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.     

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.     

Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children's Oncology Group

Childhood cancer survivors who have had pelvic or central nervous system surgery or have received alkylator-containing chemotherapy or pelvic radiotherapy as part of their cancer therapy may experience urinary bladder late effects. This article reviews the medical literature on long-term bladder complications in survivors of childhood cancer and outlines the Children's Oncology Group Long-Term Follow-up (COG LTFU) Guidelines related to bladder function. An overview of the treatment of bladder late effects and recommended counseling for survivors with these complications are presented.     

Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group

With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.     

Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group

Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).     

Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee

The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research.     

Genetic susceptibility and body mass in childhood cancer survivors

Childhood cancer survivors are at increased risk of many long-term treatment-related sequel such as second cancers, cardiovascular disease, and pulmonary complications. Certain treatments seem to influence the risk of becoming overweight, obese, or underweight, and abnormal body mass index (BMI) is associated with increased morbidity and mortality. Because BMI is modifiable, it is important to identify treatment and patient-related factors contributing to altered BMI. New research areas include exploring how genetic susceptibility through population polymorphism may contribute to BMI. Illuminating potential gene-environment interactions that influence obesity and underweight might be more readily accomplished in a study of high-risk individuals (i.e., childhood cancer survivors) with well-characterized exposures. The new Childhood Cancer Research Network in the Children's Oncology Group, when fully implemented, should make it less difficult in the future to recruit the large numbers of patients needed for such studies.     

Hepato‐biliary late effects in survivors of childhood and adolescent cancer: A report from the Children's Oncology Group

Curative therapy for childhood and adolescent cancer translates to 1 in 640 young adults being a survivor of cancer. Although acute hepato‐biliary toxicity occurs commonly during pediatric cancer therapy, the impact of antineoplastic therapy on long‐term liver health in childhood/adolescent cancer survivors is unknown. This article reviews the medical literature on late liver dysfunction following treatment for childhood/adolescent cancer. We also outline the Children's Oncology Group (COG) guidelines for screening and follow‐up of hepato‐biliary sequelae. As the population of survivors grow and age, vigilance for risks to hepatic health needs to continue based on specific exposures during curative cancer therapy. Pediatr Blood Cancer 2010;54:663–669. © 2009 Wiley‐Liss, Inc.     

Late effects risk profiles using the long-term follow-up guidelines in identical twin survivors of acute lymphoblastic leukemia

As the number of pediatric cancer survivors increases, the cost of cure (i.e., late effects) needs to be measured through a consistent mechanism. Through the use of the Children's Oncology Group's (COG) Long-Term Follow-Up (LTFU) guidelines, individualized risk profiles can be discerned for each off-therapy patient. These guidelines were used to compare and contrast risk profiles for identical twin females treated for acute lymphoblastic leukemia (ALL). The first twin was treated for high-risk leukemia and the second for standard-risk leukemia, each with different ALL protocols. Timely use of the LTFU guidelines has aided in identifying and treating their adverse late effects.     

Factors associated with health-related quality of life in pediatric cancer survivors

BACKGROUND: Childhood cancer survivors are at risk for late effects of disease and treatment that may be attributed to multiple causes. This study describes health-related quality of life (HRQOL) in childhood cancer survivors and identifies factors related to poor quality of life outcomes. PROCEDURE: Patients age 8-18 years, who attended the long-term information, follow-up, and evaluation (LIFE) clinic at Childrens Hospital Los Angeles during a 1-year time-period were eligible for the study. Eighty-six survivors (mean time off-treatment=7.8 years) completed the Pediatric Quality of Life Inventory 4.0 Generic Core Scales, a LIFE Clinic Intake Questionnaire and rated their fatigue using a 10-point scale. Oncology nurses independently rated subjects' late effects using a 3-point severity scale. Linear regression procedures were used to evaluate the association between demographic and medical factors and HRQOL. RESULTS: Fatigue and more severe late effects were associated with poorer physical functioning (fatigue, P<0.02; late effects, P<0.01). Fatigue, ethnic minority status, and a brain tumor diagnosis were associated with poorer psychosocial functioning (fatigue, P<0.0001; minority status, P<0.04; brain tumor, P<0.01). Fatigue was the only factor related to both poor physical and psychosocial HRQOL. CONCLUSIONS: Long-term follow-up clinics for childhood cancer survivors are in a unique position to monitor HRQOL over time. Factors associated with poorer HRQOL include fatigue, ethnic minority status, a brain tumor diagnosis, and more severe late effects. Future studies need to clarify relationships between ethnicity, socioeconomic status (SES), and HRQOL in cancer survivors.     

Long-term survivors of childhood central nervous system malignancies: The experience of the Childhood Cancer Survivor Study

In the last four decades, advances in neurosurgical technique, delivery of radiation therapy (RT), supportive care, and use of chemotherapy have improved 5-year survival for children with central nervous system (CNS) malignancies. Currently, in the United States 74% of children will become 5-year survivors of their primary CNS malignancy. This improved outcome has resulted in a new and growing population of childhood cancer survivors. Surgery, RT and chemotherapy, while essential components of primary treatment for most childhood CNS malignancies, have also been associated with risk of long-term morbidity and late mortality. The Childhood Cancer Survivor Study, a retrospective cohort of over 14,000 survivors of childhood cancer diagnosed between 1970 and 1986, has been an important resource for quantification of associations between these therapeutic modalities and risk of long-term adverse health and quality of life outcomes. CNS malignancy survivors are at significant risk for late mortality, development of second neoplasms, as well as increased risk for multiple endocrinopathies and adverse neurologic health conditions. Importantly, the CCSS has identified a number of dose–response relationships between RT and development of subsequent malignant neoplasms of the central nervous system, abnormal timing of menarche and neurocognitive function. Ongoing study of childhood cancer survivors is needed to establish long-term risks and evaluate impact of newer techniques such as conformal RT or proton beam delivery that limit RT exposure and may reduce long-term effects.     

A worldwide collaboration to harmonize guidelines for the long‐term follow‐up of childhood and young adult cancer survivors: A report from the international late effects of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549. © 2012 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.     

Educational achievement of long-term survivors of childhood and adolescent cancer

In a retrospective cohort study, the level of education attained by 2,283 long-term survivors of childhood and adolescent cancer was investigated and compared with that of 3,270 sibling controls. Survivors of central nervous system tumors were significantly less likely than controls to complete eight grades of school or, if they completed high school, to enter college. No significant differences in educational achievement were found for survivors of non-central nervous system cancers. The educational deficit of survivors of brain tumors was especially striking for tumors of the ventricles or cerebral hemispheres, and the deficit was more severe for those treated with radiation therapy than by surgery alone. Early age at diagnosis of a central nervous system tumor was associated with a larger educational deficit than late age at diagnosis. These findings are reassuring for the majority of long-term survivors of childhood and adolescent cancers given therapies used prior to 1975.     

Rhabdomyosarcoma: review of the Children's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies

The prognosis for children and adolescents with rhabdomyosarcoma (RMS) has improved with refinements in multi-modal therapy. Since 1972, the Intergroup Rhabdomyosarcoma Study Group (now the Children's Oncology Group Soft-Tissue Sarcoma Committee) has conducted serial studies for RMS. This review describes the IRSG and COG experience with RMS, presents the current risk stratification definitions, and provides rationale for the current generation of COG RMS studies.     

The role of twinning in sustainable care for children with cancer: A TIPPing point? SIOP PODC Working Group on Twinning,Collaboration, and Support

With the World Health Organization (WHO) Global Initiative for Childhood Cancer, there is renewed interest in sustainable interventions to improve childhood cancer care in low‐/middle‐income countries (LMICs). Practitioners in LMICs have traditionally practiced “twinning,” i.e., targeted international pediatric oncology partnerships (TIPPs) between one or more institutions in a high‐income country (HIC) and an LMIC, to improve care for children with cancer in the latter. The International Society of Paediatric Oncology Committee for Paediatric Oncology in Developing Countries Working Group on Twinning, Collaboration, and Support reviewed guidelines from https://cancerpointe.com and the current literature, gathered input from practitioners in LMICs, and in this article discuss the role of TIPPs in the WHO initiative.     

Survey of long‐term follow‐up programs in the United States for survivors of childhood brain tumors

Introduction

Despite recognition that childhood brain tumor survivors often suffer multiple late effects following therapy, little is known regarding the long‐term follow‐up (LTFU) programs for these patients.

Methods

A 16‐question survey was mailed to member institutions of the Children's Oncology Group in the United States. Institutions were asked about the size of their brain tumor program, activities of the LTFU programs and perceived barriers to follow‐up.

Results

One hundred forty‐five (74%) of 197 institutions returned surveys. Care for patients <21 years old at diagnosis who are >2 years following completion of therapy was provided at a designated neuro‐oncology LTFU clinic (31.2%), a general LTFU program for childhood cancer survivors (30.4%), or a general pediatric oncology program (29.7%). Institutions with a neuro‐oncology LTFU clinic were more likely to use neuro‐psychological testing following radiation therapy (P = 0.001), have longer duration of continued surveillance imaging (P = 0.02), use growth hormone replacement for medulloblastoma survivors (P < 0.001) and continue the use of growth hormone into adulthood (P = 0.05) than those with a general pediatric oncology program. Perceived barriers to care of brain tumor survivors included limited access and lack of insurance (32.1%), lack of funding or dedicated time for providers (22.9%), patients' uncertainty about need to follow‐up (20.6%), and patients' desire to not be followed in a pediatric cancer program (12.2%).

Conclusions

Considerable variation exists across institutions in the United States in the delivery of follow‐up care for survivors of childhood brain tumors. We encourage additional investigation to better define and implement optimal follow‐up care for childhood brain tumor survivors. Pediatr Blood Cancer 2009; 53:1295–1301. © 2009 Wiley‐Liss, Inc.     

Long-term effects of treatments for childhood cancers

PURPOSE OF REVIEW: The late effects of current treatments for childhood cancer increase the risk of morbidity and mortality and diminish the quality of life in long-term survivors. We selectively review the negative late cardiac, endocrine, and neurological effects of childhood cancer and its treatments and comment on current research and recommendations for the care of long-term survivors of childhood cancer. RECENT FINDINGS: Progressive cardiotoxicity has been established. Late cardiac effects can be mitigated with the concomitant use of dexrazoxane with anthracycline. When radiotherapy is used multiple organ systems must be monitored for known late effects dependent on the location. Proper diet, physical activity, and obesity are topics that must be addressed in survivors. Late neurocognitive effects impact intelligence quotient, behavior, and achievement. Systematic follow-up with appropriate clinical screening and testing is important in diagnosing and potentially preventing late effects of cancer therapy. SUMMARY: The new paradigm for defining successful cancer therapy is the balance between oncologic efficacy and toxicity/late effects. The complexity of late effects necessitates a multidisciplinary approach to long-term care of these patients. The high frequency, delayed onset, and potential severity of late effects demand increased and lifelong monitoring of these individuals.     

Follow up of long-term survivors after childhood cancer in Germany

BACKGROUND: In recent years, the long-term survival of childhood cancer patients has increased considerably. While this is desirable, more patients with late effects are to be expected and studies thereof become increasingly important. We will need to be able to stay in touch with as many former patients as possible in order to make a systematic and comprehensive long-term follow-up possible. PATIENTS: Childhood cancer patients under 15 years of age at diagnosis resident in Germany and registered at the German Childhood Cancer Registry (GCCR). METHODS: The GCCR has established a 3-phase procedure for follow-up. We developed principles for the long-term follow up of these patients. They are based on the many years of experience at the GCCR and were developed based on the long-standing collaboration between the therapy optimization studies (TOS) in the Society for Paediatric Oncology and Haematology (GPOH) and the GCCR. RESULTS: Currently 8 012 adult survivors diagnosed before 2000 are under observation at the GCCR and could be contacted for studies. About half of the children diagnosed in the 1980ies still in follow-up have been under observation more than 14 years. When asked to personally extend the originally parental consent to data storage at the GCCR and the TOS at about 16 years of age, about 85 % of the patients agree. CONCLUSIONS: Establishing an open-end, systematic long-term follow-up will provide a unique and broad basis for paediatric oncology in Germany to perform representative studies regarding long-term survival after childhood cancer in Germany in the long run.     

Second malignant neoplasms in survivors of childhood cancer

As the treatment of childhood cancer continues to improve, the number of survivors at risk for late effects rises. One such late effect is the risk of second malignant neoplasms. Large multicenter registries have been established to accumulate data on the incidence of second cancers. Relative risks and cumulative risks can now be calculated for retinoblastoma, Wilm's tumor and Hodgkin's disease. Early data are now available for leukemia, sarcomas and central nervous system tumors. Genetic cancer syndromes, radiation therapy and treatment with chemotherapeutic agents are known risk factors for second malignant neoplasms in survivors of childhood cancer.