survivors of childhood and adolescent cancer life long risks and responsabilities.pdf

Although cancer that occurs in individuals who are ≤20 years 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 out-comes2–5 (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 diagno-ses such as retinoblastoma, neuroblastoma, Wilms’ tumour and hepatoblastoma, which are primarily confined to the paediatric age range and occur almost exclusively in the first 5 years of life. For paediatric cancers, the highest age-specific incidence is within the first year of life.

Over the past 30 years, the survival rate in children and adolescents with cancer has steadily improved (FIG. 1) and the cancer- specific 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 ≥5 years beyond their diagnosis1. The overwhelm-ing majority of those who reach the 5-year milestone will become long-term survivors5. The US National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) programme estimates that, as of 1 January 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 post-2009, the prevalence of paediatric cancer survivors is predicted to surpass 420,000 by the end of 2013 and will approach 500,000 by 2020. We can currently estimate that approximately one of every 750 individuals in the United States is a survivor of childhood or adoles-cent cancer. This growing population reflects a highly vulnerable group of individuals who will probably experience adverse health-related and quality-of-life outcomes during their subsequent lifetimes, as a result of their curative cancer treatment7–11. Extended sur-veillance of childhood and adolescent cancer survivors has shown that they have a high

risk of early mortality from subsequent can-cers (that is, cancer other than that originally diagnosed), cardiac events and pulmonary conditions12,13. This Science and Society arti-cle 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 outcomesTo varying degrees, long-term survivors of childhood cancer experience a range of adverse outcomes12,14–19 (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 aetiol-ogy and the associated morbidity of many adverse outcomes that are experienced by childhood cancer survivors may be multi-factorial, involving combinations of factors after treatment21 (FIG. 3). Factors that relate to the primary malignancy, demographics, pre-morbid conditions, underlying genetic predisposition and health-related behav-iours can modify the risks that are associ-ated 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 follow-up 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, cumu-lative 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 manner25. Radiation-associated outcomes include cardiovascular26–29, cerebrovascular30–32,

S C I E N C E A N D S O C I E T Y

Survivors of childhood and adolescent cancer: life-long risks and responsibilitiesLeslie 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 5‑year survival rate approaches 80%. However, the vast majority of these cancer survivors will have at least one chronic health condition by 40 years 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.

PERSPECTIVES

NATURE REVIEWS | CANCER VOLUME 14 | JANUARY 2014 | 61

© 2014 Macmillan Publishers Limited. All rights reserved

3,000

Ann

ual i

ncid

ence

rate

per

105

Prop

orti

on s

urvi

ving

(%)

Age at cancer diagnosis Survival from diagnosis (years)

2,500

2,000

1,500

1,000

500

00 10

1%

20 30 40 50 60 70 80 900

50

60

70

80

90

100

0 5 10 15 20

2005

20001995

19901985–1989

1980–1984

1975–1979

300a b

250

200

150

100

50

0

Inci

denc

e pe

r 105

Age at cancer diagnosis0 4 8 12 16 20

Nature Reviews | Cancer

endocrine33–38, gastrointestinal39, reproduc-tive15,40–44, hepatic45, pulmonary46–49 and uri-nary tract50–52 dysfunction, musculoskeletal growth impairment53–55, and neurocogni-tive, neurosensory and neurological defi-cits56–61 (TABLE 1). Cancer survivors whose treatment included radiation therapy are at risk of invasive and non-invasive secondary neoplasms62–76. Among childhood cancer survivors, risks have been well-described for cancers of the skin (predominantly basal cell carcinoma)62,63,72,73, breast69,77,78, thyroid64,75,79, bone68 and brain70,80,81. Increasingly, with extended follow-up 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 kidney82 and the lung83.

Chemotherapy. Specific classes of chemo-therapeutic agents that are used in the successful treatment of children and adolescents with cancer22,23 — including alkylating agents41,42,46,51,52,84–87, 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 (TABLE 2). The risk for adverse long-term outcomes that are associated with chemotherapy is generally depend-ent 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 therapy-related late effects, which has been the

focus of research that aims to characterize and quantify the potential contribution of genetic predisposition94.

Surgery. Surgical procedures that are car-ried out as part of the diagnosis or treat-ment 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 mobility18,96; eye enucleation, which affects craniofacial development97; oophorectomy or orchi-ectomy, which affects reproduction41,42; cystectomy, which affects bladder func-tion52; 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 inconti-nence 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 mani-festation 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

with cisplatin treatment typically develops soon after treatment (an acute toxicity) and persists during long-term follow-up57. 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 hear-ing 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 interven-tions to optimize language development and academic achievement among young cancer survivors. By contrast, young women who are treated with chest radiation for child-hood cancer have an increased risk of breast cancer with a median time to diagnosis of 15–20 years after the radiation; breast cancer risk is increased as early as 8 years after radi-ation 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 ovar-ian 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 cancer100.

Evaluating evolving therapyPaediatric cancer treatment approaches have evolved over time in response to medical advances in cancer biology, developmental therapeutics, radiation technology, diag-nostic imaging and supportive care. Surprisingly, despite the many changes that have been undertaken during the past 50 years in efforts to improve the outcomes

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

improvements in overall survival, by year of cancer diagnosis, among cancer patients who were diagnosed before the age of 20 years. Data from the Surveillance, Epidemiology, and End Results programme of the US National Cancer Institute1.

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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

Organ function• Cardiac• Endocrine• GI and hepatic• Genitourinary• Musculoskeletal• Neurological• Pulmonary

Fertility and reproduction• Fertility• Health of offspring• Sexual functioning

Carcinogenesis• Recurrent primary

cancer• Subsequent neoplasms

Childhood andadolescent cancer

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 treat-ing 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 Hodgkin’s lymphoma treatment, doses of anthracyclines, as well as the fields and volumes of chest irradiation are proac-tively 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 pre-sent 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 function8–10. Pre-emptive screening and surveillance of at-risk treat-ment groups can facilitate the early detec-tion 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 treat-ments. 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 outcomesLong-term survivors of childhood and adolescent cancers are at risk of experienc-ing various psychological and social out-comes19,103–105, which may result in decreased overall quality of life. Studies of long-term survivors have investigated the prevalence of and risk factors associated with educa-tional and occupational attainment106–109, access to health insurance110,111, probability of marriage112–114, depression, anxiety and somatic distress115–117, post-traumatic distress118,119, post-traumatic growth120, fatigue121–123 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 predic-tors of change, for the psychosocial func-tioning of ageing survivors of childhood and adolescent cancer115,118.

Chronic health conditions, psychosocial sequelae and chronic symptoms may ulti-mately reduce the quality of survival through their effect on health and functional status7–11. These outcomes can be substantially influ-enced by the developmental age at the time of treatment, the presence of co-morbid conditions that precede cancer diagnosis, and the survivor’s access to remedial and preven-tive services. For example, although younger paediatric patients have higher risks of neuro-cognitive injury after central nervous system-directed therapy61, adolescent and young adult cancer survivors have been identified as a group that is particularly vulnerable to adverse psychosocial outcomes11,125. To opti-mize 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 issuesA 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’ start-ing 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 Study126 and the British Childhood Cancer Survivor Study127, have used 5 years from diagnosis, others have used 3 years post-diagnosis128, and some, such as the Bone Marrow Transplant Survivor Cohort, have applied alternative criteria using survival of ≥2 years from the time of haemato poietic 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 con-sider 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 influ-ence how results are interpreted and trans-lated into clinical practice: the study design, source and eligibility criteria for the study population; the study sample size; partici-pation rates; completeness of follow-up;

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.





• Survivorship education or training• Survivorship experience• Practice style• Perceptions regarding preventive care• Access to survivorship resources• Knowledge or access to individual survivor health history

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

• 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-efficacy• Insurance or health care access

• Financing and payment policies• Organization and affiliation of providers• Data systems and information sharing• Models of survivorship care• Insurance coverage and benefits supporting survivorship care (especially preventive and psychosocial services)• Community resources• Survivorship advocacy activity

Patient

Health caresystem

Cancer

Provider

Cancertreatment-associatedmorbidity

how treatment-related exposures were assigned; ascertainment and characteriza-tion 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 long-term adverse outcomes have been achieved through clinical and epidemiological investi-gations, which have been carried out at vari-ous 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 methodolo-gies and designs, is indicative of a power-ful scientific approach to establishing and quantifying risk.

National registries and similar admin-istrative 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 long-term 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 treatment-related 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 treatment-related toxicity profiles131,132. The St. Jude Lifetime Cohort study identified a high prevalence of undiagnosed disease among 1,713 adult (median age: 32 years; age range: 18–60 years) survivors of childhood cancer (median time from diagnosis: 25 years; range: 10–47 years) who completed comprehensive outpatient risk-based medical testing during a 2–3-day period8. In this cohort, the estimated cumulative prevalence of survivors who would develop at least one chronic health condition by 45 years of age was 95.5%, and that of survivors who would develop a serious or disabling or life-threatening chronic condi-tion by 45 years of age was 80.5%8. From this study, and other studies that report results

from systematic health screening of adult survivors of childhood cancer, it is concern-ing that there are high prevalences of health conditions typically observed in much older individuals, such as neurocognitive and neuro sensory 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 fac-tors, including co-morbid 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 researchThe ideal approach to childhood cancer survivor care involves a risk-based model that incorporates routine health care and a personalized plan of surveillance and screen-ing, as well as the management and preven-tion of late effects that are predisposed by cancer and its treatment95. 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 morbid-ity and the access of survivors to preventive and remedial interventions that can preserve health135–138. A hybrid approach featuring an evidence- and consensus-based design has been used to develop guidelines that are related to the long-term follow-up care of childhood cancer survivors135–138. This approach has been considered reasonable because of the strength of the evidence used to support numerous cancer treatment-related adverse outcomes and because of the crucial need for a resource for clinicians who manage the care of medically vulnerable sur-vivors. 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 super-vising the care of survivors139 — a problem

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




that is made worse because many survivors and their families may also lack this knowl-edge. Currently available clinical practice guidelines provide information about the potential risks of late effects that are associ-ated with specific cancer treatment modali-ties, targeted health screening, suggested methods of risk reduction and educational resources to assist providers in coordinating risk-based survivor care135–138.

It should be noted that optimal health-screening 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 spe-cific 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 (rep-resented by heterogeneous histological sub-types and treatment approaches), the diverse health risks that are associated with these treatments, and the frequency and delayed time to onset of many treatment complica-tions. Notwithstanding these limitations, in addition to standardizing follow-up 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 representative-ness to source population. Collectively, these studies show that screening identifies a sub-stantial proportion of childhood cancer sur-vivors who have previously unrecognized, treatment-related health complications of varying degrees of severity. Specifically, risk-based screening among participants in the St. Jude Lifetime Cohort identified a high prevalence of newly discovered neurocogni-tive and neurosensory deficits, heart valve disorders and pulmonary dysfunction that

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,

patient risk groups, diagnostic tests and screening intervals135–138. 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

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

26–29

Central nervous system

•Neurocognitive deficits, including learning deficits and diminished intelligence quotient, executive function, sustained attention, memory processing speed and visual–motor 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

30–32, 56–61

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

33–38

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, 42–44

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)

53–55

Pulmonary •Pulmonary fibrosis•Interstitial pneumonitis•Restrictive lung disease•Obstructive lung disease

46–49

Urinary tract •Bladder fibrosis•Dysfunctional voiding•Vesicoureteral reflux•Hydronephrosis•Renal insufficiency•Hypertension

50–52

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

62–73, 75,76

ACTH, adrenocorticotropic hormone; FSH, follicle‑stimulating hormone; LH, leutinizing hormone; TSH, thyroid‑stimulating hormone.




in 2010 with the goal of establishing a com-mon vision and an integrated strategy for the surveillance of late effects in childhood, adolescent and young adult cancer survivors throughout the world142. This collabora-tion 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 intervention-based approaches, which are designed to avoid or ameliorate adverse outcomes. It is hoped and expected that the future port-folio 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

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 compli-ance with recommended risk-based screen-ing; prevention or amelioration of adverse health outcomes such as cancer, congestive heart failure, obesity, fatigue or hyperten-sion; and promotion of positive social and quality-of-life outcomes such as education, employment, access to health insurance and mental health.

Future challengesWith the rapid increase in evidence regard-ing the health risks associated with survival after successful treatment of paediatric or adolescent cancer, medical and research communities have the ongoing responsibil-ity to critically evaluate the literature, define the characteristics of populations at high risk for morbidity and translate this evidence to clinical practice guidelines for risk-stratified follow-up care. The implementa-tion and dissemination of outcomes and of intervention-based research must consider potential barriers that occur at the level of

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 knowl-edge regarding cancer treatment history and its associated long-term health risks143–145 is an important barrier to the participation of sur-vivors in follow-up 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 sur-vivors 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 lim-ited to descriptive studies of clinic-based interventions21,147,148. Few studies assess the effect of clinic-based interventions on sur-vivor health knowledge, health perceptions or health behaviours, including their ongo-ing 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 effi-cient methods of health risk counselling that is developmentally and culturally appropriate for the survivor population.

Provider-related barriers. Knowledge defi-cits among health care providers regarding health issues that affect paediatric cancer survivors can also pose barriers to the deliv-ery 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 prefer-ences 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 thy-roid function152. These providers expressed increasing discomfort in managing the care of paediatric survivors who were ≥21 years 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

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

Class of chemotherapy

Chemotherapeutic agents

Established late effects Refs

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, 84–87

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

Acute myeloid leukaemia 86





Cum

ulat

ive

inci

denc

e

Age (years)

0.00

0.25

0.50

0.75

1.00

0 10 20

Knownlate effects

Emerginglate effects

Unknownlate effects

?

?

30 40 50 60 70

Cancer survivor

Excess lifetimemorbidity associatedwith cancer and therapy

Advanced onset ofmorbidity associatedwith cancer and therapy

General population

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 patient-specific letter detailing surveillance recom-mendations 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 dis-semination of clinical practice guidelines for treating survivors of childhood cancer, and evaluate methods to increase communica-tion and collaboration among the oncol-ogy and primary care providers who share survivorship care.

Barriers related to the health care environ-ment. Potential barriers to good care of can-cer survivors that are imposed by the health care environment relate to the availability of providers and survivorship resources, specialized late effects clinics and opera-tional models of survivorship care, which are greatly influenced by provider and payer rela-tionships 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 con-siderable 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 survi-vors to resources that remediate or prevent treatment-related toxicities, and on facilitat-ing communication and care transitions with community providers. The care of most paediatric cancer survivors is eventu-ally passed to community providers because specialized paediatric late effects pro-grammes are not universally available, and when they are available they usually have institutional age limitations that preclude follow-up beyond adolescence155. This tran-sition of care can be complicated by sub-optimal 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 recom-mendations. 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

increase the access of survivors to interven-tions that proactively address cancer-related morbidity.

Insurance and policy barriers. In countries such as the United States, where government-based health care is not provided, lack of health insurance or health policy exclusions and restrictions represent a considerable bar-rier 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 addi-tional 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 reimburse-ment for comprehensive-care coordination that includes assessment for medical and psychosocial sequelae, delivery of interven-tions to remediate or prevent treatment com-plications, counselling regarding methods of risk reduction, and referral to resources that help to address medical, psychosocial and practical needs.

ConclusionsAlthough the many individuals who have had a role in achieving the remarkable increase in the survival rates of childhood and adoles-cent cancers should be gratified, with success also comes responsibility. Simply focusing on the cure of the cancer cannot be an accept-able objective when considering the life-long risk of developing treatment-related compli-cations 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 at-large, than the acute complica-tion 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 sur-vivors from receiving optimal care to mini-mize adverse health-related outcomes and to maximize quality-of-life outcomes.

Figure 4 | A theoretical framework. This figure shows the gaps in knowledge regarding the long‑term outcomes among ageing childhood and adolescent cancer survivors.




Leslie L. Robison and Melissa M. Hudson are at the Department of Epidemiology and Cancer Control,

St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis,

Tennessee 38105, USA.

Melissa M. Hudson is also at the Department of Oncology, St. Jude Children’s Research Hospital,

262 Danny Thomas Place, Memphis, Tennessee 38105, USA.

Correspondence to L.L.R. e-mail: [email protected]

doi:10.1038/nrc3634 Published online 5 December 2013

1. Howlader, N. et al. (eds) SEER Cancer Statistics Review, 1975–2010. National Cancer Institute. Bethesda, MD [online] http://seer.cancer.gov/csr/1975_2010/ (2013).

2. Gajjar, A. et al. Children’s Oncology Group’s 2013 blueprint for research: central nervous system tumors. Pediatr. Blood Cancer 60, 1022–1026 (2013).

3. Norris, R. E. & Adamson, P. C. Challenges and opportunities in childhood cancer drug development. Nature Rev. Cancer 12, 776–782 (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, 551–565 (2011).

5. Smith, M. A. et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J. Clin. Oncol. 28, 2625–2634 (2010).

6. Mariotto, A. B. et al. Long-term survivors of childhood cancers in the United States. Cancer Epidemiol. Biomarkers Prev. 18, 1033–1040 (2009).

7. Hudson, M. M. et al. Health status of adult long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. JAMA 290, 1583–1592 (2003).

8. Hudson, M. M. et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309, 2371–2381 (2013).

9. Oeffinger, K. C. et al. Chronic health conditions in adult survivors of childhood cancer. N. Engl. J. Med. 355, 1572–1582 (2006).

10. Sun, C. L. et al. Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 116, 3129–3139, (2010).

11. Tai, E. et al. Health status of adolescent and young adult cancer survivors. Cancer 118, 4884–4891 (2012).

12. Armstrong, G. T., Pan, Z., Ness, K. K., Srivastava, D. & Robison, L. L. Temporal trends in cause-specific late mortality among 5-year survivors of childhood cancer. J. Clin. Oncol. 28, 1224–1231 (2010).

13. Mertens, A. C. et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J. Natl Cancer Inst. 100, 1368–1379 (2008).

14. Diller, L. et al. Chronic disease in the Childhood Cancer Survivor Study cohort: a review of published findings. J. Clin. Oncol. 27, 2339–2355 (2009).

15. Green, D. M. et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J. Clin. Oncol. 27, 2677–2685 (2009).

16. Gurney, J. G. et al. Social outcomes in the Childhood Cancer Survivor Study cohort. J. Clin. Oncol. 27, 2390–2395 (2009).

17. Meadows, A. T. et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J. Clin. Oncol. 27, 2356–2362 (2009).

18. Ness, K. K. et al. Physical performance limitations in the Childhood Cancer Survivor Study cohort. J. Clin. Oncol. 27, 2382–2389 (2009).

19. Zeltzer, L. K. et al. Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 27, 2396–2404 (2009).

20. Hudson, M. M. et al. High-risk populations identified in Childhood Cancer Survivor Study investigations: implications for risk-based surveillance. J. Clin. Oncol. 27, 2405–2414 (2009).

21. Hudson, M. M. A model for care across the cancer continuum. Cancer 104, 2638–2642 (2005).

22. Green, D. M. et al. Relevance of historical therapeutic approaches to the contemporary treatment of pediatric solid tumors. Pediatr. Blood Cancer 60, 1083–1094 (2013).

23. Hudson, M. M. et al. 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, 334–343 (2012).

24. Armstrong, G. T., Stovall, M. & Robison, L. L. Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study. Radiat. Res. 174, 840–850 (2010).

25. van Dijk, I. W. et al. Dose-effect relationships for adverse events after cranial radiation therapy in long-term childhood cancer survivors. Int. J. Radiat. Oncol. Biol. Phys. 85, 768–775 (2013).

26. Galper, S. L. et al. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117, 412–418 (2011).

27. Schellong, G. et al. Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. Pediatr. Blood Cancer 55, 1145–1152 (2010).

28. Tukenova, M. et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J. Clin. Oncol. 28, 1308–1315 (2010).

29. van der Pal, H. J. et al. High risk of symptomatic cardiac events in childhood cancer survivors. J. Clin. Oncol. 30, 1429–1437 (2012).

30. Bowers, D. C. et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 24, 5277–5282 (2006).

31. Bowers, D. C. et al. Stroke as a late treatment effect of Hodgkin’s Disease: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 23, 6508–6515 (2005).

32. Morris, B. et al. Cerebrovascular disease in childhood cancer survivors: A Children’s Oncology Group Report. Neurology 73, 1906–1913 (2009).

33. Chemaitilly, W. & Sklar, C. A. Endocrine complications in long-term survivors of childhood cancers. Endocr. Relat. Cancer 17, R141–R159 (2010).

34. de Vathaire, F. et al. Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol. 13, 1002–1010 (2012).

35. Laughton, S. J. et al. 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 SJMB-96 trial. J. Clin. Oncol. 26, 1112–1118 (2008).

36. Meacham, L. R. et al. 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, 1381–1388 (2009).

37. Merchant, T. E. et al. Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors. J. Clin. Oncol. 29, 4776–4780 (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, 1302–1307 (2009).

39. Goldsby, R. et al. Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology 140, 1464–1471, e1 (2011).

40. Green, D. M. et al. Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 332–339 (2010).

41. Kenney, L. B. et al. Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children’s Oncology Group. J. Clin. Oncol. 30, 3408–3416 (2012).

42. Metzger, M. L. et al. Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J. Clin. Oncol. 31, 1239–1247 (2013).

43. Signorello, L. B. et al. Female survivors of childhood cancer: preterm birth and low birth weight among their children. J. Natl Cancer Inst. 98, 1453–1461 (2006).

44. Signorello, L. B. et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 376, 624–630 (2010).

45. Castellino, S. et al. Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 54, 663–669 (2010).

46. Huang, T. T. et al. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140, 881–901 (2011).

47. Mertens, A. C. et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 95, 2431–2441 (2002).

48. Motosue, M. S. et al. Pulmonary function after whole lung irradiation in pediatric patients with solid malignancies. Cancer 118, 1450–1456 (2012).

49. Mulder, R. L. et al. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 66, 1065–1071 (2011).

50. Dawson, L. A. et al. Radiation-associated kidney injury. Int. J. Radiat. Oncol. Biol. Phys. 76, S108–S115 (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 Children’s Oncology Group. Pediatr. Blood Cancer 51, 724–731 (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 Children’s Oncology Group. Pediatr. Blood Cancer 52, 439–446 (2009).

53. Estilo, C. L. et al. 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, 215–222 (2003).

54. Merchant, T. E. et al. Differential attenuation of clavicle growth after asymmetric mantle radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 59, 556–561 (2004).

55. Paulino, A. C. Late effects of radiotherapy for pediatric extremity sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 60, 265–274 (2004).

56. Goldsby, R. E. et al. Late-occurring neurologic sequelae in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 324–331 (2010).

57. Grewal, S. et al. Auditory late effects of childhood cancer therapy: a report from the Children’s Oncology Group. Pediatrics 125, e938–e950 (2010).

58. Packer, R. J. et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J. Clin. Oncol. 21, 3255–3261 (2003).

59. Whelan, K. et al. Auditory complications in childhood cancer survivors: a report from the childhood cancer survivor study. Pediatr. Blood Cancer 57, 126–134 (2011).

60. Whelan, K. F. et al. Ocular late effects in childhood and adolescent cancer survivors: a report from the childhood cancer survivor study. Pediatr. Blood Cancer 54, 103–109 (2010).

61. Winick, N. Neurocognitive outcome in survivors of pediatric cancer. Curr. Opin. Pediatr. 23, 27–33 (2011).

62. Armstrong, G. T. et al. Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J. Clin. Oncol. 29, 3056–3064 (2011).

63. Bassal, M. et al. Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 24, 476–483 (2006).

64. Bhatti, P. et al. 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, 741–752 (2010).

65. Boukheris, H. et al. Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Int. J. Radiat. Oncol. Biol. Phys. 85, 776–783 (2013).

66. Friedman, D. L. et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J. Natl Cancer Inst. 102, 1083–1095 (2010).




mailto:les.robison%40stjude.org?subject=

http://seer.cancer.gov/csr/1975_2010/

67. Henderson, T. O. et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann. Intern. Med. 156, 757–766 (2012).

68. Henderson, T. O. et al. 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, 224–230 (2012).

69. Inskip, P. D. et al. Radiation dose and breast cancer risk in the childhood cancer survivor study. J. Clin. Oncol. 27, 3901–3907 (2009).

70. Neglia, J. P. et al. 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, 1528–1537 (2006).

71. Nottage, K. et al. Secondary colorectal carcinoma after childhood cancer. J. Clin. Oncol. 30, 2552–2558 (2012).

72. Pappo, A. S. et al. Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Pediatr. Blood Cancer 60, 461–466 (2013).

73. Perkins, J. L. et al. Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study. J. Clin. Oncol. 23, 3733–3741 (2005).

74. Reulen, R. C. et al. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 305, 2311–2319 (2011).

75. Ronckers, C. M. et al. Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat. Res. 166, 618–628 (2006).

76. Tukenova, M. et al. Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Int. J. Radiat. Oncol. Biol. Phys. 82, e383–e390 (2012).

77. De Bruin, M. L. et al. Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. J. Clin. Oncol. 27, 4239–4246 (2009).

78. Swerdlow, A. J. et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a National Cohort Study. J. Clin. Oncol. 30, 2745–2752 (2012).

79. Sigurdson, A. J. et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365, 2014–2023 (2005).

80. Bowers, D. C. et al. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol. 14, e321–e328 (2013).

81. Taylor, A. J. et al. Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 5287–5293 (2010).

82. Wilson, C. L. et al. Renal carcinoma after childhood cancer: a report from the childhood cancer survivor study. J. Natl Cancer Inst. 105, 504–508 (2013).

83. Ibrahim, E. M. et al. Increased risk of second lung cancer in Hodgkin’s lymphoma survivors: a meta-analysis. Lung 191, 117–134 (2013).

84. Brock, P. R. et al. 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, 2408–2417 (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, 537–544 (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, 23–35 (2009).

87. Skinner, R. Nephrotoxicity — what do we know and what don’t we know? J. Pediatr. Hematol. Oncol. 33, 128–134 (2011).

88. Lipshultz, S. E. et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J. Clin. Oncol. 23, 2629–2636 (2005).

89. Mulrooney, D. A. et al. 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. et al. Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics 121, e705–e713 (2008).

91. Kadan-Lottick, N. S. et al. Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study. J. Clin. Oncol. 26, 3038–3045 (2008).

92. Jain, P. et al. 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. et al. 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, 1451–1457 (2013).

94. Bhatia, S. Role of genetic susceptibility in development of treatment-related adverse outcomes in cancer survivors. Cancer Epidemiol. Biomarkers Prev. 20, 2048–2067 (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, 208–236 (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, 4046–4054 (2009).

97. Lin, H. Y. & Liao, S. L. Orbital development in survivors of retinoblastoma treated by enucleation with hydroxyapatite implant. Br. J. Ophthalmol. 95, 630–633 (2011).

98. Turner, C. D. et al. Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr. Blood Cancer 53, 417–423 (2009).

99. Kinahan, K. E. et al. 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, 2466–2474 (2012).

100. Henderson, T. O. et al. Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann. Intern. Med. 152, 444–455 (2010).

101. Pui, C. H. Prophylactic cranial irradiation: going, going, gone. Lancet Oncol. 10, 932–933 (2009).

102. Hodgson, D. C., Hudson, M. M. & Constine, L. S. Pediatric hodgkin lymphoma: maximizing efficacy and minimizing toxicity. Semin. Radiat. Oncol. 17, 230–242 (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, 532–543 (2011).

104. Nathan, P. C. 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. 161, 798–806 (2007).

105. Wakefield, C. E. et al. The psychosocial impact of completing childhood cancer treatment: a systematic review of the literature. J. Pediatr. Psychol. 35, 262–274 (2010).

106. Kirchhoff, A. C. et al. Occupational outcomes of adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer 117, 3033–3044 (2011).

107. Kuehni, C. E. et al. Educational achievement in Swiss childhood cancer survivors compared with the general population. Cancer 118, 1439–1449 (2012).

108. Lancashire, E. R. et al. Educational attainment among adult survivors of childhood cancer in Great Britain: a population-based cohort study. J. Natl Cancer Inst. 102, 254–270 (2010).

109. Mitby, P. A. et al. 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, 1115–1126 (2003).

110. Kirchhoff, A. C. et al. Employer-sponsored health insurance coverage limitations: results from the Childhood Cancer Survivor Study. Support Care Cancer 21, 377–383 (2013).

111. Park, E. R. et al. Health insurance coverage in survivors of childhood cancer: the Childhood Cancer Survivor Study. J. Clin. Oncol. 23, 9187–9197 (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, 846–855 (2007).

113. Frobisher, C. et al. Long-term population-based divorce rates among adult survivors of childhood cancer in Britain. Pediatr. Blood Cancer 54, 116–122 (2010).

114. Janson, C. et al. Predictors of marriage and divorce in adult survivors of childhood cancers: a report from the Childhood Cancer Survivor Study. Cancer Epidemiol. Biomarkers Prev. 18, 2626–2635 (2009).

115. Brinkman, T. M. et al. Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br. J. Cancer 109, 1373–1381 (2013).

116. Zebrack, B. J. et al. Psychological outcomes in long-term survivors of childhood brain cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 22, 999–1006 (2004).

117. Zebrack, B. J. et al. Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study. Pediatrics 110, 42–52 (2002).

118. Kwak, M. et al. Trajectories of psychological distress in adolescent and young adult patients with cancer: a 1-year longitudinal study. J. Clin. Oncol. 31, 2160–2166 (2013).

119. Stuber, M. L. et al. Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics 125, e1124–e1134 (2010).

120. Zebrack, B. J. et al. Perceived positive impact of cancer among long-term survivors of childhood cancer: a report from the childhood cancer survivor study. Psychooncology 21, 630–639 (2012).

121. Clanton, N. R. et al. Fatigue, vitality, sleep, and neurocognitive functioning in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 117, 2559–2568 (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, 5501–5510 (2005).

123. Mulrooney, D. A. et al. Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS). Sleep 31, 271–281 (2008).

124. Lu, Q. et al. Pain in long-term adult survivors of childhood cancers and their siblings: a report from the Childhood Cancer Survivor Study. Pain 152, 2616–2624 (2011).

125. Schultz, K. A. et al. Behavioral and social outcomes in adolescent survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 25, 3649–3656 (2007).

126. Robison, L. L. et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J. Clin. Oncol. 27, 2308–2318 (2009).

127. Hawkins, M. M. et al. The British Childhood Cancer Survivor Study: objectives, methods, population structure, response rates and initial descriptive information. Pediatr. Blood Cancer 50, 1018–1025 (2008).

128. Menu-Branthomme, A. et al. Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood. Int. J. Cancer 110, 87–93 (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, 174–178 (2006).

130. Leisenring, W. M. et al. Pediatric cancer survivorship research: experience of the Childhood Cancer Survivor Study. J. Clin. Oncol. 27, 2319–2327 (2009).

131. Hudson, M. M. et al. 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, 825–836 (2011).

132. Sieswerda, E. et al. The EKZ/AMC childhood cancer survivor cohort: methodology, clinical characteristics, and data availability. J. Cancer Surviv 7, 439–454 (2013).

133. Geenen, M. M. et al. Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 297, 2705–2715 (2007).

134. Landier, W. et al. Yield of screening for long-term complications using the children’s oncology group long-term follow-up guidelines. J. Clin. Oncol. 30, 4401–4408 (2012).




http://dx.doi.org/10.1177/0883073813491829

http://dx.doi.org/10.1177/0883073813491829

135. In Dutch Childhood Oncology Group, Richtlijn follow-up na kinderkanker meer dan 5 jaar na diagnose. SKION, Den Haag/Amsterdam [online], http://www.skion.nl/ (2010).

136. In Scottish Intercollegiate Guidelines Network, Long term follow up care of survivors of childhood cancer. A national clinical guideline [online], http://www.sign.ac.uk/ (2004).

137. In United Kingdom Children’s Cancer Study Group, Late Effects Group, Therapy based long term follow up practice statement [online], http://www.cclg.org.uk/ (2011).

138. In Children’s Oncology Group, Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Version 3.0 [online], http://www.survivorshipguidelines.org/ (2008).

139. Nathan, P. C. et al. Family physician preferences and knowledge gaps regarding the care of adolescent and young adult survivors of childhood cancer. J. Cancer Surviv 7, 275–282 (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, 682–687 (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, 976–982 (2010).

142. Kremer, L. C. et al. A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr. Blood Cancer 60, 543–549 (2013).

143. Hudson, M. M. et al. Multi-component behavioral intervention to promote health protective behaviors in childhood cancer survivors: the protect study. Med. Pediatr. Oncol. 39, 2–11 (discussion 2) (2002).

144. Kadan-Lottick, N. S. et al. Childhood cancer survivors’ knowledge about their past diagnosis and treatment: Childhood Cancer Survivor Study. JAMA 287, 1832–1839 (2002).

145. Wilkins, K. L. & Woodgate, R. L. Preventing second cancers in cancer survivors. Oncol. Nurs. Forum 35, E12–E22 (2008).

146. Oeffinger, K. C. et al. Increasing rates of breast cancer and cardiac surveillance among high-risk survivors of childhood Hodgkin lymphoma following a mailed, one-page survivorship care plan. Pediatr. Blood Cancer 56, 818–824 (2011).

147. Hinkle, A. S. et al. A clinic-based, comprehensive care model for studying late effects in long-term survivors of pediatric illnesses. Pediatrics 113, 1141–1145 (2004).

148. Kenney, L. B. et al. The current status of follow-up 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, 1062–1066 (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. et al. Factors influencing long-term follow-up clinic attendance among survivors of childhood cancer. J. Cancer Surviv 2, 225–232 (2008).

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, 878–883 (2010).

153. Blaauwbroek, R., Tuinier, W., Meyboom-de Jong, B., Kamps, W. A. & Postma, A. Shared care by paediatric oncologists and family doctors for long-term follow-up of adult childhood cancer survivors: a pilot study. Lancet Oncol. 9, 232–238 (2008).

154. In Advisory Board Company, Survivorship [online], http://www.advisory.com/Research/Oncology-Roundtable/Studies/2008/Elevating-the-Patient-Experience (2008).

155. Eshelman-Kent, D. et al. Cancer survivorship practices, services, and delivery: a report from the Children’s Oncology Group (COG) nursing discipline, adolescent/young adult, and late effects committees. J. Cancer Surviv 5, 345–357 (2011).

156. Oeffinger, K. C. & McCabe, M. S. Models for delivering survivorship care. J. Clin. Oncol. 24, 5117–5124 (2006).

157. The Patient Protection and Affordable Care Act. Public Law 111–148, (2010).

AcknowledgementsResearch 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 statementThe authors declare no competing interests.




http://www.skion.nl/

http://www.sign.ac.uk/

http://www.cclg.org.uk/

http://www.survivorshipguidelines.org/

http://dx.doi.org/10.1007/s11764-013-0291-9

http://www.advisory.com/Research/Oncology-Roundtable/Studies/2008/Elevating-the-Patient-Experience



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