Updated International Guidelines for Survivorship Care after Pediatric Cancer: Practice Implications in a German and Austrian Comprehensive Care Network Free

As progress in treatment of childhood cancer resulted in improved survival rates exceeding 80% after 5 years for many entities, management of treatment-related and other late sequelae in the growing population of childhood cancer survivors (CCS) becomes more and more relevant in order to ensure long-term survival and to reduce the burden of chronic morbidity [1, 2].

Life-long follow-up is recommended for most of these survivors to facilitate early detection and treatment of possible late effects. In Germany and in Austria, survivorship care starts at pediatric cancer centers and is continued after transition at specialized multidisciplinary clinics for adult CCS offering risk-adapted long-term follow-up (LTFU) that, for most of the survivors, is covered by health care insurance [3].

Organ- as well as cancer entity-specific guidelines have been published in many countries summarizing current evidence to actively screen for late effects in asymptomatic CCS depending on individual risk factors and treatment exposure. Several studies showed that adherence to risk-adapted surveillance can reduce long-term mortality [4]. In 2010, the International Guideline Harmonisation Group (IGHG) was established, aiming to combine these efforts in order to develop joint guidelines that can be implemented all over the world [5]. However, although current evidence suggests improvement, adherence to these guidelines in routine care of CCS is still suboptimal [4]. In order to facilitate the application of these recommendations, in 2020, we developed a practical approach by summarizing these guidelines in a format optimized for daily use and tailored to the German and Austrian health care system [6].

Although a brief period has elapsed since we published our proposed pragmatic approach, two new lines of LTFU resources were developed in the meantime. Importantly, a total of 12 new evidence-based IGHG LTFU guidelines were created [7‒18], as well as the first updated IGHG guideline, concerning risk-adapted breast cancer surveillance [19]. Among the new evidence-based IGHG LTFU guidelines, there are three focusing on psychosocial and mental health aspects, underlying the relevance of these issues for survivors as well as the importance of including these topics into the overall anamnestic interview [14‒16].

Moreover, the Pan-European PanCareFollowUp (PCFU) Recommendations Working Group applied a pragmatic approach to supplement the set of IGHG evidence-based guidelines with 25 recommendations based on a comparison of national survivorship care guidelines for selected organ-system/late health effects for which IGHG guidance was not available [20].

In order to supplement our originally proposed practice recommendation with regard to these currently available new resources for LTFU, we here present a fully integrated and updated summary of the most recent LTFU recommendations for CCS, using a practical approach for application in daily practice [6] and including adaptations tailored to the German and Austrian health care system.

In parallel, a pan-European collaborative group developed the so-called Survivorship Passport (SurPass) [21], a tool to assist both CCS and their health care providers in a care partnership aimed at further optimizing LTFU care. In particular, the SurPass was designed to improve CCS empowerment and satisfaction with care, as well as to facilitate shared decision-making by CCS and health care providers. Furthermore, the SurPass, among others, enables real-time updating of surveillance recommendations based on new evidence [20, 21].

A German translation of the SurPass is currently being tested in a clinical setting with EU (www.panCareSurPass.eu) and national (Deutsche Kinderkrebsstiftung) funding. The joint compilation of recommendations (as reported in this manuscript), additionally including recommendations for survivors aged under 18 years, will be incorporated in an electronic tool, thereby facilitating management of LTFU for survivors [21, 22].

For this update currently, available recommendations were compiled and translated into a practical tool to enable guideline implementation, as first described in 2020 [6]. In brief, the summary of LTFU recommendations from 2020 was supplemented by newly developed evidence-based IGHG guidelines published since 2020, in particular addressing ototoxicity [7], central nervous system neoplasms [17], fatigue [16], coronary artery disease [10], bone mineral density [11], hepatic toxicity [18], hypothalamic-pituitary dysfunction [8], updated breast cancer surveillance [19], obstetric care [9], mental health problems [14], education and employment outcomes [15]. We did not include the new recommendations concerning fertility preservation [12, 13] as they address pretherapeutic management. An update for the original IGHG cardiomyopathy surveillance recommendations [23] is in progress but has not been published yet. A recent Delphi Panel Consensus Recommendation has been included to address changes in surveillance intervals that have been proposed during recent years [24].

The selection criteria for the proposed LTFU recommendations have been published elsewhere [6] and also applied this time with special focus on practicability of the recommendations in a clinical setting as well as compatibility with the German and Austrian health care system. In brief, all guidelines from the IGHG have been summarized and were supplemented by PCFU recommendations if no IGHG guideline was available (exception: cardiomyopathy screening as mentioned before). Few topics (e.g., dental care) that are regularly presented in national LTFU guidelines and are of relevance in at-risk survivors and in clinical practice of survivorship care are not yet addressed in the international recommendations cited above. For these topics, we maintained our original recommendations published in 2020 [6].

This proposal for LTFU of CCS – as before – relies on a center-based model with a team of specialists offering standardized care and using a risk stratification model of three different risk groups [6, 25]. In brief, risk group 1 includes survivors with a low risk for developing late effects (e.g., following surgical therapy only or with acute lymphatic leukemia who did not receive radiation therapy). Patients with intermediate risk for late effects are considered risk group 2 (e.g., brain tumor survivors and patients following chemotherapy with or without surgery with the exception of specific subgroups mentioned in risk group 1) and risk group 3 (high risk for late effects) includes all previously irradiated patients and those after hematopoietic stem cell transplantation [6].

Of note, we chose to focus on adult survivors of childhood cancer in LTFU. Therefore, recommendations for children and adolescents as well as for patients who just completed cancer treatment are not presented in this document.

Furthermore, this update does not aim for completeness. Therefore, evidence from original papers, which were not included in the guidelines at the time of their publication, has not been considered.

LTFU regularly starts 5 years after the end of cancer treatment. The following recommendations apply to adult CCS who usually enter multidisciplinary LTFU care after transition from pediatric to internal medicine care between the age of 18–21 years.

These recommendations (see Table 1) apply to every adult CCS in LTFU. The extent of the examination or medical history may vary between subsequent presentations at the clinic and needs to be adapted based on personal history and risk factors. However, it is important to address the main aspects (darker lines) during every visit. Information sheets, where applicable, may be used for certain topics (e.g., for dental hygiene).

The additional risk-adapted examinations should be performed during every visit to the late effects clinic and vary between the 3 risk groups. They are specified in Table 2. Some examinations should only be performed at entry in LTFU (referred to as “initially” in Table 2), whereas other examinations should be repeated every 1–5 years.

These screening recommendations apply specifically to asymptomatic individuals with regard to the organ-specific health outcome of interest. Additionally, surveillance strategies for pregnant patients are presented in Table 3. Recommendations for symptomatic patients, individuals with pre-existing conditions (e.g., chronic viral hepatitis), or for patients for whom abnormalities are identified during surveillance examinations are beyond the scope of this summary and can be found in the respective guideline.

The authors decided not to include surveillance recommendations concerning colorectal cancer screening yet as this topic on when and how to screen is a subject of debate and the respective IGHG guideline is still under development [32]. However, screening options should be discussed, especially with older CCS over the age of 40 years with a history of abdominal radiotherapy, taking into account individual risk factors as well as potential benefits and harms of available screening modalities.

For some topics, e.g., MRI surveillance for subsequent CNS neoplasms, survivor information brochures have been created, providing objective background information as well as displaying potential harms (e.g., complications of unnecessary procedures) and benefits of different screening or surveillance strategies to help survivors and their physicians in weighting benefits and harms on an individual level. They can be found at www.ighg.org.

Focused surveillance of late effects among long-term survivors of childhood cancer provides the opportunity for early detection and implementation of health-preserving interventions [33]. As the risk for chronic health conditions in CCS can be significantly higher than in the general population, specialized screening recommendations are needed for timely diagnosis and treatment of late effects/chronic conditions. However, randomized clinical trials investigating optimal screening strategies are rare and difficult to conduct as the prolonged interval between end of cancer treatment and manifestation of late complications may overspan decades and the population of CCS is comparatively small and heterogeneous in terms of initial cancer diagnosis and treatment exposures [33]. As screening recommendations aim at asymptomatic individuals, by definition, balancing benefits and risks of regular screening examinations is essential to prevent harms of overdiagnosis, such as psychological stress, complications of surveillance examinations (e.g., bleeding or perforation during colonoscopy), or unnecessary procedures (e.g., thyroid surgery due to false-positive surveillance results) [34].

Additionally, personal risk factors with the potential to modify standard surveillance strategies gain importance in an increasingly person-centered form of medical care. It is important to acknowledge that, similar to the heterogeneity of chronic conditions in the general population, individual factors such as comorbid conditions, genetics, aging, health-related behaviors, and health care access as well as utilization can modify outcomes within the CCS population [35]. For example, comorbidities such as obesity, diabetes mellitus, and hypertension might have more than additive effects on cancer-related complications and as such may result in worse long-term health outcomes [35]. Consequently, these factors should be considered in order to develop individualized LTFU strategies. The presented risk-adapted approach to care of CCS in a center-based model involving a team of specialists offers the opportunity to implement current knowledge on surveillance recommendations while simultaneously integrating personal risk factors and needs into an individualized LTFU strategy.

In Germany, risk-stratified care, involving both tertiary care centers with multidisciplinary teams (MTD) and general practices collaborating to varying degrees, is aspired and has been reported to be preferred by many care providers [36, 37]. However, cooperation is challenged by the need for regular communication, instruction, and ongoing training for general practitioners as well as continuous data sharing [37, 38] in a geographically large country with many stakeholders and a strong federal regulatory landscape. The presented recommendations for practical use as well as patient-oriented clinical and care-oriented tools, like the SurPass (www.survivorshippassport.org) meant for empowerment of the survivors themselves, might serve as tools to improve collaboration between MTD and general practitioners who, as highlighted in a recent Australian interrogation, prefer highly prescriptive care plans early on from the oncologist/LTFU center, which they often do not receive [37].

This practical approach, augmented by a questionnaire-based screening for mental health and social outcomes performed by the expert for psychosocial care from the MTD including an MPH into the MTD, is going to be evaluated prospectively in a large, nation-wide study in Germany (“LE-Na – Evaluation and Implementation of a multidisciplinary, standardized, guideline-based long-term follow-up for adult childhood cancer survivors in Germany – a prospective, multicentric and nationwide study”) with more than ten participating university hospital centers providing specialized care for CCS. The harmonized guidelines can also serve as a basis for future research between Austrian and German centers.

Simultaneously, the SurPass is going to be implemented and offers an additional, harmonized tool to empower survivors in planning and monitoring their own health and LTFU [21]. Regular adaptions and integration of new guidelines are necessary in order to achieve optimal survivorship care.

Broad implementation of specialized screening recommendations for survivors is essential in order to facilitate early detection and treatment of late effects and to generate evidence about the best surveillance strategies in terms of examination modality, timing, intensity, and duration of surveillance. This summary is designed to facilitate day-to-day use and standardized application of state-of-the-art knowledge so that long-term morbidity and mortality of CCS are expected to decrease over time, through an individualized evidence-based system of LTFU.

The authors have no conflicts of interest to declare.

This research received no external funding. However, the implementation of the Survivorship Passport, as referenced in the text, received the following funding.

• Deutsche Kinderkrebsstiftung “Implementation of the Survivorship Passport in Germany” (2019.14)

• European Commission “PanCare studies of the scale-up and implementation of the digital Survivorship Passport to improve people-centred care for childhood cancer survivors” Call (part) H2020-SC1-2020-Two-Stage-RTD; Topic SC1-DTH-13-2020; Project Number 899999.

Study concept and initial draft of manuscript: J.G., T.L., and C.M.R.; data collection: J.G., K.B., E.B., G.C., and D.G.; data analysis and creation of the figures and tables: J.G., K.B., E.B., D.G., C.M.R., G.C., and T.L.; writing – review and editing: J.G., E.B., D.G., and C.M.R.; and critical revision and approval of final version: all authors. All authors have read and agreed to the published version of the manuscript.