Clinical and Health Affairs
Surviving Childhood Cancer: Cure Is Not Enough
By Daniel A. Mulrooney, M.D., M.S.
Children who are diagnosed with cancer have a five-year survival rate of nearly 80%, and many live well into adulthood. Because of their disease and treatment exposures, survivors of childhood cancer are at risk for unique long-term health effects. This article reviews some of the more common late effects of childhood cancers and their treatments—endocrine abnormalities, cardiovascular compromise, subsequent neoplasms, and psychosocial issues.
Advances in the care of children with cancer have resulted in an increasing number of survivors living many years after successful therapy. Although childhood cancer was often a fatal disease in the past, a child diagnosed with a malignancy today is expected to become a long-term survivor. Survival rates vary by diagnosis and disease stage; however, overall five-year survival now approaches 75% to 80%. An estimated one in 450 young adults now living in the United States is a survivor of a pediatric malignancy.1 These advances have led to an improved understanding of the effects of cancer treatment on future health. The sequelae of cancer and its therapy can be significant and may affect nearly every organ system and contribute to morbidity and premature mortality. Nearly two-thirds of childhood cancer survivors report at least one chronic medical condition related to their prior therapy, with more than 25% being classified as severe or life- threatening.2 Among five-year childhood cancer survivors, the risk of death from any and all causes is eight-fold higher than that of age- and sex-matched members of the general U.S. population, with a progressive decline in survival probability over time.3 Importantly, recent evidence has suggested that the mortality from late toxicities surpasses mortality from disease recurrence at approximately 30 years from initial diagnosis.4
Late effects of cancer therapy may be insidious in onset and occur years after treatment, when survivors, now adults, no longer return to their oncologist or cancer center for regular follow up. The more common late effects—endocrine abnormalities, cardiovascular compromise, subsequent neoplasms, and psychosocial issues—are reviewed in this article.
Endocrine disorders are some of the most common sequelae of childhood cancer and can have significant lifelong implications. The hypothalamic pituitary axis is particularly sensitive to radiation therapy (RT), and exposure frequently results in deficiencies of the anterior pituitary gland.
Historically, cranial radiation was commonly used for children with acute lymphoblastic leukemia (ALL), both for treatment and prophylaxis of the central nervous system (CNS). Lower doses have resulted in growth hormone (GH) deficiency, and higher doses have caused panhypopituitarism. One study found abnormally low GH levels in 64% of ALL survivors a mean of 25 years after diagnosis; nearly all had received cranial RT.5 The risk of GH deficiency is inversely related to the age at exposure. Replacement therapy may positively affect growth and development in children;6 but the role of GH replacement in adults is a subject of debate. Improvements in overall quality of life and possibly in cardiovascular health with GH replacement have been reported.7,8
Hypothyroidism is the most common thyroid abnormality reported among childhood cancer survivors, although hyperthyroidism, thyroid nodules, and thyroid cancer may also occur.9 The thyroid gland frequently falls within the radiation fields (cranial, craniospinal, cervical, mantle, and/or total body irradiation) used to treat a variety of malignancies. Hypothyroidism has been noted in 25% of childhood cancer survivors, with the highest prevalence among survivors of CNS neoplasms (46%) and Hodgkin lymphoma (48%).10 Females are at higher risk than males.9
Patients exposed to RT are at higher risk for subsequent thyroid cancer. Survivors of Hodgkin lymphoma have 18 times the risk of thyroid cancer compared with the general population, and the risk appears to be higher among those treated before age 10 or those who were exposed to higher radiation doses. Interestingly, a slight decrease at doses greater than 30 Gy has been reported.11
Effects on fertility, frequently minimized by parents at diagnosis, become more of a concern later in life. Radiation to the hypothalamus occasionally may induce precocious puberty, more often in girls; higher dose (≥50 Gy) and direct gonadal radiation (spinal/pelvic fields) may result in delayed puberty and gonadotropin and sex hormone deficiencies.12 Alkylating chemotherapy is also known to cause gonadal insufficiency, yet the exact dose and timing of exposure remains unclear. Doses of cyclophosphamide greater than 7.5 gm/m2 or ifosfamide greater than 60 g/m2 are thought to impede long-term fertility.13,14
Pubertal timing and progression should be carefully monitored in patients who have received these treatments. Adolescents should be screened for gonadotropin and sex hormone levels at approximately 15 years of age and as clinically indicated. Patients with abnormal levels should be referred to an endocrinologist. Family planning and guidance also should be initiated when appropriate.
Recently, the metabolic syndrome constellation of abnormalities (central obesity, dyslipidemias, hypertension, glucose intolerance, and insulin resistance) has been reported among childhood cancer survivors. These characteristics have been associated with the development of type 2 diabetes and premature cardiovascular disease. First reported by Talvensaari et al. in 1996, 50 childhood cancer survivors, median age 18 years (range 10.5 to 31.2) and 12.6 years from diagnosis (range 7.9 to 21.3), were found to have increased weight, body fat, and fasting plasma glucose and insulin levels, and decreased HDL cholesterol compared with age- and gender-matched controls.15 The combination of obesity, hyperinsulinemia, and low HDL found in 16% of survivors and none of the controls was significantly associated with GH deficiency (P=0.02). Among survivors of stem cell transplant, 52% were found to have insulin resistance a median of 10 years later.16 Interestingly, in this population, increased abdominal girth was noted but obesity was not.
Cardiovascular events are the leading nonmalignant cause of death among childhood cancer survivors, as this population has a seven-fold higher risk of cardiovascular mortality compared with age-matched controls.3 Both chemotherapy and RT are known to be toxic to cardiomyocytes and contribute to early mortality.3, 17
Nearly all chemotherapeutic agents (alkylators, antimetabolites, vinca alkaloids, immune modulators, and antibodies) have been reported to have some acute or chronic cardiotoxicity.18 However, the anthracylcine antibiotics (eg, doxorubicin, daunorubicin) are among the most widely used and effective anti-cancer agents and have been the most studied.19-21 Although directly contributing to improved survival rates, these drugs have been associated with adverse cardiac outcomes. Steinherz et al. first reported the association, finding a 23% incidence of echocardiographic abnormalities as late as 20 years following exposure.22 Sixty-three percent of those treated with more than 500 mg/m2 had some decrease in fractional shortening 10 years later. These findings subsequently have been confirmed by others and appear to be directly related to dose and time since exposure.23,24 These effects may be asymptomatic and progressive, presenting with early electrocardiographic changes (flattened T-waves, prolonged Q-T intervals, decreased R-wave amplitudes) followed by left ventricular dilatation, increased left ventricular end-diastolic pressure, and eventual decrease in contractility and systolic function. The pathophysiology of this injury is not fully understood, but it is believed to be related to the generation of reactive oxygen free radicals that alter redox cycling on mitochondrial membranes causing uncoupling of the electron transport chain and resulting in myocyte apoptosis.25
Radiation therapy has been effective for treating a variety of neoplasms including Hodgkin lymphomas and non-Hodgkin lymphomas, nephroblastoma, breast cancer, and lung cancer. Acute inflammation of the pericardium is a known risk. However, chronic injury to the heart and coronary vessels becomes more apparent as patients are followed. Constrictive pericarditis is a late manifestation of pericardial injury, myocardial fibrosis may lead to dysrhythmias, and endocardial fibrosis results in valvular thickening and calcifications.26 Hancock et al. described premature coronary artery disease among survivors of adult and childhood Hodgkin lymphoma treated with mediastinal RT.27,28 The relative risk of death from a myocardial infarction was 41 (95% CI, 18-82) among the pediatric survivors. Radiation-induced effects may be subclinical and present years after exposure. Risk factors include higher doses, fractions in excess of 2.0 Gy/day, larger heart volumes within the irradiated field, younger age at treatment, pre-existing cardiac disease, and concomitant use of cardiotoxic chemotherapy.29
The incidence and risk of stroke is also higher among adult survivors of childhood and adolescent cancer. Two articles based on Childhood Cancer Survivor Study (CCSS) data described the risk of stroke among survivors of Hodgkin lymphoma, leukemia, and brain tumors.30, 31 Mantle and cranial radiation were significant risk factors. Survivors of Hodgkin lymphoma treated with a mantle field had an incidence of late-occurring stroke of 109 per 100,000 person-years (95% CI, 70.8-161 per 100,000 person-years), five-times the risk compared with a sibling control group. Similar increased rates and risks were identified among survivors of leukemia and brain tumors treated with cranial radiation. The risks were associated with a mean dose of 30 Gy or more and were highest at doses of 50 Gy or greater. A more recent investigation of carotid artery intima-media thickness among childhood cancer survivors found significantly increased thickness at doses as low as 18 Gy.32 Among 30 cancer survivors previously treated with neck radiation, intima-media thickness was 0.46 mm (SD 0.12) compared with 0.41 mm (SD 0.06) in healthy controls (P<0.001). Eighteen percent of survivors (mean age: 27.5 years, range 14 to 47 years) had evidence of carotid plaque compared with 2% of controls. Injury to the carotid and/or cerebral vessels may account for premature vascular accidents among these survivors.
Rates of subsequent neoplasms among childhood cancer survivors vary by time from diagnosis and exposure history. Among more than 13,581 childhood cancer survivors with a variety of diagnoses, the CCSS found a three- to six-fold increased risk for a subsequent neoplasm compared with what would be expected in those who did not have a prior history of cancer and a 20-year cumulative incidence of more than 3.2%.33 However, among selected groups, the risks may be much higher.
Patients with a history of CNS-directed RT are at particularly high risk for secondary CNS neoplasms. Survivors of childhood ALL treated on Children’s Cancer Group protocols between 1970 and 1988, had a 22-fold increased risk for malignant CNS tumors compared with the expected rate calculated from Surveillance, Epidemiology, and End Results data. All occurred in survivors treated with cranial RT.34 Among 1,612 consecutively treated ALL patients at St. Jude Children’s Research Hospital, 22 had CNS tumors yielding a cumulative risk of 1.4% at 20 years from diagnosis.35 Significant risk factors included CNS leukemia at diagnosis, treatment with cranial RT, and diagnosis before age 6. The CCSS identified a linear dose response: increased risk with increasing RT dose. Although subsequent CNS tumors occurred five to 28 years after the initial cancer diagnosis, malignant gliomas occurred at a median of nine years and benign meningiomas at 17 years after diagnosis.36
Early breast cancer is a significant risk for female childhood cancer survivors. An actuarial incidence of 35% at 40 years of age was first reported among survivors of Hodgkin lymphoma.37 Subsequently, survivors of non-Hodgkin lymphoma, Wilms’ tumor, bone cancer, and soft-tissue sarcomas have also been found to be at increased risk.33 Chest RT is the most significantly associated exposure; yet even those not exposed to RT (survivors of bone cancer, soft-tissue sarcoma) are at risk. In the CCSS cohort, a family history of breast cancer and thyroid disease was also a risk factor, while RT to the pelvis appeared to reduce the risk.38
The incidence of secondary leukemias is less than 5% with the risk peaking four to six years after treatment and decreasing at 10 to 15 years.39 Two distinct patterns of secondary acute myeloid leukemia are evident, one associated with alkylating agents (ie, cyclophosphamide, ifosfamide, etc.) and another with exposure to topoisomerase II inhibitors (ie, epipodophyllotoxins and anthracyclines). Following alkylator exposure, the leukemia cells typically have cytogenetic abnormalities of chromosomes 5, 7, 8, or 9.40 Alternatively, exposure to the epipodophylotoxins can result in leukemias with abnormalities at the MLL gene locus on chromosome 11 (11q23).41 Risk appears to be associated with both the cumulative dose and timing of exposure.
Survivors of retinoblastoma are at considerable risk for second cancers, especially those children who have the genetic form of the disease. In a study of more than 1,600 survivors of retinoblastoma, children with an Rb gene mutation had a 36% cumulative incidence of a new cancer within 50 years of diagnosis, compared with 5.7% for children with the nonhereditary form.42 Second cancers following retinoblastoma are directly related to dose of radiotherapy and alkylating agent exposure.43,44
Survivors of childhood cancer may experience anxiety, depression, or other mental health disorders. They also may struggle with educational attainment and have vocational and employment limitations.
Having cancer affects a child’s schooling in a number of ways. Survivors treated with CNS-directed RT may have dose-related cognitive dysfunction, with those treated at an earlier age being the most vulnerable.45 In an attempt to limit such RT-induced neuropsychological sequelae, modern leukemia protocols have substituted intrathecal chemotherapy for cranial RT. Although less neurotoxic, these chemotherapy-only protocols still have subtle neurocognitive effects, particularly on attention and executive function skills.46
Employment also can be a challenge for adult survivors of childhood cancer. Unemployment and underemployment rates seem to be highest among survivors of leukemia and brain tumors and appear to be related to CNS-directed RT.47 Survivors of bone and soft-tissue sarcomas also frequently struggle long term with unemployment because of physical and functional impairments.48,49 Lack of employment only adds to the difficulties survivors experience obtaining adequate health insurance coverage.
Cancer research, both basic science and clinical, has considerably improved the care of children diagnosed with a malignancy, but as these young people mature, the long-term effects of cancer therapy and its health implications are increasingly evident. Therefore, simply curing the child is not enough. Survivors of childhood cancer require specialized care best provided by their primary care providers in partnership with a long-term follow-up program. Together, they can make sure patients are screened according to the evidence-based guidelines developed by the Children’s Oncology Group for potential late effects of childhood cancer and its therapies (www.survivorshipguidelines.org).50 In addition, a long-term follow-up clinic can develop individualized treatment summaries, educate survivors and their primary care providers about the long-terms risks associated with various treatments, and assist in the management of those risks before they become threats to health. MM
Daniel Mulrooney is an assistant professor of pediatrics at the University of Minnesota Medical School and medical director of the Long-Term Follow-Up Clinic at the Masonic Cancer Center.
1. Hewitt M WS, Simone JV. Childhood Cancer Survivorship: Improving Care and Quality of Life. Washington DC: The National Academies Press; 2003.
2. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572-82.
3. Mertens AC, Liu Q, Neglia JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100(19):1368-79.
4. Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27(14):2328-38.
5. Gurney JG, Ness KK, Sibley SD, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer. 2006;107(6):1303-12.
6. Gleeson HK, Stoeter R, Ogilvy-Stuart AL, Gattamaneni HR, Brennan BM, Shalet SM. Improvements in final height over 25 years in growth hormone (GH)-deficient childhood survivors of brain tumors receiving GH replacement. J Clin Endocrinol Metab. 2003;88(8):3682-89.
7. Link K, Moell C, Garwicz S, et al. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood. J Clin Endocrinol Metab. 2004;89(10):5003-12.
8. Murray RD, Darzy KH, Gleeson HK, Shalet SM. GH-deficient survivors of childhood cancer: GH replacement during adult life. J Clin Endocrinol Metab. 2002;87(1):129-35.
9. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2000;85(9):3227-32.
10. Madanat LM, Lahteenmaki PM, Alin J, Salmi TT. The natural history of thyroid function abnormalities after treatment for childhood cancer. Eur J Cancer. 2007;43(7):1161-70.
11. Sigurdson AJ, Ronckers CM, Mertens AC, et al. Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet. 2005;365(9476):2014-23.
12. Darzy KH, Shalet SM. Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary. 2005;8(3-4):203-11.
13. Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. 2001;91(3):613-21.
14. Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr Blood Cancer. 2008;50(2):347-51.
15. Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab. 1996;81(8):3051-55.
16. Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. 2000;356(9234):993-7.
17. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005;44(7):600-6.
18. Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23(30):7685-96.
19. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324(12):808-15.
20. Lipshultz SE, Grenier MA, Colan SD. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1999;340(8):653-4; author reply 655.
21. Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. 2001;19(1):191-6.
22. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991;266(12):1672-7.
23. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol. 2005;23(12):2629-36.
24. Kremer LC, van der Pal HJ, Offringa M, van Dalen EC, Voute PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. 2002;13(6):819-29.
25. Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children’s Oncology Group. Pediatrics. 2008;121(2):e387-96.
26. 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(21):2831-7.
27. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol. 1993;11(7):1208-15.
28. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 1993;270(16):1949-55.
29. Berry GJ, Jorden M. Pathology of radiation and anthracycline cardiotoxicity. Pediatr Blood Cancer. 2005;44(7):630-7.
30. Bowers DC, Liu Y, Leisenring W, 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. 2006;24(33):5277-82.
31. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin’s Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2005;23(27):6508-15.
32. Meeske KA, Siegel SE, Gilsanz V, et al. Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation. Pediatr Blood Cancer. 2009;53(4):615-621.
33. Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst. 2001;93(8):618-29.
34. Neglia JP, Meadows AT, Robison LL, et al. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;325(19):1330-6.
35. Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol. 1998;16(12):3761-7.
36. Neglia JP, Robison LL, Stovall M, 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. 2006;98(21):1528-37.
37. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med. 1996;334(12):745-51.
38. Kenney LB, Yasui Y, Inskip PD, et al. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. 2004;141(8):590-7.
39. Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer. 2002;2(2):124-32.
40. Dann EJ, Rowe JM. Biology and therapy of secondary leukaemias. Best Pract Res Clin Haematol. 2001;14(1):119-37.
41. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325(24):1682-7.
42. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23(10):2272-9.
43. Wong FL, Boice JD Jr., Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA. 1997;278(15):1262-7.
44. Tucker MA, D’Angio GJ, Boice JD Jr., et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987;317(10):588-93.
45. Moore BD 3rd. Neurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol. 2005;30(1):51-63.
46. Anderson FS, Kunin-Batson AS. Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function. Pediatr Blood Cancer. 2009;52(2):159-64.
47. Pang JW, Friedman DL, Whitton JA, et al. Employment status among adult survivors in the Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2008;50(1):104-10.
48. Nagarajan R, Neglia JP, Clohisy DR, et al. Education, employment, insurance, and marital status among 694 survivors of pediatric lower extremity bone tumors: a report from the childhood cancer survivor study. Cancer. 2003;97(10):2554-64.
49. Ness KK, Mertens AC, Hudson MM, et al. Limitations on physical performance and daily activities among long-term survivors of childhood cancer. Ann Intern Med. 2005;143(9):639-47.
50. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol. 2004;22(24):4979-90.