancer:
a report from the childhood cancer survivor study.
Psychooncology 21, 630639 (2012).
121. Clanton,N.R. etal. Fatigue, vitality, sleep, and
neurocognitive functioning in adult survivors of
childhood cancer: a report from the Childhood
Cancer Survivor Study. Cancer 117, 25592568
(2011).
122. Meeske,K.A., Siegel,S.E., Globe,D.R., Mack,W.J.
& Bernstein,L. Prevalence and correlates of fatigue in
long-term survivors of childhood leukemia. J.Clin.
Oncol. 23, 55015510 (2005).
123. Mulrooney,D.A. etal. Fatigue and sleep disturbance
in adult survivors of childhood cancer: a report from
the Childhood Cancer Survivor Study (CCSS). Sleep
31, 271281 (2008).
124. Lu,Q. etal. Pain in long-term adult survivors of
childhood cancers and their siblings: a report from the
Childhood Cancer Survivor Study. Pain 152,
26162624 (2011).
125. Schultz,K.A. etal. Behavioral and social outcomes in
adolescent survivors of childhood cancer: a report
from the Childhood Cancer Survivor Study. J.Clin.
Oncol. 25, 36493656 (2007).
126. Robison,L.L. etal. The Childhood Cancer Survivor
Study: a National Cancer Institute-supported resource
for outcome and intervention research. J.Clin. Oncol.
27, 23082318 (2009).
127. Hawkins,M.M. etal. The British Childhood Cancer
Survivor Study: objectives, methods, population
structure, response rates and initial descriptive
information. Pediatr. Blood Cancer 50, 10181025
(2008).
128. Menu-Branthomme,A. etal. Radiation dose,
chemotherapy and risk of soft tissue sarcoma after
solid tumours during childhood. Int. J.Cancer 110,
8793 (2004).
129. Hawkins,M.M. & Robison,L.L. Importance of clinical
and epidemiological research in defining the long-term
clinical care of pediatric cancer survivors. Pediatr.
Blood Cancer 46, 174178 (2006).
130. Leisenring,W.M. etal. Pediatric cancer survivorship
research: experience of the Childhood Cancer
Survivor Study. J.Clin. Oncol. 27, 23192327
(2009).
131. Hudson,M.M. etal. Prospective medical assessment
of adults surviving childhood cancer: study design,
cohort characteristics, and feasibility of the St. Jude
Lifetime Cohort study. Pediatr. Blood Cancer 56,
825836 (2011).
132. Sieswerda,E. etal. The EKZ/AMC childhood cancer
survivor cohort: methodology, clinical characteristics,
and data availability. J.Cancer Surviv 7, 439454
(2013).
133. Geenen,M.M. etal. Medical assessment of adverse
health outcomes in long-term survivors of childhood
cancer. JAMA 297, 27052715 (2007).
134. Landier,W. etal. Yield of screening for long-term
complications using the childrens oncology group
long-term followup guidelines. J.Clin. Oncol. 30,
44014408 (2012).

VOLUME 14 | JANUARY 2014 | 69

2014 Macmillan Publishers Limited. All rights reserved

PERSPECTIVES
135. In DutchChildhood OncologyGroup, Richtlijn followup
na kinderkanker meer dan 5 jaar na diagnose. SKION,
Den Haag/Amsterdam [online], http://www.skion.nl/
(2010).
136. In ScottishIntercollegiate GuidelinesNetwork,
Long term follow up care of survivors of childhood
cancer. A national clinical guideline [online],
http://www.sign.ac.uk/ (2004).
137. In UnitedKingdom Childrens CancerStudy
Group,Late EffectsGroup, Therapy based long
term follow up practice statement [online],
http://www.cclg.org.uk/ (2011).
138. In Childrens OncologyGroup, Long-term followup
guidelines for survivors of childhood, adolescent, and
young adult cancers. Version 3.0 [online],
http://www.survivorshipguidelines.org/ (2008).
139. Nathan,P.C. etal. Family physician preferences and
knowledge gaps regarding the care of adolescent and
young adult survivors of childhood cancer. J.Cancer
Surviv 7, 275282 (2013).
140. Staba Hogan,M.J., Ma,X. & Kadan-Lottick,N.S.
New health conditions identified at a regional
childhood cancer survivor clinic visit. Pediatr. Blood
Cancer 60, 682687 (2013).
141. Wasilewski-Masker,K., Mertens,A.C.,
Patterson,B. & Meacham,L.R. Severity of health
conditions identified in a pediatric cancer survivor
program. Pediatr. Blood Cancer 54, 976982
(2010).
142. Kremer,L.C. etal. A worldwide collaboration to
harmonize guidelines for the long-term followup of
childhood and young adult cancer survivors: a
report from the International Late Effects of
Childhood Cancer Guideline Harmonization
Group. Pediatr. Blood Cancer 60, 543549
(2013).

143. Hudson,M.M. etal. Multi-component behavioral

intervention to promote health protective behaviors
in childhood cancer survivors: the protect study.
Med. Pediatr. Oncol. 39, 211 (discussion 2)
(2002).
144. Kadan-Lottick,N.S. etal. Childhood cancer survivors
knowledge about their past diagnosis and treatment:
Childhood Cancer Survivor Study. JAMA 287,
18321839 (2002).
145. Wilkins,K.L. & Woodgate,R.L. Preventing second
cancers in cancer survivors. Oncol. Nurs. Forum 35,
E12E22 (2008).
146. Oeffinger,K.C. etal. Increasing rates of breast cancer
and cardiac surveillance among high-risk survivors of
childhood Hodgkin lymphoma following a mailed, onepage survivorship care plan. Pediatr. Blood Cancer 56,
818824 (2011).
147. Hinkle,A.S. etal. A clinic-based, comprehensive care
model for studying late effects in long-term survivors
of pediatric illnesses. Pediatrics 113, 11411145
(2004).
148. Kenney,L.B. etal. The current status of followup
services for childhood cancer survivors, are we
meeting goals and expectations: a report from the
Consortium for New England Childhood Cancer
Survivors. Pediatr. Blood Cancer 57, 10621066
(2011).
149. Ford,J.S., Chou,J.F. & Sklar,C.A. Attendance at a
survivorship clinic: impact on knowledge and
psychosocial adjustment. J.Cancer Surviv
http://dx.doi.org/10.1007/s11764-013-0291-9
(2013).
150. Klosky,J.L. etal. Factors influencing long-term
followup clinic attendance among survivors of
childhood cancer. J.Cancer Surviv 2, 225232
(2008).

70 | JANUARY 2014 | VOLUME 14

151. Hewitt,M., Greenfield,S. & Stovall,E. (eds) From

Cancer Patient to Cancer Survivor: Lost in Transition
(National Academies Press, 2006).
152. Henderson,T.O., Hlubocky,F.J., Wroblewski,K.E.,
Diller,L. & Daugherty,C.K. Physician preferences
and knowledge gaps regarding the care of childhood
cancer survivors: a mailed survey of pediatric
oncologists. J.Clin. Oncol. 28, 878883 (2010).
153. Blaauwbroek,R., Tuinier,W., Meyboomde Jong,B.,
Kamps,W.A. & Postma,A. Shared care by paediatric
oncologists and family doctors for long-term followup
of adult childhood cancer survivors: a pilot study.
Lancet Oncol. 9, 232238 (2008).
154. In Advisory Board Company, Survivorship [online],
http://www.advisory.com/Research/OncologyRoundtable/Studies/2008/Elevating-the-PatientExperience (2008).
155. Eshelman-Kent,D. etal. Cancer survivorship practices,
services, and delivery: a report from the Childrens
Oncology Group (COG) nursing discipline, adolescent/
young adult, and late effects committees. J.Cancer
Surviv 5, 345357 (2011).
156. Oeffinger,K.C. & McCabe,M.S. Models for delivering
survivorship care. J.Clin. Oncol. 24, 51175124
(2006).
157. ThePatient Protection and AffordableCare Act. Public
Law 111148, (2010).

Acknowledgements

Research grant support: L.L.R. and M.M.H. are supported in

part by the Cancer Center Support (CORE) grant CA 21765
from the US National Cancer Institute and by the American
Lebanese Syrian Associated Charities (ALSAC).

Competing interests statement

The authors declare no competing interests.

www.nature.com/reviews/cancer
2014 Macmillan Publishers Limited. All rights reserved

Copyright of Nature Reviews Cancer is the property of Nature Publishing Group and its
content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.