The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers

Abstract

Importance:

Since 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 towards continually emerging evidence relating to cancer survivorship. They are intended to inform care for individuals surviving two 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 time comprehensive literature searches pertaining to Guidelines-specific questions are performed, evidence abstracted from pertinent publications, and recommendations determined and scored following expert deliberation.

Observations:

Guideline Version 6.0, released in October 2023, is comprised of 165 sections, 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:

The current paper outlines the historical evolution of the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, the current methodology behind their development, and key recommendations from Version 6.0. The Guidelines are publicly available in their entirety at www.survivorshipguidelines.org.

Relevance:

The COG Guidelines continue to set the standard for surveillance practices in long-term childhood, adolescent, and young adult cancer survivors. The growing body of evidence supporting these recommendations will continue to guide their evolution to inform optimal survivorship care practices.

INTRODUCTION

The number of childhood cancer survivors in the U.S. will approach 580,000 by 2040.¹ While this reflects tremendous progress in the field of pediatric oncology, the population is dwarfed in comparison to the nearly 18 million survivors diagnosed at age >20 and residing in the U.S. as of 2022.² Moreover, childhood cancer survivors require inherently different follow-up care than adult survivors due to the intensity of therapy delivered while still growing and developing, and the many decades they are anticipated to live beyond diagnosis and treatment. In response, the Children’s Oncology Group (COG) developed the first comprehensive follow-up guidelines in 2003,³ which have subsequently evolved and adapted to the emerging needs of survivors. The following report outlines the methodology behind COG Guideline development and highlights key recommendations from the most recent update, Version 6.0, which became publicly available in Fall 2023.

SCOPE AND PURPOSE

History

Charged by the Institute of Medicine (now the National Academy of Medicine) in 2002, the COG Late Effects, Nursing Discipline, and Patient Advocacy Committees initiated a seminal collaboration to develop clinical practice guidelines to facilitate and standardize long-term healthcare for survivors of childhood, adolescent, and young adult cancers. Due to the heterogeneity and evolving nature of treatment strategies across and within pediatric cancer diagnostic subtypes, and extensive literature associating adverse outcomes with specific treatments, an exposure-based approach was chosen as the framework for guideline development. Guideline Version 1.0 was released in 2003, and through the efforts of multidisciplinary task forces, a late effects expert panel, and patient advocates, five subsequent versions were released that updated recommendations based on evidence from peer-reviewed publications. Iterative versions have simplified content presentation and reduced dose threshold criteria for exposure-based recommendations to facilitate implementation in busy, real-world settings where cumulative treatment doses are unavailable.⁴ For example, radiation dose thresholds and field definitions were dramatically simplified between Versions 4.0 and 5.0, acknowledging that the potential benefits toward facilitation of use outweighed the risk of performing unnecessary screening for a small proportion of individuals.

While compelling evidence exists linking specific therapeutic exposures and adverse chronic health conditions, high-quality evidence supporting mortality reduction following implementation of surveillance in survivors is limited due to the relative rarity of childhood cancer and the delayed onset of many late effects. These factors prompted a hybrid guideline development approach that includes careful review of extant evidence to identify survivors at risk of adverse health outcomes following specific treatment exposures and consensus-based surveillance recommendations from late effects experts that consider the magnitude of these risks. Over time, the quality of evidence informing specific surveillance recommendations (e.g., breast cancer surveillance after chest radiation^5–7) has improved, but the majority of surveillance recommendations featured in Version 6.0 (2023) remain consensus-based. Notably, research evaluating the yield and cost-effectiveness of specific recommendations has informed de-escalation of surveillance for specific outcomes (e.g., cardiomyopathy surveillance),^8–10 reflecting the COG’s dynamic guideline process.

Objectives

The purpose of the COG LTFU Guidelines is to guide health prevention and risk-based screening practices for long-term survivors of childhood, adolescent, and young adult cancer to optimize health education and mitigate adverse health events through early detection and intervention.

Health Questions Covered

The Guidelines are intended to answer key questions surrounding long-term health maintenance and recommended surveillance for childhood cancer survivors followed in both specialty and primary care settings.

Population

Consistent with previous versions, Version 6.0 remains directed toward individuals surviving two or more years from completion of childhood, adolescent, and young adult cancer-directed therapy. Definitions of childhood, adolescent, and young adult cancers vary. Thus, application of the Guidelines is largely based on treatment approaches received rather than a specific age at diagnosis. Additionally, treatment advances have contributed to an emerging population of survivors living with cancer as a “chronic disease” (e.g., chronic myelogenous leukemia on tyrosine kinase inhibitors). Therefore, we acknowledge scenarios exist in which the guidelines may be used to facilitate preventive health and screening practices in individuals receiving concurrent cancer treatment.

STAKEHOLDER INVOLVEMENT

Group Membership

The COG, a National Cancer Institute-supported cooperative organization, represents a collaborative group of 227 pediatric oncology centers predominantly focused on the development and delivery of therapeutic clinical trials. The COG Outcomes and Survivorship committee, formerly known as the Late Effects Committee, facilitates collaborative work relevant to COG Guidelines development, discussion, and dissemination.¹¹ The Guidelines development team comprises a multidisciplinary panel of providers, including, but not limited to, pediatric oncologists, radiation oncologists, subspecialty providers (e.g., cardiologists), primary care providers (PCPs, e.g., general internists), nurses, psychologists, social workers, physical therapists, and audiologists involved in the care of survivors of childhood cancer. The organizational structure and contributing members to Version 6.0 can be found in Figure 1 and Supplemental Table 1, respectively.

Figure 1.

Organizational structure and workflow for 5-year guideline cycles. Overall guideline Co-Chairs oversee individual Task Forces, centered around organ-specific toxicities. Each Task Force is comprised of a Task Force Chair, Vice-Chair, and Task Force Members. Larger Task Forces are divided into Subcommittees, led by the respective Task Force Vice-Chairs. The Clinical Care Translation Task Force is responsible for Health Link development and incorporation of pertinent guideline content, and as such does not participate directly in the literature review process.

COG=Children’s Oncology Group; GI=gastrointestinal; GU=genitourinary; LTFU=Long-term follow-up; NCCN=National Comprehensive Cancer Network

* To be incorporated into Version 7.0

Target Population Preferences and Views

At the Guidelines’ inception, inclusion of the target population (i.e., providers engaged in survivors’ care) in the development process was largely limited to active guideline panel participants. As the body of evidence and provider interest in cancer survivorship has grown, the number of contributing members has more than tripled and is now comprised of individuals representing multiple disciplines, practices, and diverse clinical environments. Constructive feedback from contributors has informed serial Guideline modifications (e.g., the addition of specific sections) seeking to meet provider needs (Table 1). We acknowledge, however, that patient-specific care decisions remain the prerogative of the individual patient, family, and care team. The Guidelines are not intended to replace clinical judgement or mandate specific strategies. Ultimately, we strongly encourage shared decision-making that considers the patient’s treatment history, risk factors, co-morbidities, lifestyle, and preferences to personalize screening and clinical management strategies.

Table 1.

Changes to the Children’s Oncology Group (COG) Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers versions over time.

	Version
Characteristic	1.0 (Pilot)	1.1	1.2	2.0	3.0	4.0	5.0	6.0
Release date	3/2003	9/2003	2004	2006	2008	2013	2018	2023
Number of sections	112	112	112	146	146	166	165	165
Number of pages	118	100	107	227	223	241	232	211
Number of Health Links	6	34	33	42	42	43	44	45
Core Members	3	3	3	3	4	4	4	6
Expert Panel Members	16	16	16	20	17	20	19	42
Task Forces	1	1	20	18	18	10	16	20
Health Link contributors	4	19	19	76	75	78	81	56
Total contributors	58	77	77	163	168	204	224	220

Target Users

The Guidelines were developed as a provider-facing clinical support tool for individuals delivering healthcare to childhood cancer survivors. This may include pediatric and adult medicine providers (e.g., physicians and nurse practitioners) working in both primary care (e.g., internal medicine), and subspecialty (e.g., cardiology) settings. The Guidelines assume a basic understanding of salient issues facing survivors; providers who do not regularly care for survivors are encouraged to consult with survivorship care providers as questions arise. A complementary set of educational materials (i.e., “Health Links”) accompany the guidelines and are intended for patient use. Notably, while the guidelines were not developed to be directly utilized by patients, public access has intentionally remained unrestricted. Patients who choose to review them are advised to do so with the assistance of a knowledgeable healthcare professional.

Additionally, collation of existing evidence linked to expert opinion and consensus recommendations is intended to support decision-making and inform policy and subsequent standards of care in the context of the U.S. healthcare system.¹² Thus, the resulting recommendations are most applicable to high-income settings, while also intended to guide care in lesser resourced environments.

RIGOR OF DEVELOPMENT

Each Guideline version has undergone a similarly extensive process, beginning with evidence collection and culminating in a hybrid of evidence- and consensus-based recommendations.

Search Methods

Literature searches are performed using PubMed, restricted to publications occurring after the final search date utilized by the prior version. A comprehensive list of search terms used for Version 6.0 can be found in the Supplemental Materials. Final search results are imported into Covidence¹³ for title and abstract screening by Task Force Chairs and Vice Chairs. Publications selected for full text evaluation are assigned to Task Force members for detailed review and abstracted into Late Effects Evidence Tables (LEETs), which summarize key manuscript elements, including but not limited to methodology, key findings, bias assessments, and Task Force(s) recommendations regarding impact on the Guidelines.

Evidence Selection Criteria

As LEETs are compiled, the Task Forces are charged with assessing study rigor, sample and effect sizes, and value added to current recommendations. At the Task Force level, each study is discussed and assigned one of the following categories: (1) warrants no change to guidelines, (2) warrants citation, (3) warrants replacement of citations, (4), supports need for guideline revision, or (5) suggest need for continued monitoring for emerging evidence.

Strengths and Limitations of the Evidence

Study designs included in each literature review vary by topic and body of available evidence, and may include either ‘high-quality’ (i.e., cohort studies and case-control studies) or ‘lower-level’ (i.e., case series and case-reports) data. For topics for which a large body of evidence is available (e.g., cardiac dysfunction, subsequent malignancies), Task Forces prioritize ‘high-quality’ studies. In contrast, for emerging topics (e.g., novel therapies), they may rely on lower-quality studies and/or integrate clinical experiences to formulate recommendations. In all cases, Task Force members assess the consistency of results across studies and weigh the relative benefits and harms of any screening recommendation.

Formulation of Recommendations

Recommendations are formulated in a multi-step, multi-tiered process. After identification and review of the available evidence, Task Force members draft a preliminary set of recommendations, which are then discussed and refined with other members of the Task Force and Task Force chair(s). Task Force chair(s) and vice chair(s) then present supporting evidence and recommendations to a multidisciplinary panel with subject matter expertise (the “Expert Panel”) and the Guidelines Core Committee. The Expert Panel then votes to approve or reject a proposed screening recommendation and score the proposed recommendation using a modified version of the National Comprehensive Cancer Network’s (NCCN) Categories of Consensus.¹⁴ Recommendations are scored as a category 1 (uniform consensus about existing ‘high-level evidence’ linking a late effect and therapeutic exposure), 2A (uniform consensus about ‘lower-level evidence’), or 2B (non-uniform consensus among the panel in the context of ‘lower-level evidence’). Items in Category 3, representing a major disagreement among panel members about the appropriateness of a recommendation, are not included in the Guidelines.

Consideration of Benefits and Harms

The Late Effects Expert Panel, with Task Force leaders and members, consider potential risks and benefits of each recommendation prior to endorsement.¹⁵ The risks of over- and under-screening are balanced with the costs and health benefits of early detection and intervention. For example, potential harms include increased patient anxiety related to enhanced awareness of possible complications, false-positive screening results prompting unnecessary evaluations, and out-of-pocket expenses and time off work required for recommended assessments. Conversely, early detection of asymptomatic conditions may prevent or delay the onset of symptomatic disease and thus improve quality and duration of life. While early versions’ recommendations relied upon expert consensus and often favored more aggressive surveillance practices, recent versions have benefited from the maturation of longitudinal cohort data and cost-effectiveness analyses to inform more tailored, prescriptive strategies.^3,4,16,17

Link between Recommendations and Evidence

Each recommendation, represented by a single page or section of the Guidelines, includes references to supporting evidence. These citations are updated with each iteration of the guidelines as new evidence emerges. The LEETs, with abstracted methodological and outcomes-related details, are not included in the published Guidelines but are available upon request.

External Review

The Expert Panel includes subject area experts inside and outside the field of pediatric oncology/pediatric cancer survivorship; those who work outside the field provide external input on Guideline quality and the applicability and feasibility of recommendations.

Prior to the planned release of Version 7.0 in 2028, the Core Committee will engage a panel of External Reviewers to provide insight, review, and feedback on guideline validity and feasibility. Where appropriate and feasible, recommendations from this review will be incorporated into the final Version 7.0.

Updating Procedure

The aforementioned process occurs every five years, with the most recent cycle culminating in the publication of Version 6.0 (October 2023). Each version’s publication is accompanied by an official COG press release and is immediate availability at (www.survivorshipguidelines.org). Formal presentations at the annual COG meeting highlight key recommendation changes.

CLARITY OF PRESENTATION

Specific and Unambiguous Recommendations

Among the 165 guideline sections, we have highlighted the COG recommendations aligned with the recently published International Childhood Cancer Core Outcome Set (Table 2). The International Childhood Cancer Outcome Project selected 24 conditions following a survey of healthcare providers, survivor focus groups, and an international Delphi Survey of healthcare providers who identified four to eight physical and three quality of life outcomes per cancer subtype.

Table 2.

Recommendations from the Children's Oncology Group (COG) Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers Version 6.0 mapped to the core outcomes prioritized for childhood cancer survivorship research by the International Childhood Cancer Outcome Project.

ICCOP Core Outcomes Category	Specific COG Topic	Risk Factor	COG Recommendations
			History	Exam	Screening
Disfigurements	Craniofacial abnormalities	RT (head, brain)	Yearly	Yearly craniofacial	-
	Amputation-related complications	Amputation	Yearly	Yearly of residual limb integrity	Prosthetic evaluation every 6 months until skeletally mature and yearly thereafter
Hearing problems	Ototoxicity	Alkylators Heavy metals	Yearly	Yearly	Audiological exam yearly for ages ≤5 years Audiometry every 2 years for ages 6–12 years and every 5 years for ages ≤13 years
Heart failure	Cardiac toxicity	Anthracyclines Anthraquinones RT (cardiac)	Yearly	Yearly	No echocardiogram for low-risk survivors. Echocardiogram every 5 years in moderate-risk survivors Echocardiogram every 2 years in high-risk survivors
Hypothalamic-pituitary dysfunction	Central hypothyroidism	RT (head, brain)	Yearly b	Yearly height, weight, hair, skin, and thyroid; consider more frequently during rapid growth	TSH and T4 yearly Consider more frequently during periods of rapid growth
	Diabetes insipidus	Neurosurgery (brain)	Yearly	-	-
	Gonadotropin deficiency	RT (head, brain, TBI)	Yearly	Yearly Tanner staging, testicular volume (males), and growth assessment until mature	-
	Precocious puberty	RT (head, brain)	-	Yearly height, weight, Tanner staging, and testicular volume (males) until mature	-
Motor problems	Clinical leukoencephalopathy	Antimetabolites (HD/IO/IT methotrexate) RT (head, brain, TBI)	Yearly	Yearly neurologic	-
	Motor and/or sensory deficits	Neurosurgery (brain)	Yearly	Yearly neurologic	-
	Peripheral sensory neuropathy	Heavy metals	Yearly	Yearly neurologic exam until 2–3 years after treatment, continue yearly if symptoms persist	-
Neurocognitive QOL	Neurocognitive deficits	Antimetabolites (HD cytarabine, HD/IO/IT methotrexate) RT (head, brain, TBI) Neurosurgery (brain)	Yearly	-	Formal neuropsychological evaluation at entry into LTFU and then periodically as needed
Osteonecrosis	Osteonecrosis	Corticosteroids HCT	Yearly	Yearly musculoskeletal	-
Overweight	Overweight/Obesity	RT (head, brain) Neurosurgery (brain)	-	Yearly height, weight, BMI	-
Physical QOL	Fatigue/Sleep problems	All survivors	Yearly	-	-
	Adverse psychosocial/QOL effects	All survivors	Yearly	-	-
Psychosocial QOL	Mental health disorders	All survivors	Yearly	-	-
	Psychosocial disability due to pain	All survivors	Yearly	-	-
Pulmonary dysfunction	Pulmonary fibrosis, dysfunction, toxicity	Alkylators Anti-tumor antibiotics (bleomycin) RT (chest, axilla, TBI) HCT with cGVHD Surgery (thoracic)	Yearly	Yearly	Pulmonary function testing at entry into LTFU and as clinically indicated
Reduced joint mobility	Joint contractures	HCT with cGVHD	-	Yearly musculoskeletal Yearly of residual limb integrity	Radiograph of affected limb yearly Orthopedic surgery evaluation (ideally orthopedic oncologist) every 6 months until skeletally mature, and yearly thereafter
	Conditions related to limb sparing procedure	Limb sparing procedure	Yearly	Yearly of residual limb integrity	Orthopedic surgery evaluation (ideally orthopedic oncologist) every 6 months until skeletally mature, and yearly thereafter
Renal insufficiency	Renal toxicity	Alkylators Heavy metals RT (abdomen, TBI)	-	Yearly blood pressure	BUN, Cr, electrolytes at entry into LTFU and as clinically indicated
Seizures	Seizures	Neurosurgery (brain)	Yearly	Yearly neurologic	-
Sexual dysfunction c	Psychosexual dysfunction	Neurosurgery (spinal)	Yearly	-	-
	Sexual dysfunction (anatomic)	Pelvic surgery Cystectomy Hysterectomy	Yearly	-	-
Stroke	Cerebrovascular complications	RT (head, brain)	Yearly	Yearly neurologic	-
Subfertility	Diminished ovarian reserve	RT (pelvis, spine [sacral, whole], TBI)	Yearly	Yearly Tanner staging until mature	-
	Impaired spermatogenesis	Alkylators Heavy metals RT (testes, TBI) Orchiectomy (unilateral, partial)	Yearly	Yearly Tanner staging and testicular volume until mature	-
	Oophoropexy-related complications	Oophoropexy	Yearly	-	-
	Ovarian hormone deficiencies	Alkylators Heavy metals RT (pelvis, spine [sacral, whole], TBI)	Yearly	Yearly Tanner staging and growth assessment until mature	-
		Oophorectomy	Yearly	Yearly Tanner staging and growth assessment until mature (unilateral)	Endocrinologic or gynecologic consultation for initiation of hormonal replacement therapy beginning at age 11 years or immediately if post-pubertal (bilateral)
	Testicular hormonal dysfunction	Alkylators Heavy metals RT (testes)	Yearly	Yearly Tanner staging, testicular volume, and growth assessment until mature	Morning testosterone in high-risk patients ages ≥18 years
		Orchiectomy (unilateral, partial)	Yearly	Yearly Tanner staging, testicular volume, and growth assessment until mature	-
	Testosterone deficiency	Orchiectomy (bilateral)	-	Yearly prostheses	Endocrinologic or gynecologic consultation for initiation of hormonal replacement therapy beginning at age 11 years or immediately if post-pubertal
	Diminished ovarian reserve	Alkylators Heavy metals	Yearly	Yearly Tanner staging until mature	-
Subsequent neoplasm	Acute myeloid leukemia	Alkylators Anthracyclines Epipodophyllotoxins Heavy metals Autologous HCT	Yearly a	Yearly dermatological up to 10 years after exposure	-
	Breast cancer	RT (chest, axilla, TBI)	-	Yearly breast starting at puberty Every 6 months ≥25 years	Mammogram and breast MRI yearly, starting 8 years after RT or at age 25 years, whichever occurs last
	Brain tumor (benign or malignant)	RT (head, brain, TBI)	Yearly	Yearly neurologic	-
	Colorectal cancer	RT (abdomen, pelvis, spine [lumbar, sacral, whole], TBI)	-	-	Starting 5 years after RT or at age 30 years (whichever occurs last): Colonoscopy every 5 years, OR Multitarget stool DNA every 3 years
	Lung cancer	RT (chest, axilla, TBI)	Yearly	Yearly pulmonary	Discuss spiral computed tomography in highest-risk patients
	Solid tumors	HCT	-	Monthly self-skin Yearly dermatologic and abdominal Every 3–5 years beginning at age 21 years pelvic (females)	Females: Pap every 3 years between 21–29 years of age, HPV and Pap every 5 years (optimal) or Pap alone every 3 years (alternative) for 30–65 years of age, and No testing if normal results for past 10 years for those >65 years of age
	Subsequent benign or malignant neoplasm occurring in or near RT field	Any RT	Yearly	Monthly self-skin Yearly focused on RT fields	-
	Subsequent malignancy/Risk of malignancy in offspring	All survivors	As directed	-	-
	Thyroid nodules/cancer	RT (head, brain, spine [cervical, whole], TBI) Systemic MIBG	-	Yearly thyroid	-
Visual problems	Cataracts	Alkylators (busulfan) Corticosteroids RT (head, brain, TBI)	Yearly	Yearly visual acuity and fundoscopic exam	Ophthalmology or optometry exam yearly
	Ocular toxicity	RT (head, brain)	Yearly	Yearly visual acuity and fundoscopic	Ophthalmology or optometry exam yearly

^aUp to 10 years from exposure

^bConsider more frequently during rapid growth

^cOnly male sexual dysfunction was included in recommended outcomes from the ICCOP; however, we have included both pertinent male and female recommendations for this table.

BMI = body mass index; cGVHD = chronic graft versus host disease; DNA = deoxyribonucleic acid; HPV = human papillomavirus; HCT = hematopoietic cell transplant; HD = high-dose; ICCOP = International Childhood Cancer Outcome Project; IO = intra-Ommaya; IT = intrathecal; LTFU = long-term follow-up; MIBG = iodine-131-meta-iodobenzylguanidine; Pap = Papanicolaou test; QOL = quality of life; RT = radiation; TBI = total body irradiation; TSH = thyroid stimulating hormone; T4 = thyroxine

Management Options

The COG LTFU Guidelines are intended to support asymptomatic survivors of childhood, adolescent, or young adult cancers who present for routine exposure-related medical follow-up and to guide health prevention and risk-based screening practices. They do not provide individualized treatment advice. More extensive evaluations should be undertaken when signs and symptoms suggest illness or organ dysfunction. Subsequent management and treatment decisions should be discussed with a qualified medical professional.

Identifiable Key Recommendations

Several changes were incorporated into Version 6.0. The most notable can be found in Table 3. First, a formalized genetic risk assessment for cancer predisposition syndromes was needed. In conjunction with members of the COG’s Cancer Predisposition Working Group, we developed a new section outlining indications for a germline genetic evaluation, including specifics regarding family history and history of cancers associated with increased probability of an underlying cancer predisposition. Second, contemporary evidence no longer supports an association between methotrexate exposure and reduced bone mineral density (BMD).^18–20 Specifically, the International Guideline Harmonization Group (IGHG) systematically identified moderate-quality evidence supporting no association between methotrexate exposure and reduced BMD,¹⁹ and thus does not endorse BMD screening with dual-energy x-ray absorptiometry scans after methotrexate exposure – a stance mirrored in Version 6.0 of the COG Guidelines. Third, three studies were published assessing the cost-effectiveness of cardiomyopathy surveillance in survivors exposed to anthracyclines and/or chest radiation. All suggested that prior recommendations were likely over-surveilling a proportion of individuals who were at minimal risk of cardiac dysfunction due to lower cumulative cardiotoxic exposures.^8–10 One specifically assessed the effectiveness of surveillance among risk groups categorized by the IGHG and found that survivors exposed to a cumulative dose of doxorubicin equivalent anthracyclines <100 mg/m² and <15 Gy of chest-directed radiation were at similar risk of cardiomyopathy to those exposed to neither.⁸ In concordance with the recently released IGHG cardiomyopathy surveillance guidelines,²¹ the COG Guidelines no longer recommend screening echocardiograms for this low-risk group, eliminating routine screening for approximately 40% of those previously screened. Next, we recognized that prior inclusion of recommendations for cancer screening for average risk individuals, derived from general population guidelines, were often inconsistent across cooperative groups and/or outdated given the asynchrony of our Guidelines publication cycle and that of other national cancer screening guidelines (e.g., the American Cancer Society and United States Preventative Services Task Force). As a result, Version 6.0 removes these recommendations and now defers to regionally and institutionally accepted organizational recommendations and directs guidelines users accordingly. We also recognized an emerging need to begin to formulate recommendations for long-term follow-up after receipt of novel agents such as immunotherapies. While most have limited long-term follow-up data, their additions serve as placeholders for ongoing monitoring. Lastly, a recent scoping review has suggested that specific populations of survivors may be at increased risk of loss of immunity to previously received childhood vaccinations.²² Additionally, the results of a single-arm, phase 2 clinical trial demonstrated that a three-dose human papillomavirus (HPV) vaccination series in survivors yielded similar immunogenicity to that observed in the general population.²³ As such, we now provide specific recommendations for use of a three-dose HPV vaccination series, as well as shared decision-making surrounding revaccination for other childhood vaccines.

Table 3.

Notable changes between the Children’s Oncology Group (COG) Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers Versions 5.0 and 6.0.

Pertinent Section(s)	Change	Rationale
Genetic risk assessment for cancer predisposition (Version 6.0, Section 7)	Strongly consider assessment for cancer predisposition in the following settings: any tumor listed in Guideline Section 7, Table 1a, any bilateral cancer, >1 primary cancer, ≥1 first degree relative(s) with cancer, other concerning family history including consanguinity, diagnosis of adult-type cancer in a child (basal cell carcinoma, breast, colon, gastrointestinal, ovarian, etc.), diagnosis of cancer predisposition syndrome in a relative.	There is risk for subsequent malignancy and/or malignancy in offspring based on genetic predisposition which warrants further assessment based on the determined risk factors.
Methotrexate exposure related to low bone mineral density (Version 6.0, Section 28) Anthracycline exposure related to cardiac toxicity (Version 6.0, Section 34)	Removal of screening for decreased bone mineral density after methotrexate. Echocardiogram screening is not recommended for individuals with both <15Gy radiation dose (with potential impact to heart) and a cumulative doxorubicin equivalent anthracycline dose <100 mg/m2. Doxorubicin equivalent anthracycline dose conversion updated so that the cardiotoxicity of mitoxantrone is now 10:1 rather than 4:1 with respect to doxorubicin.	No association has been found concerning decreased bone mineral density and methotrexate.
Version 5.0 sections concerning the following cancers: breast (73), cervical (100), colorectal (85), lung (75), oral (107), skin (44, 100/101, 106)	Removal of cancer screening for average risk individuals.	Cancer screening recommendations for average risk individuals are available from other key organizations (e.g., American Cancer Society, United States Preventive Services Task Force) and outside the purview of COG.
New agents (Version 6.0, Sections 158–163)	New sections were added to incorporate novel agents for which long-term follow-up data are beginning to emerge.	As individuals treated with novel agents are now experiencing or are expected to survive to experience long-term follow-up, recommendations regarding surveillance for novel agents are needed.
General health screening: age-appropriate vaccination (Version 6.0, Section 165)	The overall general health maintenance is now focused on vaccinations.	Health screening related to specific concerns are considered and covered within each guideline. This guideline now precisely targets vaccinations for all cancer survivors.

^aSolid tumors (adrenocortical carcinoma, desmoid tumor, endolymphatic sac tumor, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, medullary thyroid cancer, osteosarcoma, ovarian Sertoli cell or Sertoli-Leydig cell tumor, paraganglioma, pheochromocytoma, pleuropulmonary blastoma, renal cell carcinoma, rhabdoid tumor, and Schwannoma), central nervous system tumors (atypical teratoid rhabdoid tumor, choroid plexus carcinoma, ciliary body medulloepithelioma, hemangioblastoma, optic pathway glioma, pineoblastoma, pituitary blastoma, retinoblastoma, and subependymal giant cell astrocytoma), and non-malignant other (cystic nephroma, juvenile myelomonocytic leukemia, meningioma, and myelodysplastic syndrome).

APPLICABILITY

Facilitators and Barriers to Application

Since their inauguration, the COG LTFU Guidelines have been available for download in portable document format from www.survivorshipguidelines.org. While this has facilitated broad dissemination from ready web-based access, the size and scope of the Guidelines has been a notable barrier for providers with limited knowledge of late effects and exposure to childhood cancer survivors. While recent versions have undergone an intentional reduction in complexity and size, similar barriers remain.

Implementation Advice/Tools

Recognizing the challenges with clinical application, the Guidelines leadership partnered with Baylor College of Medicine to develop a clinical decision support tool to facilitate Guidelines dissemination and clinical implementation.²⁴ Passport for Care (PFC) was launched in 2007, employing user-entered, treatment exposure-based algorithm to generate a personally tailored survivorship care plan using the current Guidelines as source documentation.²⁵ To date, approximately 60,000 survivorship care plans are stored in a HIPAA-compliant database unique to each of the >150 clinics utilizing PFC. Survivorship care plans are automatically updated with each Guideline revision and are available to survivors in English or Spanish by logging in to the PFC website (https://cancersurvivor.passportforcare.org). PFC is free to utilize, both in the U.S. and internationally.

Increasing recognition of the ongoing need for key invested party involvement in the development and dissemination of guidelines has led to engagement of implementation scientists to enhance broader access to and impact of the Guidelines. Ongoing and future efforts involve qualitative interviews from a globally diverse group of key invested providers spanning specialty to primary care roles, and from a wide range of resource levels to facilitate the development of regionally acceptable guidelines and guideline interfaces contextualized to regional resource access. Incorporation of human-centered design approaches is expected to simplify content and formatting and enhance end-user utilization.

Resource Implications

The robust and prescriptive nature of the COG LTFU Guidelines has resulted in limitations to its use outside highly resourced settings. While studies have evaluated the cost-effectiveness of the application of individual components of the Guidelines within the U.S. healthcare system,^{8–10,26–28} barriers remain even among those highly resourced environments. Furthermore, approximately 80% of children newly diagnosed with cancer reside outside of the U.S. or Europe,²⁹ highlighting a need for resource-adapted survivorship guidelines to reach a broader, more diverse group of survivors.^30–33 To date, centers in some low- and middle-income countries, individually or in partnership with high-income collaborators are beginning to develop modified recommendations that can be delivered in region- and resource-specific contexts; however, this is labor intensive and must be continually updated. Members of the COG Core Committee, various Task Forces, St. Jude Children’s Research Hospital, and global content and context experts have begun to generate a more universally applicable set of resource-adapted guidelines to eliminate redundancies.³⁴ This approach considers the COG LTFU Guidelines as the “gold standard” in highly resourced settings, and subsequently generates resource-adapted strategies that can be effectively delivered while considering regional factors.

Monitoring/Auditing Criteria

To date, application and implementation of our Guidelines has not been systematically monitored or audited. As a publicly available PDF, a mechanism had not been implemented to monitor the number of unique users, their level of engagement, and/or Guideline adherence. However, various publications have demonstrated a lack of familiarity with COG LTFU Guideline-concordant care among PCPs,^35–38 suggesting that significant gaps exist in guideline dissemination and implementation.

Moving forward, rigorous assessment of guideline dissemination and implementation has been designated as high priority and will be developed in parallel with Version 7.0. To date, the Core Committee has engaged external Dissemination and Implementation Science experts to assist in process refinement and operationalization of strategies to monitor and improve Guideline dissemination. Ongoing and future efforts include qualitative data collection from key interested parties (e.g., survivors, PCPs), systems process mapping to understand key inflection points in care journeys, and development of user-designed, sustainable dissemination platforms.

Supplementary Material

Suppl Table 1, Literature search terms 39976936

Supplemental Table 1. The Children’s Oncology Group (COG) Long-term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers Core Leadership, Panel of Experts, Task Force Members, Health Link Authors, and Content Reviewers.