REVIEW

Late Effects in Adult Survivors of Pediatric Cancer: A Guide for the Primary Care Physician
Lisa M. Kopp, DO, Puja Gupta, MD, Luz Pelayo-Katsanis, CPNP, Brenda Wittman, MD, MPH, Emmanuel Katsanis, MD
Department of Pediatrics, University of Arizona, Tucson.

ABSTRACT Because of signicant medical advances in the past 50 years, the number of adult survivors of childhood/ adolescent cancer has increased dramatically. Unfortunately, more than 60% of these survivors will have at least 1 long-term side effect from treatment. This growing population requires dedicated care by their primary physicians because they have specic risk factors depending on their initial cancer diagnosis and the treatment modalities they received. Internists and family physicians play an integral role in providing appropriate screening, treatment, and counseling to prevent morbidity and mortality in these patients. 2012 Elsevier Inc. All rights reserved. The American Journal of Medicine (2012) 125, 636-641 KEYWORDS: Cancer treatment late effects; Childhood cancer survivors

Improvements in the treatment of pediatric cancers have led to a large increase in childhood cancer survivors, which now make up approximately 300,000 adults in the United States.1 Awareness of the short- and long-term health risks of these patients is critical as they transition from the care of a pediatric oncology center to an adult primary care setting.2 The Childrens Oncology Group (COG) assembled a task force in 2002 to develop evidence-based guidelines for screening and management of late effects resulting from treatment of childhood malignancies (http://www.survivorshipguidelines.org).3 Because these follow-up guidelines are based on therapy received, the primary care provider should request a concise summary that includes the patients cancer diagnosis and therapy. Close monitoring of these cancer survivors is vital because they are at risk for organ system complications and secondary malignancies. This article reviews late effects by system and provides recommendations for primary care physicians on the care of survivors.

ENDOCRINE
Endocrinopathies of 1 or multiple organs may be present or develop in up to half of childhood cancer survivors. These may include alterations in the hypothalamic-pituitary axis affecting growth, thyroid or gonadal dysfunction, and complications of glucose homeostasis.4 Hypothyroidism is the most common late effect of the thyroid gland. Patients exposed to radiation, such as in Hodgkins lymphoma, brain and head/neck tumors, or total body irradiation used in hematopoietic stem cell transplant conditioning, are at highest risk of hypothyroidism with an incidence of up to 50%.5,6 Thyroid-stimulating hormone and T4 screening may be done yearly as part of the lifelong evaluation for this subset of cancer survivors.7 Deciency of luteinizing hormone and follicle-stimulating hormone may result from damage to the hypothalamicpituitary axis from radiation, surgery, or alkylating chemotherapy agents leading to secondary hypogonadism. In men, germ cells are more sensitive, especially to alkylating agents, manifested by high follicle-stimulating hormone levels and azoospermia. Exposure at a young age increases the risk of infertility because the prepubertal testis is more sensitive to chemotherapy. Leydig cell dysfunction is less common; injury to Leydig cells may lead to elevated luteinizing hormone levels and low testosterone, resulting in low libido and erectile dysfunction. Semen analysis along with measurements of follicle-stimulating hormone, luteinizing hormone, and testosterone may be done for the assessment of male fertility.8

Funding: None. Conict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Lisa M. Kopp, DO, University of Arizona, Department of Pediatrics, 1501 N. Campbell Ave, PO Box 245073, Tucson, AZ 85724-5073. E-mail address: lkopp@email.arizona.edu

0002-9343/$ -see front matter 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2012.01.013

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In women, in addition to infertility, damage to the ovarthracycline-induced cardiac toxicity seems to be related to free ian follicle also leads to decreased estrogen causing a higher radical formation and direct myocyte damage, whereas radiaincidence of sexual dysfunction and dyspareunia.4 Irregular tion injury to endothelial cells within the capillary lumen leads menses can be a predictor of ovarian failure along with to brosis and ischemia, mimicking atherosclerosis.17,19 These elevated follicle-stimulating hormone and low estradiol. pathologic changes occur over time, and deterioration can rst Risk factors include exposure to present as late as 20 years after alkylating agents; central nervous treatments.17 system, pelvic, or scatter from abRecommendations based on CLINICAL SIGNIFICANCE dominal radiation; and exposure treatment received include yearly to chemotherapy after puberty. physical examination (including The number of adult survivors of pediatric There is an 8% cumulative inciblood pressure measurements) and cancer has increased dramatically over dence of premature menopause, an electrocardiogram and echocarthe years; this growing population comaccording to the Childhood Candiogram at specic intervals. The prises approximately 300,000 adults in cer Survivor Study (CCSS).9,10 COG LTFU guidelines provide the United States. Along with infertility, premature more specic monitoring recommenopause leads to an increase mendations based on additional Primary care physicians will initially evalrisk of osteoporosis and coronary therapeutic exposures. All surviuate the majority of these survivors. It is heart disease. Female survivors vors with risk factors, even those imperative they are aware of screening who are able to become pregnant asymptomatic, may be screened, and management of late effects. had no adverse pregnancy outbecause symptoms do not always The Childrens Oncology Group Long-Term comes according to the CCSS.11 correlate with ventricular dysfuncFollow-Up Guidelines are an invaluable tion.20 Female survivors need close Obesity is a multifactorial distool for physicians to care for survivors. ease associated with glucose memonitoring during pregnancy betabolism abnormalities and insulin cause increased cardiac output can resistance. Survivors of acute lymprecipitate failure.21 phoblastic leukemia and brain tumors in particular are at risk of obesity because of chronic PULMONARY steroid therapy and cranial radiation therapy. Cancer surviPatients who were exposed to radiation to the lungs or scatter vors are 1.8 times more likely to have symptoms of diabetes from the abdomen or spine, or who were a younger age at mellitus compared with siblings, mainly because of insulin exposure are at risk for long-term pulmonary morbidities.22 12 resistance. The development of the metabolic syndrome Chemotherapy-induced lung injury from bleomycin, cyclo(obesity, hypertension, dyslipidemia, or impaired glucose phosphamide, and carmustine are not uncommon.22 Chest wall tolerance) is known to cause cardiovascular complications. surgery, lobectomy, or wedge resection also can increase morSurvivors may develop metabolic syndrome without develbidity. Populations at risk for long-term pulmonary morbidities 13 oping obesity. The COG Long-Term Follow-Up (LTFU) include survivors of hematopoietic stem cell transplant, Wilms Guidelines recommend that patients with a history of total tumor, and Hodgkins lymphoma. Pulmonary brosis, bronbody irradiation, cranial radiation, or acute lymphoblastic chiolitis obliterans with organizing pneumonia, restrictive and leukemia receive a routine fasting glucose and lipid prolife obstructive lung disease, and interstitial pneumonitis are rare, every 2 years, or annually if clinically indicated, because of yet potentially serious sequelae.22 their increased risk for metabolic syndrome. Survivors with exposure risks should be discouraged from smoking and should report exercise intolerance changes, history of cough, or any other pulmonary symptoms during their CARDIOVASCULAR annual examination, which includes a yearly inuenza vaccine. Mortality due to cardiovascular disease is 7-fold higher in adult Screening for pulmonary diseases includes a chest x-ray and 14 survivors of pediatric cancers. According to the CCSS, surpulmonary function test with diffusion lung capacity for carvivors of leukemia, brain tumors, lymphoma, and rhabdomyobon monoxide at baseline and then repeated as clinically indi14 sarcoma are the most susceptible to cardiac morbidity. Risk cated.9 The COG LTFU guidelines also advise medical clearfactors include mediastinal radiation, scatter from abdominal ance by a pulmonologist for survivors with an abnormal chest radiation, cumulative doses of anthracycline treatment (300 x-ray or pulmonary function test result who plan to scuba dive 2 15 mg/m ), and younger age at time of treatment. Lower cumuor undergo general anesthesia. lative doses of anthracyclines combined with radiation involving the cardiac eld also predispose survivors to increased CENTRAL NERVOUS SYSTEM cardiac risk. Cardiac changes include hypertension and dilated or restrictive cardiomyopathy that leads to left ventricular dysSurvivors of central nervous system tumors are at highest function, congestive heart failure, or myocardial infarction. risk of neurologic sequelae related to diagnosis, surgery, These alterations in the muscle of the heart also can result in chemotherapy, and radiation.9 Survivors of acute lympho15-18 valvular defects and arrhythmias. The mechanism of anblastic leukemia also are at risk for neurocognitive decits

638 from therapy, such as cranial or craniospinal irradiation and intrathecal chemotherapy.23 Signs and symptoms may include visual decits, hearing loss, motor, sensory, coordination disorders, or seizures. Symptoms can occur during treatment or manifest even years after treatment.9,24 Neurosensory hearing loss, tinnitus, and vertigo are frequently associated with radiation or cisplatin chemotherapy. The COG LTFU guidelines recommend audiologic examination at initial follow-up. Retesting may occur yearly if there is detectable hearing loss or clinical suspicion at any time, as well as when recommended by an audiologist. Cataracts are the most common ocular changes in patients with a history of steroids, radiation to the eye, central nervous system therapy, or total body irradiation as part of hematopoietic stem cell transplant conditioning.25 Cumulative incidence of cataracts continues to increase for up to 20 years after treatment.24,26 The COG LTFU guidelines recommend visual acuity and funduscopic eye examinations annually with referral to ophthalmology if a problem is identied. Survivors of Hodgkins lymphoma, leukemia, brain tumors, and head and neck cancers have an increased risk of vascular damage related to radiation treatment. When compared with their siblings, survivors have a 10-fold increased risk of stroke.27 Vascular changes that can occur include intracranial vascular stenosis, carotid artery stenosis, and vascular malformation such as cavernomas, telangiectasias, and aneurysms. The COG LTFU guidelines recommend yearly neurologic examinations with surveillance for carotid bruits and magnetic resonance imaging with angiography, if clinically indicated.

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GENITOURINARY
Survivors of childhood cancer who received cisplatin or ifosfamide are at increased risk for nephrotoxicity. Signs and symptoms include a decreased glomerular ltration rate and proximal tubular dysfunction later in life.32 Dose-dependent radiation therapy can lead to chronic renal insufciency and hypertension.32,33 Survivors of Wilms tumor are at increased risk because of a history of nephrectomy, nephrotoxic chemotherapy, and possibly radiation. The COG guidelines recommend a yearly physical examination including blood pressure, urinalysis, blood urea nitrogen, creatinine, and electrolytes. It is recommended that survivors with abnormal diagnostic results be referred to a nephrologist for further evaluation. Bladder dysfunction can signicantly impair quality of life. Alkylating agents, cyclophosphamide and ifosfamide, can cause acute hemorrhagic cystitis during treatment, but it can also recur years after completion of therapy. Additional complications are likely to occur in survivors who have also had radiation.34 Rhabdomyosarcoma is the most common tumor that occurs in the bladder or prostate. Complications can arise from surgical resection and radiation that prevent normal prostate or bladder function. Recurrent urinary tract infections and urinary incontinence in these survivors are not uncommon.35 If hematuria is present, further workup may be done, including urine culture, spot urine calcium/ creatinine ratio, and ultrasound of the kidneys and bladder. Sexual dysfunction may be encountered in survivors of bladder/prostate tumors, such as rhabdomyosarcoma and germ cell tumors. Raney et al reported that 25% of male patients with rhabdomyosarcoma were unable to ejaculate and 8% were incapable of achieving an erection.35 Men who had retroperitoneal lymph node dissection are also at risk for the same complications; however, in recent years the incidence has decreased signicantly with improved surgical techniques.36 An analysis of 26 female survivors documented that gynecologic complications were common, including sexual dysfunction, vaginal stulas, chronic pelvic pain, pelvic oor disorder, vaginal dryness, and the inability to have children.37 At annual visits, it is important to discuss the possibility of sexual dysfunction, because survivors may not feel comfortable in bringing up these topics.

GASTROINTESTINAL
Survivors are at increased risk for gastrointestinal toxicities when compared with siblings.28 Although the toxicities may not be life threatening, they often interfere with quality of life. Radiation damage to vascular structures of the gastrointestinal tract can lead to brosis and ischemia. Chronic symptoms of radiation damage include reux, nausea, vomiting, diarrhea, constipation, and weight loss. The combined therapy of radiation and surgery causes the highest risk of complications, including esophageal strictures, chololithiasis, and abdominal adhesions leading to obstruction.29,30 The COG recommendations include an annual physical examination with appropriate referrals to surgery or gastroenterology, and diagnostic scans and blood work for symptomatic patients. Hepatic dysfunction after cancer treatment can go unrecognized because of its unknown latency period.31 Concomitant conditions, such as obesity, viral hepatitis, alcohol consumption, and hemosiderosis, increase the risk of hepatic dysfunction. Screening includes yearly physical examination assessing for hepatomegaly, splenomegaly, jaundice, scleral icterus, and ascites. Baseline aspartate aminotransferase, alanine aminotransferase, and bilirubin may be done, and repeated if clinically indicated.

MUSCULOSKELETAL
Altered bone metabolism is another long-term late effect associated with cancer treatment. Steroids and methotrexate are some of the staple drugs in treating childhood cancers and have been found to reduce bone mineral accumulation, leading to a disruption in peak bone mass. This predisposes survivors to early onset and severe complications related to osteoporosis when compared with the general population.38 Childhood cancer survivors of brain tumors are at highest risk for bone mineral density decits related to alterations in the production of growth hormone from radiation.39 The World Health Organization denition of osteoporosis and osteopenia is based on T scores of dual-radio-

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639 avoiding sun exposure. Thyroid neoplasms are associated with radiation treatment. On the basis of the British CCSS, the median latency of thyroid neoplasm was 20.8 years after radiation.46 Patients with cumulative radiation doses as low as 1000 cGy developed neoplasms.46 Routine ultrasound has not been shown to decrease morbidity or mortality; therefore, lifelong yearly thyroid examination is the current recommendation.47 Hodgkins lymphoma survivors are at highest risk of secondary malignancies, including breast, thyroid, colon, and lung. Breast cancer for women aged less than 50 years was signicantly higher (10%) in these survivors and likely related to chest radiation.44 Survivors of bone and soft tissue sarcomas are also found to have a disproportionately increased risk for cancers, particularly breast cancer, even without a history of radiation therapy.44 It is recommended that women who have had chest radiation exposure have a yearly breast examination by a physician until age 25 years.44 Beginning at age 25 years, or 8 years after radiation, patients are recommended to have breast examinations every 6 months with yearly mammograms and magnetic resonance imaging. Survivors who received abdominal radiation or total body irradiation are considered to be at increased risk of colorectal cancer. Screening for these patients includes colonoscopies at age 35 years, or 10 years after radiation is completed, and repeated every 5 years. However, patients with a personal history of ulcerative colitis, gastrointestinal malignancy, adenomatous polyps, hepatoblastoma, or a family history of colorectal cancer or polyps in a rstdegree relative may begin colonoscopy screenings at the age of 21 years.43,44 Chemotherapies, such as alkylating agents, anthracyclines, and epipodophyllotoxins, are associated with increased incidence of secondary malignancies, specically myelodysplastic syndrome and acute myeloid leukemia. Secondary acute myeloid leukemia from epipodophyllotoxins and anthracyclines exposure usually occurs 2 to 3 years after treatment. In contrast, secondary acute myeloid leukemia from alkylating agents can occur later, 5 to 7 years after exposure, rst presenting as a myelodysplastic syndrome and then slowly progressing to an overt leukemia.48 The COG guidelines recommend screening patients with yearly complete blood counts up to 10 years after exposure, because the risk of myelodysplastic syndrome/acute myeloid leukemia seems to plateau after that time.49 Genetic alterations secondary to inherited cancer predisposition syndromes also can be a factor in increasing secondary malignancies. Patients with germline mutations, such as Li-Fraumeni syndrome, neurobromatosis type 1, nevoid basal cell carcinoma, and retinoblastoma, have an increased risk of secondary cancers after treatment of their initial malignancy. Patients with a germline retinoblastoma mutation requiring enucleation only remain at risk for secondary cancers. Radiation as part of the initial cancer treatment seems to greatly increase this risk.50

graph absorptiometry on postmenopausal women. Although bone density evaluation using dual-radiograph absorptiometry is not conclusive, it provides a baseline evaluation from which further follow-up can be determined. If there is a concern for bone mineral density decit, then an endocrinology consult is recommended.38 Prevention of osteoporosis includes evaluation of nutritional status and weightbearing activity.38,40 Optimal calcium and vitamin D are essential in the treatment of bone mineral density decit, and patients may require additional supplementation, as well as calcitonin and bisphosphonates.38,41 Weight-bearing exercises, such as running, jumping, and weight lifting, have been shown to promote good bone health. Patients who experience amputation or limb salvage for treatment of sarcomas also experience long-term complications. Many of these complications require multiple surgical revisions. The most common issue in these patients is disruption of skeletal growth of the affected bone.42 If the distal epiphyseal plate is disrupted, the skeletal growth of that extremity is also disrupted. For patients with amputations, other complications include bony overgrowths at the stump, chronic skin breakdown, residual chronic osteomyelitis, deformities, and phantom limb pain.42 To account for growth and avoid limb length discrepancies, survivors with a limb salvage require surgeries to expand the end-prosthetic implants. Studies have found that more complications occur with survivors of limb salvage than those who underwent amputation.42

SECONDARY MALIGNANCIES
Survivors are at increased risk of secondary malignancies related to their type of cancer, therapy, and genetics. Survivors in the CCSS cohort had a greater than 19 times increased risk of death due to a secondary malignancy compared with the US general population.43 An increased risk of secondary neoplasms was associated with younger age at diagnosis, female sex, cancer family history, radiation, and primary diagnosis. The most common secondary malignancies are breast, bone, and thyroid cancers.44 Increased risk secondary to radiation is likely dose dependent; however, the exact pathophysiologic cause is unknown. Adults at highest risk for secondary malignancies are those who received radiation at less than 5 years of age.44 Leukemia and brain tumor survivors who received brain radiation are at risk for benign and malignant brain tumors years after treatment.9 The COG guidelines recommend yearly neurologic examinations for these patients and magnetic resonance imaging of the brain if clinically indicated. Non-melanoma skin cancers, including basal cell carcinoma, are found to occur with increased frequency in survivors and are related to sites of radiation elds. Although these cancers do not usually metastasize, they can be locally invasive and result in increased morbidity.45 Yearly skin examination is recommended. Survivors need to be aware of this risk and counseled on the importance of using sunscreen, having annual skin evaluations, and

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17. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005;44:600-606. 18. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA. 2003; 290:2831-2837. 19. Berry GJ, Jorden M. Pathology of radiation and anthracycline cardiotoxicity. Pediatr Blood Cancer. 2005;44:630-637. 20. Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart. 2008;94:525-533. 21. Landier W, Bhatia S. Cancer survivorship: a pediatric perspective. Oncologist. 2008;13:1181-1192. 22. Huang TT, Hudson MM, Stokes DC, Krasin MJ, Spunt SL, Ness KK. Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest. 2011;140:881-901. 23. Harila MJ, Winqvist S, Lanning M, Bloigu R, Harila-Saari AH. Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009;53: 156-161. 24. Packer RJ, Gurney JG, Punyko JA, et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J Clin Oncol. 2003;21:3255-3261. 25. Gurney JG, Ness KK, Rosenthal J, Forman SJ, Bhatia S, Baker KS. Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow Transplant Survivor study. Cancer. 2006;106:1402-1408. 26. Whelan KF, Stratton K, Kawashima T, et al. Ocular late effects in childhood and adolescent cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2010;54:103-109. 27. Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA. Cerebrovascular disease in childhood cancer survivors: a Childrens Oncology Group Report. Neurology. 2009;73:1906-1913. 28. Goldsby R, Chen Y, Raber S, et al. Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology. 2011;140:1464-1471, e1461. 29. Andreyev HJ. Gastrointestinal problems after pelvic radiotherapy: the past, the present and the future. Clin Oncol (R Coll Radiol). 2007;19: 790-799. 30. Andreyev J. Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients. Lancet Oncol. 2007;8:1007-1017. 31. Castellino S, Muir A, Shah A, et al. Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Childrens Oncology Group. Pediatr Blood Cancer. 2010;54:663-669. 32. Jones DP, Spunt SL, Green D, Springate JE. Renal late effects in patients treated for cancer in childhood: a report from the Childrens Oncology Group. Pediatr Blood Cancer. 2008;51:724-731. 33. Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation therapy for Wilms tumor. Int J Radiat Oncol Biol Phys. 2000;46:1239-1246. 34. Ritchey M, Ferrer F, Shearer P, Spunt SL. Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Childrens Oncology Group. Pediatr Blood Cancer. 2009;52:439-446. 35. Raney B, Anderson J, Jenney M, et al. Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop. J Urol. 2006;176:2190-2195. 36. Beck SD, Bey AL, Bihrle R, Foster RS. Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. J Urol. 2010;184:2078-2080. 37. Spunt SL, Sweeney TA, Hudson MM, Billups CA, Krasin MJ, Hester AL. Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol. 2005;23:7143-7151. 38. Wasilewski-Masker K, Kaste SC, Hudson MM, Esiashvili N, Mattano LA, Meacham LR. Bone mineral density decits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics. 2008;121:e705-713.

CONCLUSIONS
Adult survivors of pediatric cancer comprise a growing population who requires close follow-up care. Yearly health maintenance visits are crucial because of continued risk of morbidity and mortality. Patients need to be informed of their risks and encouraged to maintain a healthy lifestyle, which includes avoiding smoking, limiting alcohol intake, increasing exercise, and minimizing sun exposure. Survivors are most likely to be evaluated by primary care physicians who need a concise summary of the survivors diagnosis and therapy to better assess the survivors healthcare risks.

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