Bone-mineral density deficits from childhood cancer and its therapy

The growing population of childhood cancer survivors—currently estimated at 1 in 900 young adults aged 15–45 years—underscores the importance of studying long-term complications of oncotherapy. While these patients are returning to the mainstream of life, they carry with them toxicities from prior therapy that may compound or potentiate changes typically seen with the normal aging process. Skeletal toxicities such as scoliosis, craniofacial dysplasia, and limb-length discrepancy are readily apparent. However, others such as osteoporosis and osteonecrosis are silent until they reach advanced stages when attempts at amelioration may be unsuccessful. This review addresses bone-mineral density deficits that may predispose childhood cancer survivors to earlier onset and more severe osteopenia and osteoporosis than the normal population.This study was supported in part by grants P30 CA-21765 and P01 CA-20180 from the National Cancer Institute, a Center of Excellence grant from the state of Tennessee from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC)     

Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature

The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors who are at increased risk for a variety of health problems resulting from their cancer or its treatment. Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor attains maturity or begins to age, the ability of primary care providers to anticipate late effects of treatment is essential for providing timely interventions that prevent or correct these sequelae and their adverse effects on quality of life. Altered bone metabolism during treatment for childhood cancer may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteopenia and osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to other common cancer-related sequelae such as hypogonadism. The Children's Oncology Group long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers provide risk-based surveillance recommendations that are based on expert opinion and review of the scientific literature for potential late effects of pediatric cancer therapy including osteopenia. This review summarizes the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the surveillance and counseling recommendations outlined in the Children's Oncology group long-term follow-up guidelines.     

Host factors and consequence of chemotherapy in pediatric cancer patients

The 5-year survival rates for childhood ALL are approaching 80%, but therapy-related toxicities are common. One of the challenges in this population is determining the most efficacious therapeutic regimens for these individuals. Factors such as drug metabolism, genetics, and concomitant disease affect drug efficacy and may be important in determining therapeutic outcomes in these patients. This review will focus on these factors in the treatment of childhood ALL.     

Late effects in childhood cancer survivors: A review with a framing effect bias?

Most publications report the adverse (negative) health issues in childhood cancer survivors. Presenting information to the newly diagnosed patient in a positive manner is advocated, while noting that recurrence is the most likely adverse event. Re‐analysis of population‐based studies on life‐threatening toxicities from Nordic, Dutch, United Kingdom, French, Italian, and N. American publications shows that 5‐year survivors have a near normal life expectancy, 75% have no severe or life‐threatening treatment related toxicity and 87% remain free of a second malignancy. Children who received radiation or anthracycline >250–300 mg/m² are at greatest risk for treatment related life‐threatening toxicities. Pediatr Blood Cancer 2011; 57: 1100–1103. © 2011 Wiley Periodicals, Inc.     

Models of care for survivors of childhood cancer

With improvements in therapy for childhood cancer, the expectation that most childhood cancer patients will survive and enter adulthood is a reality. There is clear evidence that survivors are at risk for adverse health-related long-term sequelae associated with their cancer and its treatment, requiring appropriate health care resources. What is less clear is how this health care should optimally be delivered. We review the functional and operational needs for long-term follow-up for childhood cancer survivors and present alternatives for models of care. Programs for childhood cancer survivors should provide mechanisms for monitoring and management of late effects, as well as support and advocacy for addressing psychosocial issues, health education, and assistance with financial concerns. Access to research is an important component as clinical care and research are integrally related. A multidisciplinary model that provides continuity of care throughout the disease course is optimal, providing transitions from acute anti-neoplastic therapy to follow-up and primary care, as well as from pediatric care to adult-oriented care. There is no single best model of care for all childhood cancer survivors. In evaluating different models, considerations include available resources as well as the particular cancer population being served. Not all survivors require the same level of services and the service level requirement for individual patients may change with time. As outcome research progresses for childhood cancer survivors, methodological issues of optimal health care delivery for this population deserve to be the subject of such research.     

Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group

Curative therapy for childhood cancer has improved significantly in the last 2 decades such that, at present, approximately 80% of all children with cancer are likely to survive > or = 5 years after diagnosis. Prevention, early diagnosis, and treatment of long-term sequelae of therapy have become increasingly more significant as survival rates continue to improve. Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer. The Children's Oncology Group Late Effects Committee and Nursing Discipline and Patient Advocacy Committee have recently developed guidelines for follow-up of long-term survivors of pediatric cancer. A multidisciplinary task force critically reviewed the existing literature to evaluate the evidence for the cardiovascular screening recommended by the Children's Oncology Group guidelines. In this review we outline the clinical manifestations of late cardiovascular toxicities, suggest modalities and frequency of monitoring, and address some of the controversial and unresolved issues regarding cardiovascular disease in childhood cancer survivors.     

Current concepts in pediatric bone disease

It is widely believed that osteoporosis prevention may be best accomplished during childhood and adolescence, when bones are growing rapidly and are most sensitive to environmental influences, such as diet and physical activity. For children with chronic diseases, a variety of factors may influence normal bone mineralization, including altered growth, delayed maturation, inflammation, malabsorption, reduced physical activity, glucocorticoid exposure, and poor dietary intake. In healthy children, maintaining adequate levels of calcium intake, serum vitamin D, and weightbearing physical activity may be sufficient to prevent osteoporosis later in life. Far less is known about effective prevention and treatment of poor bone mineralization in children with chronic illness, such as CF or CD. Osteoporosis prevention and intervention measures during childhood are limited by the paucity of reference data on bone mineralization. Although it is widely recognized that puberty, skeletal maturation, and body size influence BMC and bone density, no reference data for bone mineralization are scaled to these important measures. In children with chronic disease with delayed growth and maturation, the creation of such reference data is of paramount importance. In addition, the dynamic changes that occur during growth and maturation in the structural characteristics of trabecular and cortical bone and the development of the bone-muscle unit may influence current and future fracture risk. Further research is needed to characterize these changes and their use in the assessment of bone health and fracture risk in children. Only then can the impact of treatment strategies be appreciated fully.     

Genetics and the etiology of childhood cancer.

A consideration of the world-wide incidences of childhood cancer and of hereditary subgroups leads to the conclusion that two successive mutations can initiate cancer cells and that such cells usually proceed to develop into detectable cancers in a period of time which is short compared with the time required for most adult cancers. Environmental carcinogens could hypothetically increase the rates at which these mutations occur, but they probably, in fact, contribute little to the incidences. Certain exceptions, notably leukemia and lymphoma, are noteworthy, and a viral origin for them has been widely hypothesized. If most solid tumors of childhood are indeed correctly attributable to mutations in germ and/or somatic cells, then the prospect for the prevention of childhood cancer becomes very dim. In fact, the incidence of the germinal forms may increase as treatment improves (18). In theory, one might be able to identify individuals harboring cancer genes germinally and even to identify them prenatally. But even if the burden of cancer attributable to the hereditary subgroups were elimanted, there would still remain the larger nonhereditary group resulting from somatic mutations. If this hypothesis is correct, then childhood cancer cannot be prevented. With this conclusion goes the admonition, however, that environmental mutagens might significantly increase the burden of childhood cancer. One such mutagen, therapeutic radiation, is known to increase the prospect that second tumors will occur in patients who carry a germinal cancer mutation. The major effort to reduce the incidence of childhood cancer by prevention should be spent in examining the possibility that leukemia and lymphoma are viral in origin. If the arguments presented are correct, then the main effort against childhood cancer must be that of early diagnosis and treatment. I realize that many have already argued for that strategy in the approach to cancer generally, but I now believe that it is particularly relevant to any program against cancer in children.     

Osteoporosis in childhood: bone density of children in health and disease

Bone mineral density in later life largely depends on the peak bone mass achieved in adolescence or young adulthood. A reduced bone density is associated with increased fracture risk in adults as well as in children. Pediatricians should therefore play an important role in the early recognition and treatment of childhood osteoporosis. Juvenile idiopathic osteoporosis and osteogenesis imperfecta are examples of primary osteoporosis in childhood. However, osteoporosis is more frequently a complication of a chronic disease or its treatment. This paper provides an overview of bone and bone metabolism in healthy children and the use of diagnostic tools, such as biochemical markers of bone turnover and several bone densitometry techniques. Furthermore, a number of diseases associated with osteoporosis in childhood and possible treatment strategies are discussed.     

Multi-component behavioral intervention to promote health protective behaviors in childhood cancer survivors: the protect study

BACKGROUND: Improved cure rates for childhood cancer have produced a growing population of survivors at risk for late toxicities of chemotherapy and radiation therapy. Healthy behaviors can modify these risks. We initiated a controlled prospective trial to determine if a multi-component behavioral intervention could induce change in childhood cancer survivors' health knowledge, health perceptions, and practice of health-protective behaviors. PROCEDURE: Adolescent cancer survivors attending a long-term follow-up clinic were randomized to receive standard follow-up care or standard care plus the educational intervention. Baseline measures were obtained at randomization (T(0)) and repeated 1 year (T(1)) later during the survivors' annual check-up. RESULTS: Of 272 patients enrolled and randomized, 251 are evaluable at both time points. Treatment and control groups were similar in regards to diagnosis, gender, race, and age. The change in outcome measures over the year (T(1)-T(0)) was not significantly different between the two groups as assessed by a two-sample pooled t test. However, additional exploratory analyses indicated a significant gender difference in knowledge with female survivors in the intervention group having higher scores. In addition, patients who choose certain individual health goals, such as breast/testicular self-examination, showed improved practice of the health behavior. In addition, in a very exploratory analysis, a gender difference in response to the intervention was noted, with females exhibiting a greater improvement in knowledge scores than did males. CONCLUSIONS: Although the multi-behavioral educational intervention did not induce change in health knowledge, perceptions, and behaviors of childhood cancer survivors for the treatment group as a whole, gender differences and specific health goal differences were found. These findings suggest that future interventions should be tailored to reflect gender differences and the nature of the health goal under assessment.     

Long-term follow-up of pediatric cancer survivors: education, surveillance, and screening

Cancer and its treatment predispose childhood cancer survivors to chronic or late occurring health problems that may not become clinically significant until many years after therapy. Frequently, long-term survivors of childhood cancer report late cancer-related effects that diminish quality of life and increase the risk of early mortality. Risk-based health care that involves a personalized plan for surveillance, screening, and prevention is recommended to reduce cancer-related morbidity in childhood cancer survivors. To implement optimal risk-based care, the survivor and health care provider must have accurate information about cancer diagnosis, treatment modalities, and potential cancer-related health risks to guide screening and risk-reducing interventions. However, previous studies evaluating health knowledge of childhood cancer survivors demonstrate noteworthy deficits and misperceptions about their cancer diagnosis, treatment, and cancer-related health risks. In addition, because of the relative rarity of childhood cancer, many health care providers lack familiarity with cancer-related health risks and risk-reduction methods relevant for this population. To correct these deficits, the Scottish Intercollegiate Guidelines Network (SIGN) and the Children's Oncology Group (COG) developed clinical practice guidelines to foster appropriate risk-based survivor care. Herein, we discuss the development, benefits, and limitations of the SIGN and COG guidelines and the foundation they provide for standardizing long-term follow-up care of the ever-growing vulnerable population of childhood cancer survivors.     

Children's Oncology Group's 2013 blueprint for research: Epidemiology

Investigators worldwide have for over 40 years conducted case–control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection. Pediatr Blood Cancer 2013; 60: 1059–1062. © 2012 Wiley Periodicals, Inc.     

Osteoporosis in children and adolescents: diagnosis, risk factors, and prevention

Bone mass acquired during childhood and adolescence is a key determinant of adult bone health. Peak bone mass, which is achieved in late adolescence, is a main determinant of osteoporosis in adulthood. Therefore, any factor adversely impacting on bone acquisition during childhood or adolescence can potentially have long-standing detrimental effects on bone health predisposing to osteoporosis and fracture risk. Thus, osteoporosis can well have its origin in childhood and adolescence. Pediatricians should be playing an active role in osteoporosis diagnosis and prevention. It is increasingly recognized that osteoporosis may occur in some disorders of children and adolescents. In this paper we review the diagnostic criteria of osteopenia/osteoporosis by densitometric assessment of bone mineral density, the contributing factors, and the mechanisms whereby several disorders may affect the acquisition of bone mass in children and adolescents. Finally, some recommendations to optimize peak bone mass in order to prevent osteopenia/osteoporosis are suggested.     

Long-term quality of life and psychosocial coping after treatment of solid tumours in childhood. A population-based study of 94 patients 11-28 years after their diagnosis

In order to assess the long-term quality of life after childhood cancer, we examined and interviewed 94 survivors of childhood solid tumours (excluding brain tumors) diagnosed in our hospital between 1960 and 1976. Their follow-up times ranged form 10.7 to 27.7 years, and their ages at the time of this study form 11.3 to 41.5 years. The subjects had a higher educational level than the Finnish general population. Fewer of the females and as many of the males were married as in the general population. Eight healthy men had been rejected for military service because of the history of cancer. An unsatisfied desire to know more about their own medical history was evident. According to our findings, some subjects after childhood solid tumour are at risk of developing emotional and social problems. However, the great majority of the survivors were well balanced psychologically, living a normal social life and showing adequate capacity to cope.     

Multiple behavioral risk factors among adolescent survivors of childhood cancer in the Survivor Health and Resilience Education (SHARE) program

BACKGROUND: Health-compromising behaviors among survivors of childhood cancer may increase their risks of cancer recurrence and the onset of chronic disease in adulthood. Regardless of whether such behaviors occur singly or in combination with one another, multiple behavioral risk factors must be identified and addressed early to promote better health outcomes within this special population. Adolescent survivors may be especially vulnerable, as reported rates of smoking and other risky behaviors are at or near levels of their healthy peers. The psychological literature suggests stress may play a role in risk behavior initiation and maintenance, including multiple behavioral risks, and that adolescent survivors are stress-prone. This report focuses on the prevalence and co-occurrence of three behavioral risk factors (cigarette use, insufficient physical activity, and non-adherence to sun protection recommendations) and describes stress-health behavior relationships in this special population. PROCEDURE: All patients in this study (n = 75) were adolescent survivors of childhood cancer and completed a baseline assessment of their health behaviors and stress as part of a randomized controlled trial of health promotion. RESULTS: Twenty-eight percent of the patients reported one of three risk factors, 12% reported two of three risk factors, and 7% reported all three risk factors. Non-adherence to sun protection was the single most common risk factor; physical inactivity and non-adherent sun protection were the most common co-occurring risk factors. Greater age and stress were significantly associated with the presence of more behavioral risk factors. CONCLUSIONS: The evidence suggests interventions to reduce multiple health-compromising behaviors in these patients are warranted, and that efforts to address these patients' personal and family stress levels are important as well.     

Physical activity and bone development during childhood and adolescence. Implications for the prevention of osteoporosis

Osteoporotic fractures are a debilitating and a frequently fatal health problem for older adults. A growing body of evidence indicates that osteoporosis has its origin in early life and that the level of development of bone mass during childhood and adolescence strongly influences the risk for osteoporotic fractures. The development of osteoporosis results from an interaction between 1) bone mass accrual via growth, remodeling, and modeling during childhood and adolescence and 2) the maintenance of bone mass (primarily via remodeling) during adulthood. Peak bone mass which occurs at the conclusion of growth may be the most important factor for preventing osteoporosis since as much bone is accrued during the adolescent years as most individuals will lose during all of adult life. In this review, I examine the contribution of physical activity as an important behavioral determinant of children's bone development, particularly of peak bone mass. Since it is a behavior, physical activity is a potentially modifiable determinant of peak bone mass; therefore, understanding activity's impact on bone health is central to developing primary prevention strategies for osteoporosis.     

Life after cancer in childhood: social adjustment and educational and vocational status of young-adult survivors

PURPOSE: To evaluate the long-term social effect of illness and its treatment on young-adult survivors of pediatric cancer by addressing a selection of general social adjustment criteria. METHODS: In a cross-sectional case-control study, 30 young-adult survivors of childhood cancer were compared with (1). controls with no history of serious illness, matched by sex, age, and geographic area of residence, and (2). general population norms on the subject of educational and vocational factors, habitation, family/partner relationships, parenthood, and leisure activities. RESULTS: The educational status of survivors was similar to that of controls, although a smaller proportion of the patients expressed concrete plans for future vocational or educational advancement. Survivors had less frequently entered higher education compared with general population norms. A longer duration of treatment was related to a lower estimated socioeconomic level, and poor psychological coping with the illness experience was associated with the fact that they were still living with their parents, a shorter education, and a lower socioeconomic level. CONCLUSIONS: The social, vocational, and educational adjustment of relapse-free survivors from childhood cancer appears as only moderately, if at all, negatively affected by the illness and treatment history. However, the treatment intensity and particularly the survivors' coping with their illness experience may influence their ability to achieve long-term social goals. These findings suggest that special attention should be given to matters concerning education and partner relationships at long-term follow-up of pediatric cancer patients.     

IS THE TREATMENT FOR CHILDHOOD SOLID TUMORS ASSOCIATED WITH LOWER BONE MASS THAN THAT FOR LEUKEMIA AND HODGKIN DISEASE?

Background: Cancer disease and its therapy (e.g., chemotherapeutic agents such as glucocorticoids, methotrexate, antymetabolities, cranial and local irradiation) may severely disturb normal growth, bone mineral acquisition, and skeletal development because most individuals go through the stages of rapid growth when childhood cancer is diagnosed. Procedures: To identify factors associated with reduced bone mineral density (BMD) in survivors of childhood cancer the authors examined 114 patients (70 males) who had been treated for acute lymphoblastic leukemia (ALL; n = 43), Hodgkin disease (HD; n = 35), and solid tumors (ST; n = 36) twice. Median age at diagnosis was 8.4 years; at the consecutive examinations it was 12.8 and 16.3 years, respectively. To assess bone density we used dual-energy x-ray absorptiometry (DXA). Results: In the first examination, patients with a history of steroid therapy had higher total and spine BMD and higher BMI (body mass index) than those who were not given steroids. At the end of the follow-up, no differences were found in BMD between subgroups, although BMI was still higher in both ALL and HD patients than in those with ST. Conclusions: Patients treated for solid tumors have reduced bone mass. Low BMI and local irradiation seem to be the factors responsible for reduced BMD in children treated for ST. The use of steroids does not disturb bone mass accumulation in patients treated for childhood malignancies. However, a long-term effect of cancer treatment on osteoporosis risk remains to be determined.     

Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer

Increasingly young people survive cancer in childhood and as a result complications of its treatment are becoming more common and important. Premature ovarian failure is recognized as a complication of radiotherapy to a field that includes the pelvis and alkylating‐agent‐based chemotherapy. Young pre‐pubertal girls are not protected from the effects of gonadal toxic therapy. A young woman, successfully treated for cancer during childhood, may experience regular periods in the presence of a significantly reduced ovarian reserve. There is, however, no reliable measure of ovarian reserve available for the individual woman. Assessment of ovarian function relies on the use of surrogate markers such as follicle stimulating hormone, inhibin‐B, and anti‐mullerian hormone as well as ultrasound assessment of ovarian volume and antral follicle count. We discuss the physiology of normal ovarian function, the effects of cancer treatments on ovarian function and the techniques for evaluation of ovarian reserve in survivors of childhood cancer. Pediatr Blood Cancer 2009;53:296–302. © 2009 Wiley‐Liss, Inc.     

Osteopenia in young adult survivors of childhood cancer

BACKGROUND: Improved survival of children with malignant diseases is in part due to the application of intensive, multimodality therapies, including radiotherapy, surgery, glucocorticoids, and cytotoxic agents. Such interventions have the potential to induce complex hormonal, metabolic and nutritional effects that may interfere with skeletal mass acquisition during childhood and adolescence: it is possible that such childhood cancer survivors may therefore reach adulthood with diminished peak bone mass and be at increased risk for clinically significant osteoporosis later in their life. PROCEDURE: A bone mineral density (BMD) was measured in 26 unselected former cancer patients attending the Pediatric Long-Term Clinic at M.D. Anderson Cancer Center. BMD was measured at the lumbar spine and the hip using dual X-ray absorptiometry (Hologic QDR-4500W). In addition, the patients' complete medical records were reviewed with particular attention to disease type, age modalities of treatment, and hormonal residual deficiencies. RESULTS: The median age of patients at the time of cancer diagnosis was 8 years (range, 0.3 to 16 years). Median age at BMD determination was 23 years (range, 18 to 41 years), and the median interval since cancer diagnosis and BMD was 18 years (range, 5 to 29). Overall, their BMD was decreased relative to peak bone mass at all sites: osteopenia was especially pronounced in patients with a history of cranial irradiation who had developed evidence of pituitary insufficiency during childhood or adolescence. Overall, the median BMD T-score was -1.41 at the lumbar spine, -1.04 at the femoral neck, and -1.06 for total hip. For patients with prior cranial irradiation, T-score at the lumbar spine was -2.18 (range, -4.06 to -0.98), at the femoral neck -1.92 (range, -4.11 to +1.10), and for total hip -1.67 (range, -4.79 to +0.56); BMD for irradiated patients was significantly lower than BMD of patients without cranial irradiation. We could not discern an independent impact of other disease characteristics or treatment modalities in this small group of patients. CONCLUSIONS: Osteopenia is a prominent finding in young adults who are survivors of childhood cancers; it is likely that antineoplastic treatments during childhood and adolescence impede peak bone mass acquisition. We suggest that systematic attention to this potential complication is needed in order to identify what subgroups of children may require regular surveillance and what interventions are required for its prevention or treatment.