Chapter 448. Cancer Survivorship and Recommendations for Follow-Up

Systematic advances in risk-based therapy for childhood cancer has been responsible for the progress in overall survival over the past four decades; five-year survival rates now approach 80%.1 This has resulted in a growing population of childhood cancer survivors—an estimated 300,000 survivors in the United States.2 Demographics of childhood cancer survivors reveal that although a third of these individuals are less than 20 years of age, one half are between 20 and 40 years old, and the remaining one fifth are over 40 years of age.

Cancer and its treatment during childhood can result in a variety of long-term sequelae, such as impairment in growth and development, endocrine dysfunction, cognitive decline, cardiopulmonary compromise, musculoskeletal sequelae, renal compromise, gastrointestinal dysfunction, auditory and visual impairments, as well as subsequent malignancies. It has been demonstrated quite convincingly that one-third of the long-term survivors report severe or life-threatening complications 30 years from primary diagnosis.3 These sequelae are primarily related to specific therapeutic exposures, and can reduce the overall quality of life (QOL) of the survivors.

The health and well-being of this rapidly growing number of childhood cancer survivors have been described fairly extensively in the literature.This chapter reviews some of these well-described, late-occurring adverse events in survivors of childhood cancer and what is now known about the relationship between these events and therapeutic exposures (Table 448-1).

Severe growth retardation (standing height below the fifth percentile for age- and sex-matched healthy individuals) has been observed in 30% of brain tumor survivors and in 15% of patients treated on certain antileukemia regimens,4,5 caused primarily by treatment with cranial irradiation. The effects of cranial irradiation are age and dose related, with children less than 8 years of age at the time of cranial irradiation at risk for adult height below the third percentile.4Treatment with growth hormone prior to closure of epiphyses in patients with documented growth hormone deficiency usually results in near normalization of final height, unless the spinal axis has also been irradiated.

Screening

Monitoring of long-term survivors for growth problems relies on the use of standardized curves available online (http://www.cdc.gov/growthcharts). Frequent serial measurements should be obtained to establish each child’s pattern of growth. Clinicians following survivors at high risk for growth retardation should be sensitive to the need to refer such patients early to the endocrinologist, so that effective interventions can be instituted in a timely fashion. Endocrine consultation may be indicated for children whose height crosses two or more percentiles, or whose growth velocity is less than 5 cm/year, or whose height is less than the third percentile.

Male Gonadal Function

All therapeutic modalities (surgery, radiation, or chemotherapy with alkylating agents) can cause both germ cell depletion and abnormalities of gonadal endocrine function among male cancer survivors. Bilateral orchiectomy results not only in infertility but also in testosterone deficiency, requiring ongoing hormonal replacement beginning in puberty. These patients should be managed in collaboration with an endocrinologist.

Radiation to the testes is known to result in germinal loss with decreases in testicular volume and sperm production, and increases in follicle-stimulating hormone (FSH). Effects are dose dependent, following exposures of 0.1 to 6 Gy.Radiation therapy may also be toxic to Leydig cells, although higher doses than those toxic to germ (Sertoli) cells are needed to induce Leydig cell damage. Leydig cell damage is dose dependent and inversely related to age at treatment.6 Boys treated prepubertally or peripubertally with Gy greater than or equal to 20 for testicular leukemia, in addition to suffering germ cell depletion, are at high risk of delayed sexual maturation associated with decreased testosterone levels, despite increased luteinizing hormone (LH) levels. Leydig cells of adolescent and young adult male testes are relatively radioresistant, and fractionated doses greater than 30 Gy to the testes may induce failure in only about 50% of patients.

Alkylating agents decrease spermatogenesis in a dose-dependent manner. Gonadal damage following cumulative doses of cyclophosphamide lower than 7.5 gm/m2(or 200 mg/kg, as used in hematopoietic cell transplantation) have been shown to be reversible in up to 70% of patients after prolonged periods of follow-up. In contrast to their prominent effects on germ cell epithelium, chemotherapy effects are less striking on slowly dividing Leydig cells, and may be age related. Following exposure to alkylating agents in prepubertal boys, normal pubertal progression and normal adult levels of testosterone are the rule; gynecomastia with low testosterone and increased luteinizing hormone (LH) have been reported in patients treated during adolescence, and compensated Leydig cell failure (increased LH with low normal testosterone levels or exaggerated follicle-stimulating hormone [FSH] and LH responses to LH-releasing hormone) without gynecomastia is common in adults.7

Screening

Screening includes an annual age-appropriate history with specific attention to problems with libido, impotence, or fertility and examination for gynecomastia, Tanner staging, of body hair, and assessment of penile and testicular size. Hormonal evaluation, including at least a single measurement of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, is recommended as a baseline at age 14 years, and in boys in whom puberty appears to be delayed. Males at risk of infertility8 may benefit from semen analysis; honest and sensitive discussions of fertility should be part of their follow-up visit. When abnormalities in testicular function are detected, close cooperation with an endocrinologist is essential in planning hormonal replacement therapy or in monitoring patients for spontaneous recovery. When no abnormalities are noted on history and physical examination but sexual maturity has not been completed, these studies should be repeated every 1 to 2 years. Conversely, in light of the potential for recovery of spermatogenesis and interpatient variations in gonadal toxicity, reminders about contraception should be given.

Female Gonadal Function

In contrast to the process in male survivors, germ cell failure and loss of ovarian endocrine function occur concomitantly in females. Radiation effects are both age and dose dependent.9In women older than 40 years at the time of treatment, irreversible ovarian failure is an almost universal result of 4 to 7 Gy of conventionally fractionated radiation delivered to both ovaries. Prepubertal ovaries are relatively radioresistant and, despite higher doses (12–50 Gy), primary amenorrhea and delayed puberty eventually occurred in only 68% of patients treated at a mean age of 6.9 years. Secondary amenorrhea resulting from such modest doses appears to be reversible within several months to 4 years in 50% to 60% of patients.10

Total body irradiation (10 Gy single fraction) has been associated with primary amenorrhea and absent secondary sexual characteristics in most patients treated prior to puberty and followed for as long as 10 years.11 However, others have reported normal pubertal progression, although with elevated follicle-stimulating hormone (FSH) levels following total body irradiation during early childhood.12 As with standard radiation, increasing age at the time of total body irradiation has been found to predict ovarian failure.13 Premature menopause has also been reported in the setting of hematopoietic cell transplantation.11

Ovarian failure has also been associated with chemotherapy, especially the alkylating agents, and the toxicity demonstrates dose and age dependence. Following myeloablative doses of alkylating agents, including busulfan and cyclophosphamide, permanent ovarian failure can be expected at all ages.14 For survivors who retain normal ovarian function after cancer therapy, there is an increased risk of premature menopause.15 The risk factors associated with an early menopause include exposure to high doses of alkylating agents and abdomino-pelvic radiation.

Screening

The diagnostic evaluation of ovarian dysfunction should include history (primary or secondary amenorrhea, menstrual irregularity, and pregnancies or difficulty with conception), and physical examination (Tanner staging of breast and genital development). Serum gonadotropin (FSH, LH) and estradiol levels should be obtained as a baseline at age 13 years and as clinically indicated, in the absence of clinical evidence of puberty (menarche, development of secondary sexual characteristics), in order to assess the need for hormone therapy to induce puberty. In addition, because young women who have progressed through puberty may experience early onset of menopause, they should also undergo assessment of gonadotropin and estradiol levels if there are clinical symptoms of estrogen deficiency (eg, irregular menses, amenorrhea, hot flashes, and vaginal dryness). Survivors with concerns regarding fertility should be urged to seek consultation with a reproductive endocrinologist.

Hypothyroidism is a common late effect and almost always is the result of radiation to the neck. The likelihood of abnormalities depends on radiation dose. Children treated with less than 20 Gy have a less than 20% incidence of hypothyroidism, whereas for those exposed to radiation doses exceeding 45 Gy, the actuarial risk of hypothyroidism at 20 years approaches 50%.16 Adolescents may experience more severe abnormalities with higher thyroid-stimulating hormone (TSH) levels than those seen in young children, and females are at a higher risk. In some instances, hypothyroidism has been reversible after as long as 3 years, even without replacement therapy.17 The risk of thyroid nodules has been reported to be 27-fold that of sibling controls occurring at a mean latency of 14 years after treatment.16 Female sex and radiation dose exceeding 25 Gy are independent risk factors. About 7% of nodules are malignant. Careful shielding of the thyroid during irradiation, elimination of radiation or the use of lower doses, and avoidance of the concurrent use of radiation and iodide-containing contrast materials should help to decrease the incidence of thyroid abnormalities.

Screening

Patients who have received direct radiation to the neck should be routinely screened for thyroid abnormalities by physical examination indefinitely, since nodules may be late appearing. Recommendations, as per the Children’s Oncology Group’s (COG’s) Long-Term Follow-Up Guidelines,18 for monitoring include annual assessment of thyroid functions (thyroid-stimulating hormone and free T4).

Cognitive decline can be seen in children treated with cranial irradiation, high-dose systemic methotrexate and/or cytarabine, or intrathecal methotrexate. Risk factors include increasing radiation dose, young age at the time of therapy, treatment with both cranial irradiation and systemic or intrathecal chemotherapy, and female gender.19 The impact of school absenteeism during active cancer treatment needs to be factored in for all cancer survivors, regardless of treatment. Severe deficits are most frequently noted in children with brain tumors treated with cranial irradiation, especially in children who were younger than 5 years of age at the time of treatment. Neurocognitive deficits usually become evident within 1 to 2 years following radiation, and are progressive.20 The decline over time is typically reflective of the child’s failure to acquire new abilities or information at a rate similar to peers, rather than of a progressive loss of skills and knowledge. Affected children are particularly prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills, with irradiation- or chemotherapy-induced destruction in normal white matter partially explaining intellectual and academic achievement deficits.21 They most often experience academic difficulties in the areas of reading, language, and mathematics. Children in the younger age groups treated with cranial irradiation may experience significant drops in IQ scores. Utilization of special education services has been reported to be significantly higher among leukemia and brain tumor survivors, when compared with age- and sex-matched siblings.22Exposure to cranial irradiation at higher doses increases the risk of needing special education services.

Screening

Patients who received therapy that may potentially have an impact on neurocognitive function should undergo a baseline neuropsychological evaluation, repeated as clinically indicated and at key transition points (eg, when moving from grade school to middle/junior high school), as well as annual assessment of the survivor’s vocational or educational progress.23

Anthracyclines (eg, doxorubicin, daunomycin and idarubicin) are a well-known cause of cardiotoxicity.24,25 Chronic cardiotoxicity usually manifests itself as cardiomyopathy with progression to congestive heart failure, although other cardiac complications such as pericarditis and arrhythmias have also been described. The incidence of cardiomyopathy is dose dependent, and may exceed 30% among adult patients who received a cumulative anthracycline dose in excess of 600 mg/m2. With a total dose of 500 to 600 mg/m2, the incidence is 11%, falling to less than 1% for cumulative doses less than 500 mg/m2.24Children are at increased risk for cardiac compromise following considerably lower cumulative doses of anthracyclines. A cumulative dose exceeding 250 mg/m2 (in association with radiation to the heart) is associated with a cumulative incidence of heart failure of 20% at age 25 years compared with an incidence of 5% at a lesser dose.26Other risk factors include a younger age at exposure to anthracyclines, exposure to radiation to the chest, female sex, and presence of other cardiac-compromising comorbidities (such as hypertension, diabetes, and hyperlipidemia). It has been abundantly demonstrated that the risk increases with increasing cumulative exposures to anthracyclines. Cardiomyopathy can occur many years after completion of therapy in asymptomatic individuals, and the onset may be spontaneous or coincide with exertion or pregnancy, especially during the third trimester or at the time of labor and delivery.

Chronic cardiac toxicity associated with radiation alone most commonly results in pericardial effusions or constrictive pericarditis, usually with radiation doses exceeding 40 Gy.27Coronary artery disease has been reported following radiation to the mediastinum, with a cumulative risk of 21% at 20 years after radiation.28

Screening

Patients who have received anthracycline chemotherapy need ongoing monitoring for late-onset cardiomyopathy, with frequency of evaluation based on total cumulative dose and age at the time of initial therapy.29,30 In addition to monitoring for cardiomyopathy, survivors who received radiation to fields that include the heart also need monitoring for potential early-onset atherosclerotic heart disease, valvular disease, and pericardial complications. Fasting lipids should be evaluated and patients counseled with regard to diet, weight, and exercise, because known risk factors for cardiovascular disease can add to those imposed by previous therapy. Specific recommendations for monitoring based on age and therapeutic exposure are available at http://www.survivorshipguidelines.org.18

Pulmonary radiation can lead to pulmonary fibrosis and pneumonitis. Clinically apparent pneumonitis with cough, fever, or dyspnea occurs in 5% to 15% of patients who received more than 30 Gy31 in standard fractions to more than 50% of the lung. Obstructive changes have also been reported after conventional radiation therapy. Following hematopoietic cell transplantation, both restrictive and obstructive lung disease, including bronchiolitis obliterans, are well described.

Several chemotherapeutic agents have also been associated with pulmonary disease in long-term survivors. Interstitial pneumonitis and pulmonary fibrosis have been reported after exposure to bleomycin and nitosoureas,32 with the chronic lung toxicity being dose dependent above a threshold cumulative dose of 400 units/m2 and exacerbated by concurrent or previous radiation therapy. As with bleomycin, carmustine- and lomustine-related pulmonary toxicity is dose related. Cumulative carmustine doses greater than 600 mg/m2 result in a 50% incidence of symptoms. Female patients are at a higher risk for this complication than their male counterparts.

Additional factors contributing to chronic pulmonary toxicity include superimposed infection, underlying pneumonopathy (eg, asthma), cigarette smoking, respiratory toxicity, chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation, and the effects of chronic pulmonary involvement by tumor or reaction to tumor. Increased oxygen concentrations associated with general anesthesia or scuba diving also have been found to exacerbate pulmonary fibrosis.33

Screening

Monitoring for pulmonary dysfunction in childhood cancer survivors includes assessment of symptoms such as chronic cough or dyspnea on annual follow-up. Risks of smoking and exposure to secondhand smoke should be discussed with all patients, and they should be counseled accordingly. Pulmonary function tests (including carbon monoxide diffusing capacity [DLCO] and spirometry) and chest x-ray are recommended at baseline upon entry into long-term follow-up for patients at risk, and repeated as clinically indicated in symptomatic patients. Repeat evaluation should also be considered for at-risk patients prior to general anesthesia. Patients with risk factors for lung complications are discouraged from scuba diving.

Ocular Effects

Risk for the development of cataracts is increased in survivors exposed to corticosteroids, cranial irradiation,34,35 total body irradiation,36 or busulfan.37 Although approximately 50% of patients exposed to these agents develop cataracts long term, these are mainly posterior subcapsular cataracts, with minimal ocular morbidity. Single-dose total body irradiation is associated with a 60% incidence of cataracts, and fractionated total body irradiation with a 43% incidence for those receiving 6 or fewer fractions, and a 7% incidence for those receiving more than 6 fractions. Factors independently associated with an increased risk of cataract formation are older age (23 years), allogeneic hematopoietic cell transplantation, higher radiation dose rate, and prolonged steroid administration. Xerophthalmia may also occur as a late complication due to decreased lacrimation resulting from damage to the lacrimal gland during radiation, or in patients undergoing hematopoietic cell transplantation who developed chronic graft-versus-host disease.38

Audiologic Effects

Platinum chemotherapy, cranial irradiation at a young age (especially during infancy),39 and exposure to aminoglycoside antibiotics40 place patients at increased risk for therapy-related hearing loss. Hearing loss associated with ototoxic agents is generally sensorineural in origin and is usually irreversible. Young children require attention to hearing, because deficits have a significant impact on the development of normal speech.

Children whose permanent teeth have not completely developed at the time of cancer treatment are most vulnerable to dental complications, and treatment with chemotherapy during early childhood may result in qualitative problems with enamel and root development.41 However, patients of all ages who received cranial or total body irradiation are susceptible to dental complications, most often manifesting as increased susceptibility to dental caries and gingivitis as a result of diminished salivary gland function. Patients who have undergone hematopoietic cell transplantation are at increased risks for dental caries and gum disease; abnormalities of tooth development are seen in survivors who underwent hematocrit (HCT) during childhood.42 Younger age at transplantation (especially under 6 years) and total body irradiation (TBI) doses 10 Gy are associated with the greatest risk.43

Chronic hepatotoxicity and portal hypertension have emerged in survivors of childhood acute lymphoblastic leukemia who received 6-thioguanine-based maintenance therapy,44 and these survivors should receive long-term surveillance for this complication. Chronic viral hepatitis resulting from transfusion of contaminated blood products should be considered in the differential diagnosis of all survivors with persistently elevated alanine aminotransferase (ALT) levels. Hepatitis C is the most prevalent type of hepatitis seen in survivors transfused before universal screening of the blood supply for this infection (implemented in the United States in July 1992). Both cirrhosis and hepatocellular cancer are potential sequelae of untreated chronic viral hepatitis and potential causes of morbidity and mortality in this population.45 It is estimated that approximately 30% to 35% of patients exposed to blood products before 1991 are infected with hepatitis C and are at risk for development of cirrhosis and related complications.46

Avascular necrosis (osteonecrosis) is most often a consequence of therapy with corticosteroids, particularly dexamethasone, and occurs in up to 10% of such patients.47 This complication usually develops during or shortly after completion of therapy, but may progress over time. Avascular necrosis of bone is also reported after allogeneic hematopoietic cell transplantation, with the incidence reported to be as high as 8% to 10% in long-term survivors.48 Identified risk factors include prolonged steroid therapy for graft-versus-host disease, male gender, and total body irradiation. The hip is the most commonly involved joint (80%); however, the knee, wrist, and ankle joints are also affected in some patients. The probability of a patient’s requiring total hip replacement after diagnosis of avascular necrosis of the femoral head is 80% at 5 years.49

Osteopenia is commonly seen in survivors of hematologic malignancies.50 Risk factors include therapy with corticosteroids, methotrexate (at higher doses), and cranial irradiation with resultant pituitary insufficiency or gonadal dysfunction. Survivors of hematopoietic cell transplantation are also at increased risk for reduced bone mineral density; identified risk factors in these patients include treatment with corticosteroids for chronic graft-versus-host disease, prior cranial irradiation (resulting in growth hormone deficiency), and gonadal failure.51 Lifestyle factors that increase the risk for osteopenia include lack of regular weight-bearing exercise, inadequate calcium and vitamin D intake, smoking, and excessive alcohol consumption.52,53

Second malignant neoplasms are defined as histologically distinct malignancies developing at least 2 months after follow-up for a primary cancer. Childhood cancer survivors demonstrate a 6-fold increased risk of developing a second cancer, when compared with the general population, and this risk continues to increase as the cohort ages.54 The incidence and type of second malignancies differ with the primary diagnosis, type of therapy received, and presence of genetic predispositions. The more commonly reported second malignant neoplasms in childhood cancer survivors are basal cell carcinomas and breast, thyroid, and bone cancers; therapy-related leukemia is less frequently observed.

Ionizing radiation is associated with several types of second cancers, with the risk being highest when the exposure occurs at a younger age.55,56 The risk increases with the total dose of radiation,57-60 and with increasing follow-up.61 Examples of radiation-associated tumors include breast,62lung, and thyroid cancers59; brain tumors60; and sarcomas.63 As survivors age, they develop other carcinomas at an earlier age than seen in the general population; these occur in areas exposed to radiation.

Female patients treated with mantle radiation before age 30 years are at a significantly higher risk of developing radiation-related breast cancer, in comparison with those treated in their adult years.62,64 The risk increases with increasing doses of radiation; exposure to alkylating agents or radiation to the ovaries confer some degree of protection, with blunting in the magnitude of the radiation-related risk. The latent period between radiation exposure and diagnosis of breast cancer is approximately 15 to 20 years. The large majority of childhood cancer survivors are diagnosed with secondary breast cancer at a relatively young age, often before 40 years of age. Because outcome is closely linked to stage at diagnosis, early diagnosis should confer survival advantage.65 Mammography has been the screening mechanism of choice for the general population. However, mammography in isolation may not be the ideal screening tool for radiation-related breast cancers occurring in relatively young women with dense breasts, hence the recommendations by the American Cancer Society to use adjunct screening with magnetic resonance imaging (MRI).66

An increased risk of developing thyroid cancer has been described after radiation therapy for several primary cancers, including Hodgkin lymphoma, acute lymphoblastic leukemia, and brain tumors.59 Increasing doses of radiation as well as exposures to radiation at a young age have been identified as risk factors, although a recent study demonstrates a threshold effect, with a decreasing risk at very high doses, due to cell killing at the higher doses of radiation.

Therapy-related leukemia has been associated with specific chemotherapeutic agents, such as alkylating agents and topoisomerase II inhibitors.56 A dose-dependent relationship is noted with alkylating agents, which typically cause therapy-related leukemia after latencies of 5 to 10 years. Cytogenetic abnormalities in the alkylating agent-associated t-MDS/AML characteristically involve chromosome 5 or 7. Therapy-related leukemia associated with exposure to topoisomerase II inhibitors classically has a shorter latency, no preceding dysplastic phase, and cytogenetic abnormalities involving chromosome 11q23. Although the risk for t-MDS/AML plateaus after 10 years, that for radiation-related solid tumors continues to climb with increasing follow-up.62

Genetic predisposition may play a role in the development of second malignant neoplasms, as evidenced by the increased risk of secondary sarcomas among patients with the hereditary form of retinoblastoma, especially after increasing doses of radiation.57 Furthermore, members of families with Li-Fraumeni syndrome have been reported to be at an increased risk of multiple subsequent cancers, with the highest risk observed among survivors of childhood cancer.67 It therefore appears that germ line mutations in tumor suppressor genes, such as those occurring in the Li-Fraumeni syndrome, might interact with therapeutic exposures, resulting in an increased risk of second cancers. However, because of the relative rarity of these disorders in the general population as well as among the childhood cancer survivors, the attributable risk due to these syndromes is negligible.

Screening

Because second malignancies remain a significant concern in the health of survivors treated for cancer during childhood, vigilant screening is important for those at risk. The second solid nonhematopoietic malignancies are associated with radiation exposure. Screening recommendations include careful annual physical examination of the radiation field with radiographic or other cancer-screening evaluations as indicated. Recommendations for females who received radiation with potential impact to the breast (ie, radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty, annual clinical breast examinations beginning at puberty until age 25 years, and then a clinical breast examination every 6 months, with annual mammograms and magnetic resonance imaging (MRIs) beginning 8 years after radiation or at age 25 (whichever occurs later). Screening of those at risk for early-onset colorectal cancer (ie, radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine) should include colonoscopy every 5 years beginning at age 35 years or 10 years following radiation (whichever occurs last).

Risk for therapy-related leukemia usually manifests within 10 years following exposure. Recommendations for monitoring for therapy-related leukemia include annual complete blood count for 10 years after exposure to alkylating agents or topoisomerase II inhibitors.

Several investigators have described the burden of morbidity experienced by long-term cancer survivors.68-70 Chronic medical conditions used to summarize the burden of morbidity by these investigators are defined as health problems that cause physical, psychological, or social difficulty and therefore justify ongoing medical intervention. These reports suggest that approximately two-thirds of the survivors will experience at least one chronic medical problem and about one third will experience a late effect that is severe or life threatening.3 Overall, the survivors were at an 8-fold higher risk of reporting a severe chronic health condition, when compared with age- and sex-matched siblings. Individuals identified to be at highest risk included those who were treated for Hodgkin lymphoma or brain tumors, or those exposed to chest radiation or anthracyclines.

These studies demonstrate quite conclusively that the implications of cure are not trivial, and that indeed the burden of morbidity carried by childhood cancer survivors is quite substantial. Furthermore, these data support a critical need for continuing follow-up of childhood cancer survivors into adult life, and, more important, an imminent need to identify the resources necessary to provide such longitudinal care. There is also an urgent need for the survivors and their health care providers to be aware of the “at risk” populations in order to develop appropriate surveillance strategies.

An investigation of the childhood cancer survivors’ knowledge about past cancer diagnosis and treatment demonstrated that only 72% of the cancer survivors were able to accurately and precisely report their cancer diagnosis. Furthermore, although 94% of the cancer survivors reported past exposure to chemotherapy, only 52% of those having received doxorubicin could report exposure to the drug, and only 30% of those exposed to daunomycin could report the exposure accurately. Similarly, although exposure to radiation therapy was reported by 89%, only 70% of the childhood cancer survivors exposed to radiation could accurately describe the site of radiation. Only 35% of the survivors understood that serious health problems could result from their past treatment.71

Health care utilization by a large cohort of long-term survivors of childhood cancer revealed that although 87% of the survivors reported general medical contact within the past 2 years, and 72% reported a general physical examination within the same time period, only 42% reported a cancer-related visit, and only 19% reported a visit to the cancer center.72 Furthermore, cancer-related visits declined with time since diagnosis, placing the burden on the general practitioner for providing ongoing care of these survivors. Factors associated with no contact with the health care system by these survivors included lack of health insurance, male sex, and lack of concern about future health.

Childhood cancer survivors, an especially high-risk population, seek and receive care from a wide variety of health care professionals, including oncologists, medical and pediatric specialists, surgeons, primary care physicians, gynecologists, advanced practice nurses, psychologists, and social workers. Providing appropriate health care for survivors of cancer is emerging as one of the major challenges in medicine. The challenge arises due to the heterogeneity of this patient population treated with numerous therapeutic modalities in an era of rapidly advancing understanding of late effects. The Institute of Medicine has recognized the need for a systematic plan for lifelong surveillance that incorporates risks based on therapeutic exposures, genetic predisposition, health-related behaviors, and comorbid health conditions.2 Optimal health care delivery to this unique population requires the establishment of necessary infrastructure, including several key components:73(1) longitudinal care utilizing a comprehensive multidisciplinary team approach; (2) continuity, with a single health care provider coordinating needed services; and (3) an emphasis on the whole person, with sensitivity to the cancer experience and its impact on the entire family.

Although the number of childhood cancer survivors is rapidly increasing, health care professionals outside academic centers are likely to see only a small number in their practice, and, due to the heterogeneity of treatments received, there will likely be little similarity in their required follow-up care. It is increasingly apparent that primary care physicians are generally unfamiliar with the risks and health care problems of childhood cancer survivors. There is a veritable absence of information regarding this population in the primary-care-based literature,73 driven in part by the fact that adult survivors of childhood cancer represent a small fraction of a primary cancer physician’s practice.74

Ideally, a multidisciplinary team approach needs to be utilized in addressing the needs of this population, and academic settings allow for the establishment of such specialized teams. Most long-term follow-up centers have a core team consisting of a pediatric oncologist, advanced practice nurse, and psychosocial support, with additional optional subspecialist support in the form of endocrinology, cardiology, pulmonology, and so on. Most well-established long-term follow-up clinics are located within the pediatric unit. However, a pediatric environment is not the ideal venue for providing follow-up care to adult cancer survivors who need to become independent with regard to seeking health care. Financial and other constraints, such as dependence on pediatric oncologists who are not aware of late complications and appropriate surveillance and counseling, often delay or prevent adequate long term care. Some pediatric oncology centers have implemented transition models, in which care of adolescent and young adult survivors is provided by a more age-appropriate provider, such as specialized oncology-led transition programs75 or nonspecialist primary care providers. Survivor-directed education regarding future risks and adult health care needs may be the best way to ensure that the wide range of complications that might occur during long-term follow-up of childhood cancer survivors can be appropriately addressed considering individual needs and the financial and geographic constraints of young adults in our society. Therefore, finding ways to educate survivors and their local health care providers regarding needed follow-up is a priority.

The aim of transition to adult health care is to enable all survivors to maintain the best possible physical health and achieve their full psychosocial, educational, and vocational potential.76 This model is well established in the transitional care of adolescents or young adults with various chronic disorders,77 by various providers.78

The Children’s Oncology Group (COG) has developed risk-based, exposure-related guidelines18 specifically designed to direct follow-up care for patients who have completed treatment for pediatric malignancies. These guidelines represent a set of comprehensive screening recommendations that can be used to standardize and direct the follow-up care for this group of cancer survivors. Ongoing monitoring facilitates early identification of and intervention for treatment-related complications in order to increase quality of life for these patients. Specially tailored patient education materials, known as Health Links, accompany the guidelines, offering detailed information on guideline-specific topics in order to enhance health promotion in this population with specialized health care needs. Examples of screening strategies outlined within the COG are summarized in Table 448-1. The Guidelines and the Health Links are available at http://www.survivorshipguidelines.org.

In addition, the COG has developed a resource guide to assist institutions in establishing and enhancing long-term follow-up programs and services for childhood cancer survivors. The Long-Term Follow-Up Program Resource Guide offers a broad perspective from a variety of long-term follow-up programs within the Children’s Oncology Group and can be downloaded from http://www.survivorshpguidelines.org.

Regardless of the setting for follow-up, the first step in any evaluation is to have at hand an outline of the patient’s medical history and, most important, a treatment summary (Table 448-2). Once completed, the treatment summary allows the survivor or his health care provider to interface with the COG’s Long-Term Follow-Up Guidelines to determine recommended follow-up care. Before the long-term survivor of childhood cancer manages a transition from a pediatric oncologist’s care, this treatment record and possible long-term problems should be reviewed with the family and the adolescent or young adult. Correspondence between the pediatric oncologist and subsequent caretakers should address these same issues.

The growing population of childhood cancer survivors carries a significant burden of morbidity, necessitating comprehensive long-term follow-up for all. This follow-up should ideally begin at the completion of active therapy, with a documented summary of therapeutic exposures that dictates recommendations within the long-term follow-up guidelines, thus ensuring standardization of care received by the survivors. However, many barriers prevent effective follow-up—the most fundamental barrier being the lack of knowledge of long-term survivors and the primary care physicians caring for them. Another barrier is the expressed need for survivors to “get on with their lives” and to avoid situations that recall their previous cancer and its therapy. This is especially the case for the many who suffer from posttraumatic stress syndrome, in which avoidance of health care is a prominent symptom. Shortcomings of the health care system are also potential barriers to long-term follow-up, including logistical issues such as a lack of capacity within centers, training and educational deficiencies, and ineffective communication between pediatric oncologists and primary care physicians who subsequently provide the large bulk of follow-up. Finally, a major obstacle faced by the long-term survivors of childhood cancer in the United States is associated with difficulties in obtaining affordable health insurance that may make it impossible for these survivors to seek and obtain appropriate long-term care, even if they are aware and willing to undergo it.79

Improvement in childhood cancer diagnostic and treatment strategies, with the resultant growing population of survivors, has also resulted in increasing emphasis on research focusing on adverse health-related outcomes and identification of high-risk groups. Appropriate surveillance will facilitate timely identification and appropriate management of incipient or established late effects, and could reduce the morbidity and mortality associated with these complications. In addition, the long-term costs and benefits of surveillance, early detection, and management need further investigation.

Attention also needs to focus on development of intervention strategies, such as behavior modification, educational interventions, screening for early detection of late effects, and chemoprevention. Execution of these intervention strategies in the setting of clinical trials would allow us to understand the impact of the specific interventions in early detection, with an overall reduction in morbidity and mortality and an ultimate improvement in the overall quality of life of childhood cancer survivors.