Guidelines for Long-Term Follow-Up after Childhood Cancer: Practical Implications for the Daily Work

Long-term survival after childhood cancer has improved significantly over the last decades. As a consequence, the population of cancer survivors worldwide is rapidly growing [1]. However, a substantial part of these survivors is affected by therapy-related complications that may persist after the end of treatment or occur many years later. Thirty years after their initial cancer diagnosis, up to 70% of childhood cancer survivors (CCS) report at least one chronic health condition [2].

The most common late complications include subsequent malignancies, endocrine disturbances, and cardiovascular disease. Multiple health conditions result in a high cumulative chronic disease burden of CCS in comparison with a community-based control population [3]. The prognosis of these conditions is often determined by an early diagnosis to prevent further organ damage or spreading of the disease. Many of these conditions rarely occur in young adults, and as knowledge of late effects among general practitioners (GPs) varies substantially, diagnosis may be delayed even if patients present with typical symptoms. As a consequence, premature mortality, primarily caused by late relapses, secondary malignancies and cardiac causes, is significantly elevated in comparison with the general population [4, 5].

Long-term follow-up (LTFU) in specialized late effects clinics offers optimal and standardized care for CCS based on current guidelines and recommendations. LTFU clinics are supposed to reduce the severity of treatment-related sequelae through appropriate surveillance [6]. The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG), initiated in 2010, aims to facilitate LTFU through international collaboration in guideline development and to establish an integrated strategy for the surveillance of late effects in CCS. A specific panel of experts for specific late effects has been formed and reviews existing data according to a common methodology adherent to the Appraisal of Guidelines for Research and Evaluation (AGREE) Collaboration [7].

Several models of survivorship care have been developed including shared care between GPs and cancer centers, and GP-led as well as clinic-based models [8-12]. However, many GPs or general internists, although involved in the care of CCS, may be unfamiliar with surveillance guidelines and thus prefer a collaboration with a cancer center [13]. Furthermore, many existing guidelines, although of high quality and level of evidence, are of high complexity or need to be combined with other guidelines as they only cover specific late effects. As a consequence, the implementation of these recommendations in daily practice is frequently poor [14]. Patients’ satisfaction with regard to LTFU strongly depends on a successful coordination and communication between the specialists involved and their knowledge of late effects and LTFU recommendations [10, 12]. Multidisciplinary teams including pediatric and adult oncologists, specialists in internal medicine, psychologists or experts for psychosocial care as well as specialists from other disciplines provide all required consultations so that the patients can receive treatment in a single institution [1].

Cancer treatment, personal factors and existing comorbidities (e.g., graft-versus-host disease) determine the risk to develop late effects. During LTFU, risk-adapted surveillance strategies, which take all this information into account, are used to create individualized surveillance plans.

National and international guidelines addressing LTFU of CCS were reviewed and compared in order to create a useful tool for the daily practice in late effects clinics [15-21].

The selection criteria for the proposed LTFU recommendations were consistency of recommendations in the guidelines, level of evidence according to the rating system used in Kremer et al. [7] for each recommendation, specifics of the German healthcare system (e.g., possibilities of cost coverage/reimbursement by the health insurance companies) and practicability of the recommendations in a clinical setting. In brief, this procedure resulted in the following heuristic approach. The guidelines from the DCOG [17] were supplemented by guidelines from the IGHG as far as available [16, 19-21]. To acknowledge the complexity of endocrine late effects and late effects after radiotherapy, the recommendations by Denzer et al. [15] and the COG [18], respectively, were implemented. Subsequently, the result was screened for its compatibility with the German healthcare system.

This review was designed to facilitate long-term follow up in accordance with current guidelines without aiming for absolute completeness. Evidence from original papers, which were not included in the guidelines at the time of their publication [15-21], has been not considered.

In order to implement these LTFU screening recommendations, several models of care have been reviewed and transformed into a center-based model with a team of specialists to offer standardized care [6, 8-12, 22]. Moreover, a risk stratification model already established in the UK has been revised and adapted [22, 23].

LTFU starts after the end of routine oncological aftercare; thus, usually 5 years after the end of cancer treatment. As patients grow up and pass into adulthood, LTFU has to proceed in internal medicine. Interdisciplinary late effects clinics have been established to offer risk-adapted standardized care for this patient cohort. In these clinics, a team of specialists with experience in LTFU of CCS is required to manage the complexity of potential sequelae and persistent chronic health conditions that first occurred during cancer treatment. The core team is supposed to consist of

• A specialist in internal medicine who performs the physical examination and makes decisions on further diagnostics or treatments in consultation with the pediatric oncologist. Both oncologists review the cancer history and agree on risk stratification

• A psychosocial coworker who assesses psychosocial needs, offers low-threshold service and information about LTFU as required

• A study nurse/case manager coordinates the patient appointments and documents the results of the consultations

Further specialists are consulted as required, e.g. cardiologists or dermatologists (Fig. 1). Apart from the first visit of the patient in the late effects clinic, the pediatric oncologist does not routinely attend the visits but remains part of the multidisciplinary team and can be consulted if needed.

All the specialists involved in the care of these patients meet regularly every 3–6 months to discuss complex cases (“late effects board”). Especially after the diagnosis of a secondary malignancy, treatment options considering all previous therapies should be discussed in a multidisciplinary tumor board.

During the first attendance of the late effects clinic, patients are stratified into three different risk groups, according to their individual history. The frequency of LTFU visits as well as the recommended examinations differ between these groups and need to be adapted regularly based on previous findings, personal risk factors, and comorbidities as well as in order to reflect new guidelines and findings in late effects research work.

Group 1 – low risk of developing late effects:

• Patients with surgery only (exception: brain tumor patients)

• Patients with standard risk acute lymphoblastic leukemia (ALL) without radiotherapy

• Patients with nonheritable retinoblastoma without radiotherapy

→ Attendance to the clinic: once every 5 years

Group 2 – medium risk of developing late effects:

• Patients with chemotherapy (exception: ALL and nonheritable retinoblastoma → Group 1)

• Patients with chemotherapy and surgery (exception: nonheritable retinoblastoma → Group 1)

• Patients with brain tumors and surgery

→ Attendance to the clinic: every 2–3 years

Group 3 – high risk of developing late effects:

• Patients following allogeneic HSCT

• Patients receiving radiotherapy [18]

→ Attendance to the clinic: at least yearly

Please note: Patients following allogeneic HSCT may need closer and more frequent follow-up, especially those with chronic graft-versus-host disease (for further information, see Chow et al. [24]). Additional examinations have to be considered in patients receiving ongoing immunosuppressive therapy (e.g., skin cancer screening [25]).

Applies to every patient in LTFU during every visit

• Detailed history

✓ Medical history

✓ Family history (especially with regard to cardiovascular events and malignancies)

✓ Social history

✓Sexual history/menstrual cycle

• Physical examination

✓ Height, weight, body mass index, waist circumference, blood pressure measurement [15]

• Education about late effects and LTFU

• Advice on healthy lifestyle

• Advice on dental care and dental hygiene [17]

• Offering nutrition/physical activity consultation

• Offering psychosocial consultation

• Vaccination recommendations

• Screening-questionnaires for anxiety/depression (GAD-7 [26] in combination with PHQ-9 [27]) and posttraumatic stress (IES-R) [28](at the first visit and every 5 years) [17]

• Questionnaire for chronic fatigue syndrome (EORTC QLQ) (at the first visit and every 5 years) [17]

• General fertility counseling

→ Using the knowledge of fertility centers (https://fertiprotekt.com/) for patients following

✓ Chemotherapy with alkylating agents, cyclophosphamide, procarbazine (females) [21]

✓ Chemotherapy with cyclophosphamide, procarbazine, mechloretamine, ifosfamide (males) [20]

✓ Busulfan, melphalan, cyclophosphamide, fludarabine prior to HSCT (males) [20]

✓ Radiotherapy of the ovaries/testes [20, 21]

The additional risk-adapted examinations for each risk group are specified in Table 1.

Please note: Recommendations concerning examinations for the early detection of several late effects in asymptomatic patients are inconsistent due to the lack of evidence. This includes:

• Carotid artery stenosis following neck radiation [29]

• Coronary heart disease following chest radiation [30]

• Meningiomas following cranial irradiation [31]

• Osteoporosis (especially following ALL, craniospinal radiation, high-dose glucocorticoids, MTX) [32]

• Dropped head syndrome following neck radiation [33, 34]

• Pituitary failure, especially growth hormone deficiency following cranial irradiation [32].

However, in case of clinical suspicion, appropriate assessment should be initiated in patients at risk.

• Screening for thyroid dysfunction following neck radiation

• Additional echocardiogram during the first trimester following chest radiation/chemotherapy with anthracyclines

• Blood pressure surveillance following nephrotoxic drugs

Over the last decades, reductions in treatment intensity and toxicity have been implemented. These modifications decreased late effects as well as late mortality in long-term CCS successfully while maintaining high cure rates [5, 35]. However, many toxic treatment modalities are not yet fully dispensable so that, although diminished, late effects are still likely to affect a relevant share of current cancer patients in addition to the large group of long-term survivors already living worldwide.

Evidence-based risk stratification models are designed to facilitate early detection and surveillance of possible late effects in patients at risk without exposing healthy long-term survivors to the risk of unnecessary diagnostic procedures. A detailed treatment summary is essential for this risk stratification and the survivorship care plan and should be handed out to every survivor once relapse centered follow-up is finished. However, existing guidelines are not universally implemented in daily practice [36].

Furthermore, adherence rates to recommended LTFU screening examinations are suboptimal, especially in patients older than 18 years of age [37]. As late effects often develop years to decades after the end of treatment, a successful transition from pediatric to internal medicine care is required to ensure optimal long-term surveillance. This transition includes a change in the focus of care, from relapse-centered follow-up to late effects-centered long-term surveillance. Standardized and optimized transition processes in specialized late effects clinics may be eligible to improve LTFU in young adults. Previous studies demonstrated that an increased utilization of late effects clinics is associated with improved patient adherence to screening so that the implementation of specialized late effects clinics as well as feasible risk stratification and surveillance strategies may improve health outcome in CCS [38].

Lifestyle factors as well as genetic variations further modify the risk of treatment-related chronic health conditions. Although susceptibility genes for various late effects have been identified, their predictive impact remains indeterminate in many cases [30, 39]. Current recommendations thus do not consider genetic variations as a factor altering LTFU, although these might contribute to a patient’s individual risk profile and potentially help shaping future surveillance strategies.

Healthy lifestyle promotion for the general population, including a balanced diet, regular physical activity, and smoking cessation is particularly important for this population at risk and should be addressed during regular LTFU in the late effects clinics [32, 40-42].

The proposals regarding frequency of clinic attendance represent current screening recommendations but also consider increasing knowledge about late effects and thus the necessity to regularly adapt follow-up care. For some patients, e.g. former low-risk nephroblastoma patients treated with surgery and chemotherapy only, less frequent attendances to the clinics as proposed might be sufficient, whereas other patients may need closer follow-up, in which case evaluation will have to take place in the late effects clinics. Furthermore, specific recommendations based on individual factors such as age at the time of exposure to the cancer treatment which modifies the risk for several, e.g. cardiac or pulmonal sequelae as well as subsequent neoplasms [43, 44], are already mentioned in the current guidelines but did not result in different LTFU approaches so far, which may be reassessed in the clinics. Based on current LTFU guidelines, as the occurrence of late effects increases with time since initial cancer diagnosis, life-long surveillance in these clinics should be offered [17, 18].

The proposed risk stratification was developed for daily practice in late effects centers which are currently forming a comprehensive clinic network in Germany. By amalgamating current guidelines in the proposed concise format, standardized LTFU is facilitated and thus is likely to result in better health outcomes and higher health-related quality of life in CCS.

The authors have no ethical conflicts to disclose.

The authors have no conflicts of interest to declare.

J.G. and T.L. performed the analysis and interpretation of the data, J.G. wrote the manuscript in consultation with T.L., A.S, G.C., K.B., E.B., H.J.v.d.P. and D.G. All authors provided critical feedback and helped shape the analysis and manuscript.