An Integrated Review of Health Care in Child and Adolescent Cancer Survivors Based on Roy’s Adaptation Model

The incidence of childhood, adolescent, and young adult (AYA) cancers have been increasing since 1975.[1][1] In 2014, an estimated 10 450 and 5330 new cancers will be diagnosed among children aged birth–14 and adolescents aged 15 to 19 years old, respectively.[2][2] For young adults aged 20 to 34

Female childhood, adolescent, and young adult cancer survivors have an increased risk of adverse pregnancy outcomes related to their cancer- or treatment-associated sequelae. Optimal care for childhood, adolescent, and young adult cancer survivors can be facilitated by clinical practice guidelines that identify specific adverse pregnancy outcomes and the clinical characteristics of at-risk subgroups. However, national guidelines are scarce and vary in content. Here, the International Late Effects of Childhood Cancer Guideline Harmonization Group offers recommendations for the counseling and surveillance of obstetrical risks of childhood, adolescent, and young adult survivors. A systematic literature search in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018. Published articles on pregnancy and perinatal or congenital risks in female cancer survivors were screened for eligibility. Study designs with a sample size larger than 40 pregnancies in childhood, adolescent, and young adult cancer survivors (diagnosed before the age of 25 years, not pregnant at that time) were eligible. This guideline from the International Late Effects of Childhood Cancer Guideline Harmonization Group systematically appraised the quality of available evidence for adverse obstetrical outcomes in childhood, adolescent, and young adult cancer survivors using Grading of Recommendations Assessment, Development, and Evaluation methodology and formulated recommendations to enhance evidence-based obstetrical care and preconception counseling of female childhood, adolescent, and young adult cancer survivors. Healthcare providers should discuss the risk of adverse obstetrical outcomes based on cancer treatment exposures with all female childhood, adolescent, and young adult cancer survivors of reproductive age, before conception. Healthcare providers should be aware that there is no evidence to support an increased risk of giving birth to a child with congenital anomalies (high-quality evidence). Survivors treated with radiotherapy to volumes exposing the uterus and their healthcare providers should be aware of the risk of adverse obstetrical outcomes such as miscarriage (moderate-quality evidence), premature birth (high-quality evidence), and low birthweight (high-quality evidence); therefore, high-risk obstetrical surveillance is recommended. Cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for all female survivors treated with anthracyclines and chest radiation. Female cancer survivors have increased risks of premature delivery and low birthweight associated with radiotherapy targeting the lower body and thereby exposing the uterus, which warrant high-risk pregnancy surveillance.

ImportanceSince 2003, the Children’s Oncology Group (COG) has developed and disseminated the Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. These guidelines have benchmarked the standard of care for long-term survivors of childhood cancer in North America and beyond. Since their inception, they have evolved in depth, scope, and contributors to maintain fidelity toward continually emerging evidence related to cancer survivorship. They are intended to inform care for individuals who survived 2 or more years from completion of childhood, adolescent, and young adult cancer–directed therapy and receiving care in either specialty or primary care environments. The guidelines are updated on a 5-year cycle, during which comprehensive literature searches pertaining to guideline-specific questions are performed, evidence abstracted from pertinent publications, and recommendations determined and scored following expert deliberation.ObservationsVersion 6.0 of the guidelines, released in October 2023, comprised 165 sections and 45 health links and represents the cooperative efforts of 220 individuals. Major changes include the addition of recommendations regarding surveillance for genetic cancer predisposition, surveillance following the use of novel cancer treatment modalities, and routine vaccination practices during long-term follow-up. In addition, surveillance echocardiograms were omitted for those at low risk of cardiomyopathy.Conclusions and RelevanceThis narrative review outlines the historical evolution of the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, current methods guiding their development, and key recommendations from version 6.0. The guidelines are publicly available in their entirety online. The COG guidelines continue to set the standard for surveillance practices for long-term survivors of childhood, adolescent, and young adult cancer. The growing body of evidence supporting these recommendations will continue to guide their evolution to inform optimal survivorship care practices.

BackgroundSurvivors of Hodgkin lymphoma (HL) are at risk of developing non‐Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide.MethodsThe Pan‐European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow‐Up Studies (PanCareSurFup) cohort includes 69,460 five‐year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression.ResultsOverall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4–1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9–2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1–10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7–5.7), leukemia (SIR, 2.8; 95% CI, 1.8–4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4–5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2–3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7–2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8–1.5).ConclusionsIn addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

The survival rates for childhood and adolescent cancer have improved significantly over recent decades, with the five-year survival now exceeding 80% in many regions. However, cancer therapies, while lifesaving, are associated with late effects, or health complications that emerge months to years after treatment. These effects, which include physical, psychological, and cognitive issues, affect over 60% of survivors and often persist or worsen with age. Common late effects involve the cardiovascular, endocrine, and musculoskeletal systems, as well as neurocognitive impairment, infertility, and the risk of subsequent malignancies. Long-term follow-up (LTFU) care is critical for identifying and managing these conditions. Risk-based, individualized LTFU can enhance survivors’ health awareness, promote timely interventions, and improve quality of life. Guidelines from international organizations like PanCare and the International Guideline Harmonization Group support structured, evidence-based care pathways. Nurse-led models for the organization of LTFU are emerging as effective and patient-centered approaches within multidisciplinary teams. Despite its importance, LTFU participation remains suboptimal. Survivorship care plans and improved communication may help increase engagement. As therapies evolve, personalized follow-up strategies based on treatment history and risk profiling will be essential. This narrative review article explores the prevalence and burden of late effects; highlights the role of LTFU; and examines future directions for optimizing survivorship care in childhood and adolescent cancer survivors.

Childhood cancer survivors are at risk for long-term morbidity and early mortality. Since most adult and some adolescent survivors of childhood cancer will receive their long-term care from a primary care physician, we sought to determine family physicians' comfort with caring for this population. A survey was mailed to 2,520 United States (US) and Canadian family physicians to assess their attitudes and knowledge regarding the care of adolescent and young adult survivors of childhood cancer. One thousand one hundred twenty-four family physicians responded (704 US, 420 Canadian). Median age was 53years; 63% were men; 81% had cared for ≤2 childhood cancer survivors in the past 5years. Of those who had cared for a survivor, 48% had never or almost never received a treatment summary from the referring cancer center; 85% preferred to care for survivors in consultation with a cancer center-based physician or long-term follow-up program. Only 33, 27, and 23% of respondents were very comfortable caring for survivors of childhood Hodgkin lymphoma, acute lymphoblastic leukemia or osteosarcoma, respectively. Only 16, 10, and 74% of respondents correctly identified the guideline recommended surveillance for secondary breast cancer, cardiac dysfunction and hypothyroidism in response to a vignette describing a Hodgkin lymphoma survivor. Respondents rated access to clinical care guidelines and receipt of a patient-specific letter from specialists with surveillance recommendations as the modalities most likely to assist them in caring for survivors. Most family physicians are willing to care for childhood cancer survivors in consultation with a cancer center, and with specific tools to facilitate this care. Adult and adolescent survivors of childhood cancer who receive their follow-up care from a family physician must be empowered to choose a physician who is comfortable with caring for survivors. Further, the survivor must ensure that their physician has access to a treatment summary as well as to patient-specific recommendations for surveillance for late effects of cancer therapy.

Young adult survivors of childhood and adolescent cancer are an ever-growing population of patients, many of whom remain at lifelong risk for potentially serious complications of their cancer therapy. Yet research shows that many of these older survivors have deficient health-related knowledge and are not engaging in recommended health promotion and screening practices that could improve their long-term outcomes. The purpose of this review is to address these disparities by discussing how formal transition of care from pediatric to adult-focused survivorship services may help meet the unique medical, developmental, and psychosocial challenges of these young adults. Literature review and discussion. This article summarizes current research documenting the medical needs of young adult survivors, their suboptimal compliance with recommended follow-up, and the rationale, essential functions, current models, and innovative approaches for transition of follow-up care. Systematic health care transition constitutes the standard of care for young adult survivors of childhood cancer. In developing a transitional care program, it is necessary to consider the scope of services to be provided, available resources, and other local exigencies that help determine the optimal model for use. Additional research is needed to improve health services delivery to this population. Effective advocacy is needed, particularly in the United States, to ensure the availability of uninterrupted health insurance coverage for survivorship services in young adulthood.

Late Mortality in Childhood Cancer: Time to Count Our Chips

Survivors of childhood or adolescent cancer have high long-term survival rates due to improved therapies but often suffer from complex late and long-term effects which should be diagnosed and treated early. Existing models of transition and long-term follow-up care for adult survivors of childhood and adolescent cancer in Germany are presented and perspectives for care and research in this field are outlined. There is potential for improvement in the area of networking of the medical disciplines involved as well as in the involvement and education of patients. Nationwide harmonization and standardization of long-term follow-up care and transition is important to ensure that all childhood cancer survivors in Germany have access to care according to guideline recommendations.

Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed. Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold). Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.

Advances in cancer therapy have led to increased survival; there aremore than9million 5-year survivors of cancer in the UnitedStates.1 As this number continues to grow, focuson improved health and quality of life becomes a priority. It is especially important in survivors of childhood, adolescent, and young adult cancer who have 5-year survival rates exceeding 80%1 and who are expected to live many decades after diagnosis and treatment. Because of their young ageat treatment, thispopulation is themostvulnerable to longtermdetrimental effects of cancer therapy.Many studieshave shown that childhood and adolescent cancer survivors are at increased risk for chronicmedicalproblemsandemotional late effectsas theyage.2-5These lateeffects influenceoverallhealth and quality of life. While the impact of cancer and its treatment on children is an area of increasing research, there is a paucity of lateeffectsdata foryoungadults.The riskofdeveloping treatmentrelated sequelae and the type of surveillance screening necessary for this population are often extrapolated fromstudies of children ormiddle-aged adults. However, adolescents and young adults (AYAs) have auniquepattern of cancer development with distinct biological findings6 and different psychosocial stressors associated with the transition to adulthood. This distinctive biology and psychosocial environment suggest that the late-effects burden inAYAsmaydiffer greatly from that of other survivors. Studies are needed in this age group to describe the breadth of late effects to guide screening and treatment. In this issue of JAMA Oncology, Rugbjerg and Olsen7 provide a glimpse into the late-effects burden among AYA survivors through theuseofnationalDanish registries. Theauthors compare the long-term risk of hospitalization in 33 555 5-year survivorsofAYAcancer (diagnosedatage 15-39years)with that of 228 447 ageand sex-matched population controls. They identified 53 032 hospitalizations among survivors compared with 38 423 expected, based on the control population, leading to a standardized hospitalization rate ratio (RR) of 1.38 (95%CI, 1.37-1.39)andabsoluteexcess risk (AER)of2803 (95% CI, 2712-2893) hospitalizations per 100 000 personyears. The highest AERs were found for malignant neoplasms, diseases of the digestive system, and cardiovascular disorders. Those with the highest risk of hospitalization included survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain tumors (RR, 1.93; 95% CI, 1.86-2.00), and Hodgkin lymphoma (RR, 1.87; 95%CI, 1.80-1.94), which aremalignant conditions known to have increased late effects in pediatric survivors. More than 50% of the cancer-specific AER for survivors of brain cancerwas due toneurologic or endocrine disorders, while approximately 50% of the AER for survivors of Hodgkin lymphoma was attributed to malignant neoplasms and cardiovascular disease. Of interest, the AER for leukemia survivorswasattributedmostly to infectious andparasiticdiseases (20%) and respiratory conditions (28%), especially influenza and pneumonia. The large sample size and low attrition rate of this study7 allow for a comprehensive view of the inpatient treatment of AYA survivors and offer early insight into their overall diseaseburden.However, the full rangeof treatmentsequelaecannot be evaluated using these data, since many late effects of cancer therapy are treated in the outpatient setting. For example, in contrast to infectious or respiratory complications seen in the Rugbjerg and Olsen study,7 the preponderance of treatment-related sequelae inpreviously published reports of survivors of childhood leukemia are musculoskeletal, cardiac, endocrine, or neurologic in origin8,9; these are often treated inoutpatient clinics.Because leukemia treatment isoften longer than treatment for othermalignant conditions, and many patients who have relapsed are treated more than 5 years after the original diagnosis, it is difficult to determine if the infectious and respiratory complications observed in this study are owing to long-term immunocompromise in these survivors, which requires further surveillance, or acute sequelae in patients who have experienced a relapse requiring hospitalization. Importantly, the subsequent malignant neoplasms described in this study7 differ greatly from those previously observed in survivors of childhood and adolescent cancers. The most common malignant conditions leading to hospitalization in AYA survivors were nonmelanoma skin cancer, neoplasms of the digestive organs, and cancers of the respiratory system. It is surprising that breast and thyroid cancer, 2 of the most commonly reported subsequentmalignantneoplasms in survivors of childhood and adolescent cancer,10 were not as prevalent in this study.However, this variation in typesof subsequentcancersmaybeowing to thedifference inprimarycancer location and treatment. In this study,7 survivors of cervical, testicular, andprimarybreast cancermadeupnearly 50% of the study population. These cancers are often treatedwith irradiation to the pelvis or chest, which increases the risk of gastrointestinal and lung cancer. As evidenced by Rugbjerg and Olsen,7 treatment sequelae in AYA cancer survivors, including subsequent malignant neoplasms, differ from those in survivors of childhood cancer. Prevention and management of late effects necessitate early detection and intervention, which require a comprehensive view of the treatment-related sequelae that canRelated articles Opinion

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer.

Emerging and Ongoing Survivorship Challenges Among Childhood Cancer Survivors and Providing Risk-Based Focused Follow-Up Care.

Objectives. Survival rates for pediatric cancer have dramatically increased since the 1970s, and the population of childhood cancer survivors (CCS) exceeds 500,000 in the United States. Cancer during childhood and related treatments lead to long-term health problems, many of which are poorly understood. These problems can be amplified by suboptimal survivorship care. This report provides an overview of the existing evidence and forthcoming research relevant to disparities and barriers for pediatric cancer survivorship care, outlines pending questions, and offers guidance for future research. Data sources. This Technical Brief reviews published peer-reviewed literature, grey literature, and Key Informant interviews to answer five Guiding Questions regarding disparities in the care of pediatric survivors, barriers to cancer survivorship care, proposed strategies, evaluated interventions, and future directions. Review methods. We searched research databases, research registries, and published reviews for ongoing and published studies in CCS to October 2020. We used the authors’ definition of CCS; where not specified, CCS included those diagnosed with any cancer prior to age 21. The grey literature search included relevant professional and nonprofit organizational websites and guideline clearinghouses. Key Informants provided content expertise regarding published and ongoing research, and recommended approaches to fill identified gaps. Results. In total, 110 studies met inclusion criteria. We identified 26 studies that assessed disparities in survivorship care for CCS. Key Informants discussed subgroups of CCS by race or ethnicity, sex, socioeconomic status, and insurance coverage that may experience disparities in survivorship care, and these were supported in the published literature. Key Informants indicated that major barriers to care are providers (e.g., insufficient knowledge), the health system (e.g., availability of services), and payers (e.g., network adequacy); we identified 47 studies that assessed a large range of barriers to survivorship care. Sixteen organizations have outlined strategies to address pediatric survivorship care. Our searches identified only 27 published studies that evaluated interventions to alleviate disparities and reduce barriers to care. These predominantly assessed approaches that targeted patients. We found only eight ongoing studies that evaluated strategies to address disparities and barriers. Conclusions. While research has addressed disparities and barriers to survivorship care for childhood cancer survivors, evidence-based interventions to address these disparities and barriers to care are sparse. Additional research is also needed to examine less frequently studied disparities and barriers and to evaluate ameliorative strategies in order to improve the survivorship care for CCS.

Childhood cancer survivors require specific care that includes monitoring for late effects of cancer therapy. Current knowledge on how to deliver survivorship care is based on experience in high-income countries, which may not be applicable to other settings. We thus conducted a scoping review to characterize and describe the models of survivorship care available to childhood cancer survivors in low- and middle-income countries (LMICs). Fifty-one studies were selected from a comprehensive literature search of 8 electronic and 2 grey-literature databases followed by title, abstract, and full-text screening. Elements of survivorship care were categorized within the domains of the Quality of Cancer Survivorship Care Framework using representative Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers guidelines for childhood cancer survivors. The Quality of Cancer Survivorship Care Framework is comprised of 5 domains related to survivorship care services, and 4 domains related to health care delivery. From the 51 studies chosen for data extraction, 61 LMICs were identified. Of these 61 LMICs, only 11 countries reported having active survivorship care services. The most reported services in the included papers from LMICs are related to the surveillance and management of chronic medical conditions and psychosocial effects. Of the countries that that reported survivorship services, literature from India reported on the four fundamental health care delivery domains identified by the Quality Cancer Survivorship Care Framework, which include clinical structure, communication and decision-making, care coordination, and patient/caregiver experience. Additionally, 8 of the 11 countries publishing about their survivorship care documented access to specialty medical care and healthcare professionals for childhood cancer survivors, such as onco-endocrinologists and psychologists. There are patient, clinician, and health system-related barriers to developing and implementing survivorship care in LMICs. Efforts to optimize the delivery of survivorship care include increased patient and family education about treatment late effects, optimized healthcare provider staffing, staff education, and training, and implementation of standardized practice guidelines that are resource-stratified and therefore applicable in multiple settings. Citation Format: Celine Lecce, Avram E. Denburg, Sumit Gupta, Alexandra Martiniuk, Ariel Qi. Survivorship care models for childhood cancer survivors in low- and middle-income countries: A scoping review [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B080.