Challenges After Curative Treatment
for Childhood Cancer and Long-Term
Follow up of Survivors
Kevin C. Oeffinger, MDa,*, Paul C. Nathan, MD, MScb,
Leontien C.M. Kremer, MD, PhDc
aDepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,
New York, NY 10021, USA
bDivision of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue,
Toronto, ON M5G 1X8, Canada
cDepartment of Paediatric Oncology, Emma Children’s Hospital/Academic Medical Center,
Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Cancer in childhood or adolescence is rare. Each year, for every 100,000
persons under the age of 21 years, 16 are diagnosed with cancer. Today,
more than 80% of those diagnosed with a childhood cancer will become
a long-term survivor . Many cancer survivors will develop serious mor-
bidity, die at a young age from noncancer causes, and experience diminished
health status. Among children treated in the 1970s to 1990s, about 75% will
develop a chronic disease by 40 years of age, and over 40% will develop a se-
rious health problem [2,3]. The absolute excess risk of premature death from
a second cancer, cardiovascular disease, or pulmonary disease is signifi-
cantly elevated beyond 30 years after the cancer diagnosis [4,5]. Almost
half of long-term survivors will have moderate to extremely diminished
health status, including limitations in activity and functional impairment
[6,7]. Although some serious problems occur during the cancer therapy or
soon thereafter (long-term effects), the majority do not become clinically ap-
parent until many years after the cancer has been cured (late effects) .
Contemporary therapy has evolved with a primary aim of not only improv-
ing cure but also decreasing the risk of long-term sequelae. It is anticipated
that children treated in the 21stcentury will not experience the frequency
and severity of morbidity of those treated in the late 1900s. Furthermore,
with proactive and anticipatory risk-based care and healthy lifestyles, the
* Corresponding author.
E-mail address: firstname.lastname@example.org (K.C. Oeffinger).
0031-3955/08/$ - see front matter ? 2008 Elsevier Inc. All rights reserved.
Pediatr Clin N Am 55 (2008) 251–273
frequency and severity of many late effects of cancer therapy can be signif-
icantly reduced [8,9].
Most childhood cancer survivors in North America and Europe are not
followed at a cancer center [10,11]. Instead, over time, they generally drift
back to the care of a primary care physician without a formal transition
from the cancer center, generally unaware of their risks, without a summary
of their cancer or cancer treatment, and with an inadequate understanding
of their previous therapy [11,12]. In a routine year in a typical primary care
practice, a clinician is likely to see fewer than five childhood cancer survi-
vors, each with a different cancer treated with a different regimen. Recogniz-
ing the competing demands of a busy primary care practice and the relative
infrequency of seeing a childhood cancer survivor, it can be difficult to stay
up-to-date with the health risks associated with different types of cancer
therapy, much less with the recommendations for surveillance. However,
the primary care physician can play a pivotal role in the health and well
being of a childhood cancer survivor by delivering risk-based health care.
This article is intended to assist the primary care physician in this role.
With a focus on contemporary therapy, the authors begin by providing
a brief discussion of four major types of late effects about which survivors
and their families commonly have questions, including neurocognitive dys-
function, cardiovascular disease, infertility and gonadal dysfunction, and
psychosocial problems. While these questions are often directed to the on-
cologist during therapy, families may seek further input from their primary
care physician. In the authors’ experience, these are also the most common
questions that survivors or their families will ask years after the cancer ther-
apy, often when they are no longer followed by the oncologist. Following
these four topics, the authors discuss the concept of risk-based care, pro-
mote the use of recently developed evidence-based guidelines, describe cur-
rent care in the United States, Canada, and the Netherlands, and articulate
a model for shared survivor care that aims to optimize life-long health of
survivors and improve two-way communication between the cancer center
and the primary care physician. It is not the intent of this article to provide
an exhaustive review of late effects, as recent publications have provided this
information based upon treatment exposure  or affected organ system
[14,15]. Two excellent books also provide much detail regarding late effects
and the care of this population [16,17]. Rather, the goal of this article is
to orient the reader regarding the key problems, highlight ways that a pri-
mary care physician can positively influence the health of childhood cancer
survivors, and point toward reliable resources for further inquiry.
The potential for neurocognitive dysfunction is perhaps the most worri-
some outcome to survivors and parents alike. When neurocognitive
OEFFINGER et al
problems occur, children commonly present with school difficulties. Primary
care physicians that deliver care for survivors should be aware of those at
greatest risk, recognize the school difficulties associated with prior cancer
therapy, and have an approach to screening, intervention and advocacy.
Often this will involve helping the child and the family obtain the legally
mandated supports required from the school system . Survivors of cen-
tral nervous system (CNS) tumors and acute lymphoblastic leukemia (ALL)
are at particular risk of neurocognitive late effects, but difficulties have been
observed in patients treated with a stem cell transplant  or with radiation
for tumors of the head or neck. Cranial radiotherapy, particularly higher
doses, is the major risk factor for adverse neurocognitive functioning [20–
22], and survivors of CNS tumors treated with radiation at a young age
are at considerable risk of global neurocognitive difficulties. Fortunately,
neurocognitive dysfunction is much less common and severe with contempo-
rary ALL therapy, where cranial radiotherapy is no longer used in patients
at low or standard risk of CNS relapse . However, two-thirds of studies
of children treated for ALL with chemotherapy alone demonstrate some de-
gree of neurocognitive decline , with methotrexate [24–27], corticoste-
roids , and high-dose cytarabine  most frequently associated with
neurocognitive late effects. Female gender [30–32], younger age at therapy
(particularly children less than 3 years) [21,32–39], and increasing time
from treatment increase the risk of these sequelae. Worsening academic per-
formance is usually related to a reduced rate of skill acquisition rather than
to loss of previously learned information , and is independent of the
number of days of school missed because of therapy.
Survivors may have impairment in any area of neurocognitive function,
but problems with attention and concentration [24,41,42], processing speed,
visual perceptual skills , executive function , and memory  are
most common. Deficits in attention often manifest without hyperactivity,
and can be misinterpreted as disinterest or bad behavior. Careless errors, in-
complete assignments, and inconsistent academic performance are common
, and these survivors often need extra time to complete their schoolwork.
This can be compounded by difficulties with planning and organization .
Mathematics, reading, and spelling are the most frequently impacted aca-
demic areas,  and many survivors of ALL and CNS tumors require spe-
cial education services . School difficulties may not manifest during the
primary grades when rote-learning (memorization by repetition) may be rel-
atively intact, but become evident as children transition to middle or high
school where organizational, reasoning, and time management skills become
essential to successful school performance .
When following a childhood cancer survivor, a primary care physician
should assess school performance annually. Many pediatric cancer survivor
programs obtain detailed neuropsychologic assessments in survivors at
higher risk of difficulties, but in some circumstances these tests must be
arranged by the survivor’s primary care physician. Unfortunately, many
FOLLOW UP CARE OF SURVIVORS
insurance providers do not cover this service, and test results may be avail-
able only from evaluations performed through the school system. While
school-based testing can be helpful in developing an individualized educa-
tion program, some important, subtle late effects may be missed. The pri-
mary care physician can assist parents by educating school personnel
about the academic challenges faced by survivors. Several United States fed-
eral laws protect the rights of children with mental and physical limitations
to receive special education, accommodation, and related services within the
school system, and in many cases, these statutes can be applied to cancer
survivors with learning difficulties .
Once completed, information from neuropsychologic assessments should
be shared with the school. Simple educational accommodations include
locating the child in the front of the classroom where there is less distraction,
reducing the number of items on multiple choice tests, breaking assignments
into discrete steps, and allowing more time for the completion of examina-
tions . Other interventions, such as cognitive remediation  and phar-
macotherapy , are currently undergoing investigation with multicenter
trials. Even if no specific educational intervention is identified after an initial
assessment, it is important to continually reassess a survivor’s needs,
because deficits may develop over time.
The developing cardiovascular system of a child or adolescent is very vul-
nerable to cancer therapy. A cardiomyopathy may develop following expo-
sure to anthracyclines. Mantle radiotherapy promotes the development of
coronary and carotid artery disease. In addition, perhaps most commonly,
premature cardiovascular disease may result from alterations in multiple
organ systems. The following sections describe each of these outcomes
and emphasize the role of surveillance and prevention.
Anthracyclines, including doxorubicin and daunorubicin, are an impor-
tant class of chemotherapeutic agents in the treatment of children with can-
cer. About half of those treated with contemporary therapy receive an
anthracycline. Unfortunately, anthracycline cardiotoxicity is a major and
generally unavoidable complication of childhood cancer therapy. The con-
sequences of anthracycline cardiotoxicity for survivors are extensive. Late
effects, resulting from myocardial damage, can manifest as left ventricular
dysfunction, clinical heart failure, or as cardiac death. Anthracycline cardi-
otoxicity can be divided in asymptomatic (subclinical) and symptomatic
(clinical) cardiotoxicity. Asymptomatic cardiotoxicity is defined as various
cardiac abnormalities diagnosed with different diagnostic methods in
asymptomatic patients; symptomatic cardiotoxicity is defined as clinical
OEFFINGER et al
heart failure (CHF). Anthracycline-induced left ventricular dysfunction de-
velops via two mechanisms: depressed contractility and an increased after-
load . Late-onset anthracycline cardiotoxicity, occurring after the first
year of survivorship, is the direct result of damage done during therapy,
and is progressive .
Numerous studies have evaluated the cardiotoxic effects of anthracycline
therapy in survivors of childhood cancer. As described in previous system-
atic reviews [49,50], some studies have methodologic limitations: only a se-
lected subgroup of survivors have been evaluated, follow-up is incomplete,
or nonstandardized diagnostic measurements have been used. For asymp-
tomatic cardiotoxicity in childhood cancer survivors, a wide variation in
the prevalence, from 0% to 56%, has been described [50–53]. Differences
in the selection of study groups, cumulative anthracycline dose, outcome
definitions, and follow-up period could explain a part of this wide range.
The risk of anthracycline-induced (A-) CHF in childhood cancer survivors
has been evaluated in several cohort studies . In a cohort study of 831
subjects treated with anthracyclines for childhood cancer, the estimated
risk of A-CHF, 20 years after the first dose of anthracyclines, was 9.8%
for subjects who received a cumulative dose of greater than or equal to
300 mg/m2. Risk factors for anthracycline cardiotoxicity include higher
cumulative dose of anthracyclines, radiotherapy involving the heart region,
and a few studies suggest younger age at treatment and the female sex
The risk of developing clinical heart failure for survivors treated with
anthracyclines remains a life-long threat, and guidelines for long-term fol-
low-up advise life-long cardiac monitoring for survivors treated with anthra-
cycline [55,56]. However, management of childhood cancer survivors with
asymptomatic cardiotoxicity is unclear . Two studies have investigated
the effect of angiotensin converting enzyme inhibitors in childhood cancer
survivors [58,59]. Although the results were promising, the noncontrolled
trial suggested that enalapril treatment could delay, but not completely pre-
vent, progression of subclinical and clinical cardiotoxicity in survivors .
So primary prevention during treatment is essential, such as reducing the
cumulative dose of anthracyclines, the use of possible less cardiotoxic
anthracycline analogs, and reducing the peak dose or the use of cardiopro-
tective agents [60,61].
Coronary and carotid artery disease following mantle radiotherapy
Moderate dose mantle irradiation (3,500 centigray or cGy–4,500 cGy)
was the mainstay for treatment of early stage supradiaphragmatic Hodg-
kin’s disease from the 1960s to the 1980s. The mantle field encompasses
the primary lymph node regions of the neck, supraclavicular, infraclavicu-
lar, axillary, and mediastinal areas. In a British cohort of 7,003 Hodgkin’s
survivors with an average of 11.2 years of follow-up, the standardized
FOLLOW UP CARE OF SURVIVORS
mortality risk secondary to myocardial infarction was 3.2 for those who
were treated with mantle irradiation . The absolute excess risk was
125.8 per 100,000 person-years. Aleman and colleagues  reported that
by 30 years after mediastinal irradiation, the cumulative incidence of myo-
cardial infarction was 12.9%. They reported a standardized incidence ratio
of 3.6 for myocardial infarction, with 357 excess cases per 100,000 person-
years. Traditional risk factors (smoking, hypercholesterolemia, diabetes) in-
creased risk. In Dutch Hodgkin’s survivors treated with moderate dose
mediastinal irradiation (median, 3,720 cGy), Reinders and colleagues 
reported an actuarial risk of symptomatic ischemic coronary artery disease
of 21.2% by 20 years after irradiation. This increased risk of premature cor-
onary artery disease and myocardial infarction following mediastinal irradi-
ation has been consistently reported in several other well-designed studies
[65–70]. Carotid artery disease has also been reported following mantle
In the past 15 years, modified mantle radiotherapy with a lower total dose
(2,000 cGy–2,500 cGy) to involved fields has been used in combination with
multiagent therapy. More recent methods, of shielding the heart and equally
weighting the anterior and posterior fields, appear to decrease the risk of
cardiac disease. However, even with current shielding techniques, the prox-
imal coronary arteries are within the modified mantle fields. So, despite
modifications in therapy aimed at reducing risk, children and adolescents
treated on contemporary Hodgkin’s disease protocols likely still face an in-
creased risk of coronary and carotid artery disease. Longitudinal studies of
survivors treated with contemporary therapy are needed to delineate the fre-
quency, onset, and modifying factors of this risk. Aggressive risk reduction
of traditional coronary artery disease risk factors (tobacco avoidance and
cessation; optimum management of lipid disorders, diabetes mellitus, and
hypertension; promotion of physical activity) should also reduce morbidity.
Cardiovascular disease following childhood acute lymphoblastic
leukemia a model for multifactorial cardiovascular disease
Children who have survived ALL are more likely to be physically inactive
[73,74] and obese [75,76], have increased visceral adiposity , develop in-
sulin resistance [78,79] and dyslipidemia [75,80] at a young age, and have
poor cardiorespiratory fitness . These outcomes are in part related to
cranial radiation, a therapy that is currently used in about 5% to 15% of
children with ALL. However, children treated with chemotherapy alone
also develop these outcomes, although the risk appears to be somewhat at-
tenuated and possibly later in onset. This constellation of risk factors can be
expected to lead to an increased incidence of cardiovascular disease, likely at
a relatively young age. Similar outcomes have also been reported in brain
tumor survivors  and in those treated with a stem cell transplant
[83,84]. Research aimed at better understanding these relationships and
OEFFINGER et al
the mechanisms leading to these outcomes is under way. In addition, the pri-
mary care physician should promote healthy behaviors (tobacco avoidance,
healthy diet, and physical activity), screen for lipid disorders and insulin
resistance, and closely monitor these survivors.
Fertility and gonadal dysfunction
When a child or adolescent is diagnosed with cancer, the discussion of
cancer therapy is difficult and complicated, as the oncologist describes the
response rates of various protocols, the associated acute toxicities of ther-
apy, and the potential for future health problems related to the therapy.
During this stress laden period when therapeutic decisions are made, as
a parent faces the potential of losing a child, details regarding the potential
for infertility and gonadal dysfunction are often not understood or remem-
bered by families, and sometimes are not adequately provided by the cancer
treating team . Later, as the cancer is cured and the interval from com-
pletion of the cancer therapy lengthens, questions regarding fertility and
gonadal function become more prevalent. The loss of fertility (or even the
fear of impaired fertility) and alterations in gonadal function influence the
survivor’s developing body image, dating relationships, and marriage
Fertility is the most difficult outcome to study in survivors, as the primary
endpoint is pregnancy, an outcome that is influenced by many physical and
societal factors beyond the direct effect of the cancer therapy on ovarian or
testicular function. Fertility is particularly difficult to study in males, as
many men are not willing to have a semen analysis and self-reporting a suc-
cessful impregnation is subject to both over- and under-reporting biases.
Further compounding the investigation of fertility in both genders are the
often overlapping effects of different cancer therapies on the reproductive
system, and the sometimes late recovery of function. Recognizing the com-
plexity of this subject, a detailed description is beyond the scope of this
article. Following is a brief overview; for the clinician interested in better un-
derstanding these outcomes, two excellent articles written by leading
researchers in this area are helpful resources [87,88].
Female survivors, acute ovarian failure, premature menopause,
and fertility preservation
Though the ovaries during childhood and adolescence are relatively resis-
tant to chemotherapy-induced damage, they are sensitive to radiation.
Among 3,390 women in the Childhood Cancer Survivor Study (CCSS),
loss of ovarian function during or shortly following completion of therapy
(acute ovarian failure) was reported in 6.3% . More than 70% of women
who had been treated with 2,000 cGy or more of ovarian irradiation had
acute ovarian failure. Doses of ovarian irradiation below 1,000 cGy were
FOLLOW UP CARE OF SURVIVORS
capable of inducing acute ovarian failure in women who received concomi-
tant alkylating agents (eg, cyclophosphamide) or were older at exposure.
Survivors at greatest risk for acute ovarian failure are those treated with
total body irradiation (TBI) in preparation for a stem cell transplant. Virtu-
ally all women treated with TBI after age 10 years will develop acute ovarian
failure [90,91]. In contrast, only 50% of those treated before 10 years of age
will develop this outcome. In addition, women treated with high dose mye-
loablative therapy (eg, busulfan, melphalan, thiotepa), rather than TBI,
before a stem cell transplant are at high risk of developing acute ovarian
Female survivors who do not develop acute ovarian failure are poten-
tially at risk of developing premature menopause (ie, menopause before
age 40 years) and having reduced ovarian reserve. Among 2,819 women
in the CCSS cohort who did not have acute ovarian failure, Sklar and col-
leagues  reported a relative risk of nonsurgical premature menopause of
13.2, when compared with 1,065 siblings. Risk factors for premature meno-
pause among survivors included older attained age, exposure to increasing
dose of radiation to the ovaries, increasing dose of alkylating agents, and
a diagnosis of Hodgkin’s disease. For women treated with an alkylating
agent plus abdominopelvic radiation, the cumulative incidence of nonsurgi-
cal menopause approached 30% by 40 years of age.
In an assessment of 100 Danish childhood cancer survivors with a median
age of 26 years, Larsen and colleagues  reported that women with pre-
served menstrual cycles had sonographic and endocrine changes suggestive
of diminished ovarian reserve. Decreased number of antral follicles per
ovary was associated with treatment that included ovarian irradiation or
use of alkylating agents, older age at diagnosis, and increasing years of ther-
apy. With cranial radiation doses of 3,000 cGy or higher to the hypotha-
affecting fertility and sex hormone production [96–98]. The consequences
of ovarian failure and premature menopause extend beyond the issue of
fertility and may include alterations in bone metabolism, leading to osteopo-
rosis, sexual dysfunction, and body image changes.
In recent years, much attention has been directed toward preserving fer-
tility in females undergoing cancer therapy during their childhood years.
When radiation fields include the pelvis, the ovaries can be surgically trans-
posed to a more protected location [99,100]. However, even after transposi-
tion of the ovaries, some women will develop premature menopause
secondary to their chemotherapy. Hormonal protection of the ovaries with
a gonadotropin-releasing hormone analog has been attempted, with varying
success,insmalluncontrolledtrials inpatientsundergoing therapy withmod-
erate to high dose alkylating agents . Because the success rate of cryo-
preservation of unfertilized oocytes is very low, and the necessary ovarian
hormonal stimulation before removal of the oocytes may delay cancer ther-
apy, this approach is used infrequently in adolescents with cancer .
OEFFINGER et al
Lastly, ovarian tissue cryopreservation is an investigational method of
fertility preservation that has the advantage of requiring neither a sperm
donor nor ovarian stimulation . The American Society of Clinical On-
cology recommends that oncologists discuss fertility preservation options
as appropriate, and to refer interested patients and their families to repro-
ductive specialists .
Encouragingly, women who become pregnant following childhood can-
cer generally have favorable outcomes. Among 1,953 women in the CCSS,
4,029 live births were reported and no association was found between che-
motherapy and an adverse pregnancy outcome . Previous pelvic irradi-
ation was associated with lower birth weight.
Male survivors, infertility, fertility preservation, and androgen deficiency
The germinal epithelium of the testis is sensitive to radiation. Even low-
dose testicular irradiation is associated with decreased spermatogenesis,
with doses above 200 cGy invariably causing oligospermia or azoospermia
. Thus, males treated TBI, with a fractionated dose of 1,200 cGy to
1500 cGy, are often rendered infertile . Similarly, males with ALL
who are treated with irradiation of the testis for a testicular relapse will al-
most always be azoospermic. Though the testes are shielded with modern
techniques, scatter radiation from high-dose radiation can result in oligo-
spermia or azoospermia. Examples include pelvic, inguinal, or spinal radia-
tion for a sarcoma, Hodgkin’s disease, or CNS tumor, respectively
[105,106]. Lastly, radiation to the hypothalamic-pituitary axis may result
in a gonadotropin deficiency, thus indirectly affecting spermatogenesis and
Spermatogenesis is also quite affected by several chemotherapeutic drugs,
including alkylating agents (eg, cyclophosphamide and ifosfamide), procar-
bazine, and cisplatin. Outcomes are agent specific and dose-dependent.
Treatment with moderate to high-dose cyclophosphamide or ifosfamide of-
ten results in azoospermia. The combination of these two agents, used in the
treatment of patients with Ewing sarcoma, causes infertility in virtually all
males . Similarly, the combination of cisplatin with either ifosfamide
or cyclophosphamide, used in the contemporary treatment of osteosarcoma,
results in oligospermia or azoospermia in over 90% of males . High-
dose melphalan or busulfan, used in some preconditioning regimens before
a stem cell transplant, also causes impaired spermatogenesis in the vast ma-
jority of males . Early chemotherapeutic regimens used for Hodgkin’s
disease, including six courses of mechlorethamine, vincristine, procarbazine,
and prednisone, generally resulted in a high incidence of azoospermia. To
preserve fertility, contemporary multimodality therapy of Hodgkin’s disease
and non-Hodgkin lymphoma generally includes only three courses of an
alkylating agent or procarbazine, alternating with another group of agents
with a different set of toxicities.
FOLLOW UP CARE OF SURVIVORS
Sperm cryopreservation is an effective method of fertility preservation in
males [85,108]. Unfortunately, spermarche does not occur until about 13 to
14 years of age, thus limiting sperm banking to adolescent males. In general,
methods to preserve fertility in younger males, including testicular tissue
cryopreservation, have not been successful . While it is recommended
that the oncologist discuss sperm banking with all appropriate patients, it
is also important for the primary care physician to be aware of this option
if the patient or the family has any questions.
In comparison with the germinal epithelium, the Leydig cells are less af-
fected by chemotherapy and radiotherapy. Testicular irradiation with doses
of greater than 2,000 cGy and 3,000 cGy are associated with Leydig cell
dysfunction in prepubertal and sexually mature males, respectively .
Even with high dose cyclophosphamide, frankly subnormal levels of testos-
terone are rare, though Leydig cell dysfunction may be evidenced by an el-
evated luteinizing hormone level . Whether or not mild Leydig cell
dysfunction will lead to premature androgen deficiency as this population
ages is not known. Androgen deficiency can also result from hypogonado-
tropic hypogonadism following cranial radiotherapy.
Psychosocial issues in survivors and their families
The experience of being diagnosed and treated for cancer during child-
hood exerts considerable psychologic strain on both the patient and the fam-
ily. Despite this, many survivors report normal psychologic health, and
some even demonstrate psychologic growth as a result of their cancer expe-
rience. Additionally, most studies suggest that survivors are less likely to
exhibit risky behaviors, such as cigarette smoking or drug use [110–112].
However, on average, childhood cancer survivors are more likely to present
with mental health disorders and to complain of chronic pain or fatigue than
the general population. Hudson and colleagues  reported that 17% of
9,535 young adult survivors of childhood cancer in the CCSS had depres-
sive, somatic, or anxiety symptoms, and 10% reported moderate to extreme
pain as a result of their cancer. Approximately one out five young adult sur-
vivors of childhood cancer reports symptoms of posttraumatic stress disor-
der (PTSD) [113,114], characterized by re-experiencing elements of their
prior cancer experience or its associated emotions, avoidance of people or
places that remind them of their previous cancer, and increased anxiety or
arousal. Avoidant behaviors may inhibit survivors from seeking appropriate
follow-up care, particularly if care is delivered in the hospital where they re-
ceived their cancer therapy. Additionally, both parents [115,116] and sib-
lings  of survivors may develop symptoms of PTSD, and thus the
primary care physician must extend their assessment of mental health to sur-
vivors’ families. Rather than developing PTSD, some survivors demonstrate
posttraumatic growth  and psychosocial thriving  as a result of
their cancer experience. Many rate themselves highly on their ability to
OEFFINGER et al
cope as a result of their prior cancer, suggesting that this life-altering event
promotes resiliency . When survivors do report psychologic distress, it
is associated frequently with poorer health status, lower levels of income,
and poorer social functioning [121,122].
Physicians need to be sensitive to the concerns expressed by survivors
who often worry about fertility and parenthood, obtaining health and life
insurance, educational difficulties, job availability after completing school,
and their risk for future health problems, including second cancers
[123,124]. Although most survivors become socially independent and leave
home at a similar age to the general population, rates of marriage are
slightly lower [125–127]. Survivors of CNS tumors are at particular risk of
not marrying, and many are unable to live independently . Addition-
ally, survivors of CNS tumors (but not other cancers) may be at increased
risk of hospitalization for a psychiatric disorder . Primary care physi-
cians can support these patients by providing interventions that improve
health, support educational or occupational advancement to improve in-
come potential, and promote social interaction . In particular, the
development of a social network has been shown to enhance quality of
life in survivors .
Several organizations provide services that can assist survivors, their par-
ents, and their health care providers in dealing with the various challenges
that may arise as these children and adolescents move beyond their primary
cancer (Table 1). Two books written for survivors or their families provide
quality information and address the specific challenges of the cancer experi-
ence and survivorship [131,132].
Risk-based health care and shared care of cancer survivors
Because the risk and severity of many late effects is modifiable, and some
are preventable, life long health care is recommended for all childhood can-
cer survivors . A systematic plan for longitudinal screening, surveillance,
and prevention that incorporates risks based on the previous cancer, cancer
therapy, genetic predispositions, lifestyle behaviors, and comorbid health
conditions should be developed for all childhood cancer survivors.
To facilitate and standardize risk-based care of childhood cancer survi-
vors, several evidence-based guidelines have been developed [55,56,
133,134]. In the development of these guidelines, the evidence of the associ-
ation between a therapeutic exposure and a late effect is generally of high
quality. However, with a relatively small population of childhood cancer
survivors limiting prospective study design, there are no studies that have
estimated the reduction in morbidity or mortality with surveillance. Thus,
principles of screening in the general population and other high-risk groups
have been applied, in addition to the collective clinical experience of expert
panels, in the development of surveillance recommendations .
FOLLOW UP CARE OF SURVIVORS
Resources for childhood cancer survivors, their parent and caregivers
Service and disability organizationsService provided
National Childhood Cancer Foundation
440 E. Huntington Dr., Arcadia, CA 91066-6012, (800) 458-6223.
American Cancer Society
1599 Clifton Rd NE, Atlanta, GA 30329-4215, (800) ACS-2345.
Canadian Cancer Society
565 W. 10thAve., Vancouver, BC V5Z 4J4 Canada.
Association of Cancer Online Resources
Candlelighters Childhood Cancer Foundation
3910 Warner St., Kensington, MD 20895, (800) 366-CCCF.
Candlelighters Childhood Cancer Foundation Canada
55 Eglington Ave. E., Suite 401, Toronto, Ontario M4P 1G8 Canada, (800)
Childhood Cancer Ombudsman Program
27 Witch Duck Lane, Heathsville, VA 22473. email@example.com
Provides information and resources for pediatric cancer survivors.
Programs include equipment and supplies, support groups, educational
literature, and summer camps for childhood cancer survivors.
Programs include those that the American Cancer Society provides.
Online information and electronic support groups for pediatric cancer
survivors and their caregivers.
Provides resource guides, quarterly newsletters, referrals, information, and
publishes books for pediatric cancer survivors, including Educating the
Child with Cancer.
Provides resource guides, newsletters, and information.
Provides help for pediatric cancer survivors experiencing problems getting
access to appropriate education, medical care, health care cost coverage,
OEFFINGER et al
Federation for Children with Special Needs
1135 Tremont St, Suite 420, Boston, MA 02120, (617) 236-7210.
Lance Armstrong Foundation
P.O. Box 161150, Austin, TX 78716, (866) 235-7205. www.livestrong.org
National Center for Learning Disabilities
381 Park Ave. S., Suite 1401, New York, NY 10016, (888) 575-7373.
US Department of Justice
ADA Information Line, Civil Rights Division, PO Box 66738, Washington,
DC 20035, (800) 514-0301. http://www.usdoj.gov/crt/ada/adahom1.htm
Federally funded organization providing information on special education
rights and laws, conferences, referrals for services, parent training
workshops, publications, and advocacy information.
A nonprofit organization that offers extensive education, advocacy and
public health resources.
Offers extensive resources, referral services, and educational programs
related to learning disabilities.
Answers questions about the Americans with Disabilities Act, explains how
to file a complaint, and provides dispute resolution information.
Data from Nathan PC, Patel SK, Dilley K, et al. Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of
childhood cancer: a report from the Children’s Oncology Group. Arch Pediatr Adolesc Med 2007;161(8):798–806.
FOLLOW UP CARE OF SURVIVORS
In North America, the 240-institution Children’s Oncology Group
(COG) ‘‘Long-Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers’’ (available at www.survivor
shipguidelines.org) are widely used . Recommendations for periodic
evaluations are based upon different treatment exposures or therapeutic
modalities and include modifying risk factors. For each late effect, a score
of the quality of the evidence is provided, along with supporting references.
In addition, over 40 different patient education handouts (Health Links)
that discuss frequent problems or questions are accessible through the
Web site. The guidelines are periodically reviewed by the COG Late Effects
Committee and updated as new evidence becomes available.
In the Netherlands, 16 multidisciplinary teams summarized the evidence
in existing guidelines, systematic reviews, books, and papers based on clin-
ical questions regarding the magnitude of the risk of selected late effects, the
efficacy of screening, and possible treatments. Ten nationwide meetings were
held to define the final Dutch recommendations based on available evidence
. These recommendations led to standardization and improvement of
patient care for survivors in the Netherlands .
Long-term follow up practices vary across the United States, Canada,
and the Netherlands. In the United States, most COG institutions have
a specialized long-term follow up (LTFU) program that delivers risk-based
health care for survivors during their childhood years [135,136]. However,
because of insurance limitations, travel distances, and other barriers, survi-
vors are gradually lost to follow-up over time. Moreover, very few LTFU
programs in the United States provide care for childhood cancer survivors
who are in their adult years. In Canada, Ontario is the only province with
a coordinated system of care for both pediatric and adult survivors of child-
hood cancer. The province funds a group of coordinated Aftercare Clinics,
located in cancer centers in five major cities across the province (see
http://www.pogo.ca/care/aftercareclinics/, accessed August 29, 2007). Al-
though the majority of survivors receive their medical care in such a program
during their childhood years, many adult survivors are not seen regularly in
these Aftercare programs, despite such care being provided free of charge.
The majority of adult survivors of childhood cancer in Canada report re-
ceiving care from a family physician . In the Netherlands, all pediatric
oncology centers have an LTFU program and most children are followed
through these programs. As in the United States, financial support limits
the care of adult survivors.
The majority of late effects become clinically apparent many years after
the cancer therapy, generally when survivors are in their adult years .
This is the time period when most survivors in North America and Europe
are no longer followed in a specialized LTFU program. Formal transition of
survivors to their primary care physician, with proper communication, is
rare. Instead, follow-up care tends to be haphazard for most survivors. If
our common goal is to optimize the life-long health of survivors, it is
OEFFINGER et al
imperative that LTFU programs implement strategies that efficiently allo-
cate limited resources where they are most needed.
As illustrated in Fig. 1, one potential strategy is to integrate primary care
physicians into a risk-stratified shared care model [11,138,139]. This strategy
stratifies survivors into three groups based upon their risk of late effects (see
Fig. 1 for potential groupings). Given their expertise in this area, the strat-
ification would be determined by the LTFU staff. All survivors would con-
tinue to have their noncancer-related care delivered by the primary care
physician. At the time of diagnosis, the primary oncologist would mail (or
Group 1. Low risk of late effects:
Chemotherapy did not include
alkylating agent, anthracycline,
bleomycin, or epipodophyllotoxin
Group 2. Moderate risk:
Low or moderate dose alkylating
agent, anthracycline, bleomycin, or
Group 3. High risk:
High dose alkylating agent,
anthracycline, bleomycin, or
Stem cell transplant
Communication points with primary care physician
a. Cancer diagnosis and planned therapeutic approach, brief overview of chemotherapy, radiation therapy, and/or surgery
b. Cancer summary: cancer diagnosis, cancer therapy, surveillance recommendations, contact information
c. Periodic update with changes in surveillance recommendations and new information regarding potential late effects
d. Periodic update of survivor’s health for primary care physician’s record
Fig. 1. Proposed risk-stratified shared care model for childhood cancer survivors. Solid line de-
notes primary responsibility for risk-based care; risk stratification based upon determination of
the LTFU staff. CA, cancer; DX, diagnosis; Onc, Oncologist; PCP, primary care provider; RX,
therapy. (Adapted from Oeffinger KC, McCabe MS. Models for delivering survivorship care.
FOLLOW UP CARE OF SURVIVORS
fax) the primary care physician a summary of the cancer treatment plan. At
2 years following the completion of therapy, the survivor would be transi-
tioned from the oncology team to the LTFU program for a single visit.
At this visit, a cancer summary would be developed and include information
about the cancer, cancer therapy, and recommended surveillance. A copy of
the summary would be sent to the primary care physician, with a lay version
provided to the survivor (and his or her family). After this single LTFU
visit, the survivor at low risk would be transitioned to the primary care phy-
sician for periodic risk-based care. The LTFU staff would communicate
with the primary care physician every 3 to 5 years and inquire about changes
in the survivor’s health and any new findings that might change surveillance
recommendations. Survivors at moderate risk would be followed annually
through the LTFU program for their risk-based care until 5 to 10 years after
the completion of cancer therapy. During this time period, in addition to
monitoring for late effects and surveillance for recurrence, age- and develop-
mental stage-appropriate education and counseling highlighting the benefits
of healthy lifestyles would be provided. At 5 to 10 years after cancer ther-
apy, depending upon the program, the survivor would be transitioned to
their primary care physician for the delivery of risk-based care. At the
time of transition, the LTFU staff would provide the primary care physician
with an updated treatment summary and surveillance plan, and then annu-
ally communicate with the primary care physician (and survivor if needed)
to document any new late effects, changes in lifestyle behaviors and family
history, and update the surveillance recommendations. The LTFU program
would also serve in a consultative mode, as needed, for survivors at low or
moderate risk who develop a late effect or need further evaluation. A survi-
vor at high risk of developing late effects would continue to be monitored
through the LTFU program, with continued communication with the pri-
mary care physician regarding any new health problems and planned sur-
veillance (to avoid duplication of testing).
This strategy would allow LTFU programs to concentrate their resources
on the survivors at highest risk and provide foundational education and
counseling to those at moderate risk. Furthermore, the standardized and
systematic communication between the LTFU staff and the primary care
physician would serve to inform both groups of the evolving health and
health care needs of the survivor. To implement this strategy, LTFU pro-
grams located at a children’s hospital that restricts care of adult patients
would need to develop an alternative strategy for the care of their high
Late effects of therapy for childhood cancer are frequent and serious.
Fortunately, many late effects are also modifiable. Proactive and
OEFFINGER et al
anticipatory risk-based care can reduce the frequency and severity of treat-
ment-related morbidity. The primary care physician should be an integral
component in risk-based care of survivors.
The authors would like to acknowledge Dr. Charles Sklar for his insight-
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