Current Opinion in Pediatrics:
HEMATOLOGY AND ONCOLOGY: Edited by Stephen Hunger
Childhood cancer survivorship: an update on evolving paradigms for understanding pathogenesis and screening for therapy-related late effects
Armenian, Saro H.a; Robison, Leslie L.b
aDepartment of Population Sciences, City of Hope National Medical Center, Duarte, California
bEpidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee, USA
Correspondence to Saro H. Armenian, DO, MPH, City of Hope, 1500, East Duarte Road, Duarte, CA 91010-3000, USA. Tel: +1 626 471 7320; fax: +1 626 301 8983; e-mail: firstname.lastname@example.org
Purpose of review: Five-year survival for many childhood cancers approaches 80%, and there is a growing number of long-term survivors in the United States. These survivors are at risk for developing adverse health-related complications. We highlight recently published studies that provide new insight into the association between specific therapeutic exposures and late-occurring complications such as second malignant neoplasms, cardiovascular disease, endocrinopathies, and neurocognitive impairment.
Recent findings: The incidence for many long-term complications continues to increase with longer follow-up. Investigators have begun to explore the impact of aging and the role of genetic susceptibility as modifiers of risk in diseases wherein there is a clear association between therapeutic exposure and adverse outcome. Increased awareness of the importance of screening has set the stage for assessment of the impact of early detection for reduction of long-term morbidity and mortality among childhood cancer survivors at highest risk for therapy-related complications.
Summary: The long-term health-related burden in childhood cancer survivors is substantial. Recent studies exploring the etiopathogenesis of treatment-related late effects have provided important information that will assist in ongoing efforts to develop personalized cancer care. Efficacious medical interventions are needed to help mitigate treatment-related complications in high-risk survivors.
Advances in treatment strategies for childhood cancer and supportive care have resulted in marked improvements in survival, with 5-year survival rates approaching 80% . As of 2009, there were an estimated 363 000 survivors of childhood cancer in the United States ; of these approximately 24% have survived more than 30 years since their diagnosis, contributing to the growing number of long-term survivors of childhood and adult-onset cancer in the United States . Unlike adults, children tolerate the acute effects of therapy relatively well. However, the use of chemotherapy, radiation, and/or surgery at an early age can contribute to complications that may not become apparent until years after completion of therapy. A recent article from the Childhood Cancer Survivor Study (CCSS) cohort reported that two out of three survivors will develop a chronic health condition, and more than one-third will develop a condition that is severe or life-threatening . The CCSS cohort consists of 14 357 5-year survivors of childhood cancer, diagnosed between 1970 and 1986 at one of 26 collaborating CCSS institutions, who completed a comprehensive questionnaire regarding a wide range of health-related outcomes; 4023 siblings were recruited to compare outcomes . Overall, childhood cancer survivors were at an eight-fold increased risk of developing a severe or life-threatening health condition when compared with age-matched and sex-matched siblings .
During the past three decades, research on survivorship issues has demonstrated well-established associations between specific therapeutic exposures and adverse outcomes such as subsequent malignant neoplasms, cardiopulmonary dysfunction, endocrinopathies, and neurosensory disorders (Table 1). Recognizing the need for a systematic plan for lifelong surveillance of health-related outcomes, the Children's Oncology Group (COG) developed risk-based exposure-related guidelines, designed for follow-up care of children who completed treatment for their malignancies . The Guidelines and patient-directed informational ‘Health Links’ can be downloaded from http://www.survivorshipguidelines.org. We present here selected highlights from recently published studies that demonstrate how research is shedding new light on the etiopathogenesis and risk factors for some of the more commonly occurring late effects.
SECOND MALIGNANT NEOPLASMS
Childhood cancer survivors are at risk for development of subsequent malignant neoplasms (SMN) [7–10,11▪▪]. This risk is approximately 10-fold greater than in the general population, and an important health-related concern for the aging childhood cancer survivor population . SMNs are the leading cause of treatment-related mortality in long-term childhood cancer survivors [standardized mortality ratio (SMR), 15.2; 95% confidence interval (CI) 13.9–16.6] . Commonly reported solid SMNs include breast, thyroid, skin and brain cancer, and there is a strong and well-defined association with radiation exposure that is characterized by a latency that exceeds 10 years . Other SMNs such as therapy-associated leukemia (t-MDS/AML) are notable for their shorter latency (typically <10 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitor chemotherapy . Much of the information on incidence and risk factors for SMNs has come from studies involving large cohorts of survivors (CCSS , British Childhood Cancer Survivor Study (BCCSS) ], followed more than 5 years from initial cancer diagnosis. These studies have found that for many SMNs, such as solid cancers, the incidence continues to increase with longer follow-up, with no plateau of risk over time [11▪▪,12]. Importantly, survivors who develop a first SMN (SN1) are at an especially high risk of multiple occurrences of subsequent neoplasms, such that, within 20 years from diagnosis of SN1, the estimated cumulative incidence of another neoplasm is 47% [15▪]. Although not evaluated in the study, the experience of children with Li-Fraumeni syndrome (LFS) or retinoblastoma would suggest that underlying genetic susceptibility [i.e. TP53 or CHEK2 (LFS), RB1 (retinoblastoma) gene alterations] may play a role in the development of multiple SMNs in a subset of childhood cancer survivors.
A recent report [11▪▪] from the BCCSS found that the cumulative incidence of survivors developing an SMN increased steadily with sustained age from 1.6% at age 20 years to nearly 14% at age 60 years, compared with 8.4% expected at the latter age in the general population. The overall standardized incidence ratio (SIR) was four times more than expected (SIR = 3.9; 95% CI 3.6–4.2), and the absolute excess risk (AER) in survivors older than 40 years was highest for digestive and genitourinary SMNs [AER = 5.9 (95% CI 2.5–9.3) and 6.0 (95% CI 2.3–9.6) per 100 000 person-years, respectively]. Especially sobering were the findings that, by age 50, the incidence of colorectal cancer (CRC) for survivors treated with direct abdominopelvic irradiation was comparable to the risk in individuals with at least two first-degree relatives affected by CRC. Two additional studies [16▪,17▪] have reported a high incidence of gastrointestinal cancers in childhood cancer survivors when compared with the general population, with the highest risk associated with abdominal radiation (SIR = 11.2; 95% CI 7.6–16.4) [17▪]. This supports the current COG Guidelines recommendation that CRC surveillance for high-risk survivors should begin at a much younger age (beginning 10 years after radiation or at age 35 years, whichever is later) than that currently recommended for the general population. A recent study [18▪▪] has raised the possibility of host genetic susceptibility as a modifier of SMN risk. Investigators found two variants at chromosome 6p21 to be associated with radiation-induced SMNs in survivors of Hodgkin's lymphoma. Although these findings require further validation, they raise the possibility of novel gene–exposure associations that may help direct prevention strategies in survivors at highest risk for radiation-associated SMNs.
Although it is well recognized that radiation exposure largely contributes to the risk of solid SMNs, there is emerging evidence that chemotherapy may further modify the increasing risk over time. A report from the CCSS found that, although children treated with abdominopelvic radiation were at the highest risk of gastrointestinal cancer, the overall risk among those not treated with radiation remained higher (SIR = 2.4; 95% CI 1.4–3.9) than in the general population; high-dose procarbazine [relative risk (RR) = 3.2; 95% CI 1.1–9.4] and platinum chemotherapy (RR = 7.6; 95% CI 2.3–25.5) independently increased the risk of gastrointestinal SMNs [17▪]. Another study evaluating risk of thyroid cancer reported a higher risk with alkylating chemotherapy exposure (RR = 2.4; 95% CI 1.3–4.5), but only in radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing . These findings add to the evidence that chemotherapy alone may increase the risk of solid SMNs, which, to date, was mainly thought to be related to prior radiation therapy.
Cardiovascular complications are a leading cause of therapy-related morbidity and mortality in long-term survivors of childhood malignancy . These survivors are at a 15-fold increased risk of developing congestive heart failure (CHF) compared with age-matched controls . There is a strong dose-dependent association between anthracycline exposure and risk of CHF; this risk is modified by younger age at exposure, female sex, and chest irradiation . The cardiotoxicity may manifest as symptomatic CHF or asymptomatic functional cardiac abnormalities (i.e., systolic or diastolic dysfunction) detected on imaging studies . The incidence of CHF is below 5% with cumulative anthracycline exposure of less than 300 mg/m2; the incidence approaches 20% at doses between 300 and 600 mg/m2, and exceeds 35% for doses more than 600 mg/m2[20–22]. A recent study of 5-year survivors of childhood cancer confirmed the previously reported exponentially increasing risk of CHF with anthracycline dose [23▪▪]. CHF often develops years after cessation of therapy, and the incidence rises with follow-up . Outcome following clinical CHF is poor; 5-year overall survival rate is less than 50% [24,25]. Current estimates are that, of the more than 363 000 childhood cancer survivors, nearly 60% will have been exposed to anthracyclines .
With longer follow-up of childhood cancer survivors, it has become apparent that lower cumulative doses of anthracyclines (<150 mg/m2) may place children at risk for cardiac compromise while others do not appear to be affected despite very high doses, raising the possibility that interindividual variability in anthracycline pharmacodynamics may modify risk of cardiotoxicity . Using a biologically plausible candidate gene approach, investigators have begun to identify host polymorphisms that could alter metabolic pathways of anthracyclines. A recent report from the COG found that homozygosis for the G allele in carbonyl reductase-3 (CBR3) contributes to increased cardiomyopathy risk associated with low-dose to moderate-dose (1–250 mg/m2) anthracyclines, such that there seems to be no ‘well-tolerated dose’ for patients homozygous for the CBR3 V244 M G allele [26▪▪]. A subsequent study evaluating genetic modifiers of early-occurring and late-occurring cardiotoxicity identified multiple variants of the SLC28A3 gene as important modifiers of anthracycline-related cardiotoxicity risk [27▪▪]. Many of these genomic variables, when fully established, could be important in facilitating the implementation of targeted primary prevention strategies.
Advances in noninvasive cardiac imaging have allowed investigators to identify a growing population of survivors who may be at risk for late occurring CHF, setting the stage for pharmacologic interventions to prevent progression to clinical CHF [28,29]. Traditionally, monitoring of anthracycline-related cardiotoxicity has relied upon serial two-dimensional echocardiography using resting left ventricular ejection fraction (LVEF) or shortening fraction (LVSF) . However, serial screening using echocardiography-derived LVEF/SF has increasingly been recognized as inadequate for detecting subtle changes in myocardial function. Often, at the point when changes in LVEF/SF are detected, functional deterioration proceeds rapidly and is often irreversible [29–31]. Cardiac magnetic resonance (CMR) has emerged as an alternative to traditional two-dimensional echocardiography due to its superior intraobserver and interobserver reproducibility and ability to detect functional LV systolic changes at an earlier timepoint . A recent report found that, among survivors previously undiagnosed with cardiotoxicity, a substantial proportion had abnormal LVEF (32%) and cardiac mass (48%), defined as more than two SDs below the mean of normative CMR data [33▪]. In fact, two-dimensional echocardiography overestimated the mean LVEF for this population by 5%, and had a sensitivity of 25% and a false-negative rate of 75% for detection of LVEF <50%, a threshold that typically warrants cardiology referral for potential pharmacologic intervention [33▪]. It remains to be seen whether newer two-dimensional echocardiographic measurements of myocardial remodeling (tissue Doppler, strain) or three-dimensional echocardiography can be successfully integrated into screening strategies in centers wherein CMR is either unavailable or cost-prohibitive [34▪].
Endocrine late effects after cancer therapy include problems with growth, weight, puberty and gonadal function, bone health, thyroid and adrenal function . Studies evaluating endocrine-related complications in childhood cancer survivors have generally focused on specific outcomes, often limited to cohorts with single cancer diagnoses . A recent single-institution study found that 57.6% of patients followed at a designated childhood cancer survivorship clinic had at least one endocrine condition, and 22.7% had multiple endocrine disorders [36▪]. Commonly reported endocrine problems were weight related [under/overweight (31%)], abnormal gonadal function (25.2%) and growth disorders (19.4%) [36▪]. Survivors of hematopoietic cell transplantation (HCT) and children who were older during cancer treatment were at a significantly increased risk for having an endocrine complication.
An emerging area of concern is the development of metabolic syndrome, defined as a cluster of health conditions that include insulin resistance, overweight/obesity, hypertension, and dyslipidemia, in long-term survivors of childhood cancer [35,37]. This is especially problematic for survivors treated with cardiotoxic therapies such as anthracyclines and radiation, wherein certain components of the metabolic syndrome (hypertension, insulin resistance) have been shown to substantially modify cardiovascular disease risk . A study in acute lymphoblastic leukemia (ALL) survivors found the prevalence of metabolic syndrome to be 9.2%, with the highest prevalence noted in HCT survivors (18.6%) [38▪]. HCT with total body irradiation was associated with a higher rate of hypertriglyceridemia [odds ratio (OR) = 4.5, P = 0.004], low level of high-density lipoprotein cholesterol (OR = 2.5, P = 0.02) and elevated fasting glucose (OR = 6.1, P = 0.04) [38▪]. Although the pathophysiology of therapy-related metabolic syndrome has not been elucidated, several investigators have proposed growth hormone (GH) deficiency as a critical modifier of risk [37,39], a finding validated in a subsequent cross-sectional study evaluating cardiovascular risk and insulin resistance in long-term survivors of childhood cancer [40▪].
Adult survivors of childhood cancer may also have reduced bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry scans . Cancer treatments that interfere with bone accretion during adolescence and young adulthood are thought to increase the risk of osteoporosis and osteoporotic fractures later in life , a notion that is not supported by a recent CCSS report [42▪]. Known factors for reduced BMD in childhood cancer survivors include treatment with corticosteroids, radiation, methotrexate chemotherapy, and other endocrinopathies such as GH deficiency and hypogonadism . As in previously described late effects, low BMD is likely a result of a combination of treatment-specific exposures and other host–environment interactions [35,43]. A cross-sectional study of long-term cancer survivors revealed that, in addition to treatment-related variables such as radiation and corticosteroids, lower levels of physical activity and higher daily television viewing time significantly increased the risk of osteopenia [44▪▪]. The identification of modifiable risk factors such as physical inactivity may provide opportunities for the development of interventions for risk reduction in childhood cancer survivors at high risk for osteopenia in adulthood.
Neurocognitive complications can occur as a result of surgery and/or radiation to the brain, systemic therapy with high-dose methotrexate, or intrathecal therapy [45,46]. As a result, children with brain tumor, ALL, or non-Hodgkin's lymphoma appear to be at highest risk [45,46]. In children treated with cranial radiation, neurocognitive deficits typically become apparent within 1–2 years following completion of therapy, and may be progressive in nature [45,46]. Affected children may experience information-processing deficits resulting in academic difficulties, and are prone to problems with visual perceptual motor skills, receptive attention span, and expressive language. The reduction of cranial radiation dose for children with ALL and combined dose/field modification for children with brain tumors has resulted in a decrease in prevalence and severity of neurocognitive complications for children treated on contemporary protocols [47–49]. The evidence for neurocognitive complications due to chemotherapy alone is less established; described deficits are primarily restricted to attention, executive function, and complex fine-motor functioning [49,50].
For many long-term survivors of childhood cancer, neurocognitive deficits may affect the opportunities to participate in adult life roles, including their ability to find and maintain employment. A recent study examined the association of psychosocial, physical, and neurocognitive deficits with inability to work because of health or disability problems [51▪]. Survivors with task efficiency and memory problems were more likely to report health-related unemployment or to work part-time. Employed female survivors with task efficiency, emotional regulation, and memory limitations were 20% less likely to report working in higher-skilled professional or managerial positions. The findings from this study suggest that interventions to improve employment outcomes for childhood cancer survivors should not only target physical health barriers to employment, but also include screening for mental health and neurocognitive problems.
Having poor neurocognitive function can also affect survivors’ ability to access preventive care or engage in recommended physical activity. Survivors with neurocognitive problems in task efficiency are less likely to meet the Centers for Disease Control guidelines for weekly physical activity (RR = 0.8, 95% CI 0.7–0.8) and less likely to engage in preventive health practices such as dental care (RR = 0.92, 95% CI 0.9–1.0) [52▪]. Although the cause of many of these behavioral outcomes is likely to be complex, it is increasingly clear that certain subsets of cancer survivors may warrant closer surveillance for neurocognitive impairment so that proper interventions can be initiated prior to the development of additional adverse psychosocial and health-related complications.
Research on survivorship-related issues has produced a wealth of knowledge regarding therapy-related risk factors for late effects. There is emerging data to suggest that genetic susceptibility could be an important modifier of these adverse outcomes. Future studies evaluating etiopathogenesis of late effects in survivors of childhood cancer will need to inform approaches for personalized cancer care that weighs treatment efficacy with the future risk for treatment-related complications. The promise for primary prevention notwithstanding, there is a growing childhood cancer survivor population that remains at risk for late effects due to past treatment exposures for their primary cancer. Randomized trials of medical interventions are needed to help identify novel approaches to mitigate many of the complications described in the current article. Lastly, it is important to note that much of the data presented on health-related outcomes is derived from children treated for malignancies prior to the mid-1990s. Future studies will need to evaluate the long-term impact of reduction in intensity of treatment for many childhood malignancies, such as ALL, Hodgkin's and non-Hodgkin's lymphoma, Wilm's tumor, rhabdomyosarcoma, and certain central nervous system malignancies such as medulloblastoma. Information obtained from these studies will help caregivers in cancer treatment planning and counseling of families regarding late effects of therapy, and facilitate the ongoing modification of the current COG long-term follow-up screening recommendations.
Funding: National Institutes of Health [K12 CA001727-14 (S.H.A.), U10 CA098543 (S.H.A.), P30 CA21765 (L.L.R.)], and the American Lebanese Syrian Associated Charities [St Jude Children's Research Hospital (L.L.R.)].
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 146).
1. Ries L, Eisner M, Kosary C, et al.
Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD; 2008. http://seer.cancer.gov/csr/1975_2005/. [Accessed 31 August 2012]
2. Howlader N, Noone AM, Krapcho M, et al
., editors. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER website April 2012. [Accessed 31 August 2012]
3. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term survivors of childhood cancers in the United States. Cancer Epidemiol Biomarkers Prev 2009; 18:1033–1040.
4. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355:1572–1582.
5. Robison LL, Armstrong GT, Boice JD, et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol 2009; 27:2308–2318.
6. 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; 22:4979–4990.
7. Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer 2002; 2:124–132.
8. Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2010; 102:1083–1095.
9. de Vathaire F, Hawkins M, Campbell S, et al. Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment. Br J Cancer 1999; 79:1884–1893.
10. Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009; 101:806–813.
11▪▪. Reulen RC, Frobisher C, Winter DL, et al. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 2011; 305:2311–2319.
Study evaluates SMN risk in a very large cohort of survivors treated between 1940 and 1991, median follow-up 24 years. The risk for second malignancies continues to increase with time. Novel finding of similar risk of CRC between cancer survivors treated with abdominal radiation and noncancer survivors with strong family history of CRC. Implications for early screening.
12. 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; 93:618–629.
13. Armstrong GT, Plana JC, Zhang N, et al
. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 2012; 30:2876–2884.
14. Hawkins MM, Lancashire ER, Winter DL, et al. The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information. Pediatr Blood Cancer 2008; 50:1018–1025.
15▪. Armstrong GT, Liu W, Leisenring W, et al. Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2011; 29:3056–3064.
Study shows that multiple SMNs are common among survivors. Implications for lifelong surveillance in high-risk subgroups.
16▪. Nottage K, McFarlane J, Krasin MJ, et al. Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 2012; 30:2552–2558.
Confirms findings by Reulen et al.[11▪▪] of increased CRC risk.
17▪. Henderson TO, Oeffinger KC, Whitton J, et al. Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med 2012; 156:757–766.
Confirms findings by Reulen et al.[11▪▪] of increased CRC risk. The highest risk was following abdominal radiation (SIR 11.2).
18▪▪. Best T, Li D, Skol AD, et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin lymphoma. Nat Med 2012; 17:941–943.
Important study demonstrating an interaction between specific genetic variants and therapeutic exposures as cause of treatment-related morbidity.
19. Veiga LH, Bhatti P, Ronckers CM, et al. Chemotherapy and thyroid cancer risk: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 2011; 21:92–101.
20. Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94:525–533.
21. Mulrooney DA, Yeazel MW, Kawashima T, et al.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009; 339:b4606.
22. van Dalen EC, van der Pal HJ, Kok WE, et al. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 2006; 42:3191–3198.
23▪▪. van der Pal HJ, van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 2012; 30:1429–1437.
Large cohort study with long follow-up, relying on clinically validated cardiovascular outcomes. Demonstrates exponential increase of CHF risk with cumulative anthracycline and chest radiation doses. One in eight survivors treated with radiation and anthracyclines will develop severe heart disease.
24. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077–1084.
25. Armenian SH, Sun CL, Shannon T, et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood 2011; 118:6023–6029.
26▪▪. Blanco JG, Sun CL, Landier W, et al.
Anthracycline-Related Cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes: a report from the Children's Oncology Group. J Clin Oncol 2012; 30:1415–1421.
Novel approach to understanding pharmacogenetic modifiers of anthracycline-related cardiomyopathy risk. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low-dose to moderate-dose anthracyclines such that there seems to be no safe dose for individuals homozygous for a variant of the CBR3 gene. Important implications for future prevention strategies.
27▪▪. Visscher H, Ross CJ, Rassekh SR, et al.
Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol 2012; 30:1422–1428.
Another study evaluating the role of certain genetic variants in modifying risk for anthracycline-related cardiotoxicity. Large sample size that includes a validation subset. Sets the stage for genetic profiling of high-risk cancer patients, taking into consideration other clinical modifiers of risk.
28. 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; 23:2629–2636.
29. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 2005; 44:600–606.
30. 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:e387–e396.
31. Ewer MS, Lenihan DJ. Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground? J Clin Oncol 2008; 26:1201–1203.
32. Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol 2010; 55:2614–2662.
33▪. Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 2012; 30:2876–2884.
Explores the role of CMR in detecting cardiac dysfunction at an earlier timepoint, prior to onset of irreversible myocardial injury, setting the stage for future medical interventions.
34▪. Fallah-Rad N, Walker JR, Wassef A, et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011; 57:2263–2270.
Study in survivors of adult-onset cancer. Explores the role of novel echocardiographic measurements in detecting therapy-related cardiotoxicity. Has potential implications for childhood cancer survivors.
35. Chemaitilly W, Sklar CA. Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer 2010; 17:R141–R159.
36▪. Patterson BC, Wasilewski-Masker K, Ryerson AB, et al. Endocrine health problems detected in 519 patients evaluated in a pediatric cancer survivor program. J Clin Endocrinol Metab 2012; 97:810–818.
Single-center study describing the overall prevalence and burden of endocrine complications in patients followed at an established survivorship clinic.
37. Meacham LR, Chow EJ, Ness KK, et al. Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 2010; 19:170–181.
38▪. Oudin C, Simeoni MC, Sirvent N, et al. Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 2011; 117:4442–4448.
Study confirms a high prevalence of metabolic syndrome in long-term survivors of HCT; the highest risk was among patients who received total body irradiation for HCT.
39. Gurney JG, Ness KK, Sibley SD, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 2006; 107:1303–1312.
40▪. Steinberger J, Sinaiko AR, Kelly AS, et al. Cardiovascular risk and insulin resistance in childhood cancer survivors. J Pediatr 2011; 160:494–499.
A cross-sectional study that included a comprehensive assessment of cardiovascular risk profile. Demonstrated a significantly higher waist circumference and percentage body fat and lower lean body mass in cancer survivors compared with controls, without an associated difference in BMI.
41. Baxter-Jones AD, Faulkner RA, Forwood MR, et al. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res 2011; 26:1729–1739.
42▪. Wilson CL, Dilley K, Ness KK, et al.
Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 2012. [Epub ahead of print]
Despite a higher reported prevalence of low bone mineral density in survivors, no increase in clinically meaningful outcomes such as fractures.
43. Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 2001; 15:728–734.
44▪▪. Polgreen LE, Petryk A, Dietz AC, et al. Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr 2012; 12:40.
The identification of modifiable risk factors such as physical inactivity may provide opportunities for the development of interventions for risk reduction in childhood cancer survivors at high risk for osteopenia in adulthood.
45. Reimers TS, Ehrenfels S, Mortensen EL, et al. Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol 2003; 40:26–34.
46. Campbell LK, Scaduto M, Sharp W, et al. A meta-analysis of the neurocognitive sequelae of treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 2007; 49:65–73.
47. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 1998; 16:1723–1728.
48. Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 2001; 19:3470–3476.
49. Kadan-Lottick NS, Brouwers P, Breiger D, et al. Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2009; 27:5986–5992.
50. Kadan-Lottick NS, Brouwers P, Breiger D, et al. A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 2009; 114:1746–1752.
51▪. Kirchhoff AC, Krull KR, Ness KK, et al. Physical, mental, and neurocognitive status and employment outcomes in the childhood cancer survivor study cohort. Cancer Epidemiol Biomarkers Prev 2011; 20:1838–1849.
Examines the association between neurocognitive impairment and employment outcomes.
52▪. Krull KR, Annett RD, Pan Z, et al. Neurocognitive functioning and health-related behaviours in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Eur J Cancer 2011; 47:1380–1388.
Examines the association between neurocognitive impairment and health-related behaviors such as cancer screening, dental care, and regular medical follow-up.
childhood cancer; genetics; late effects; medical interventions; survivorship
© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.