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Background: Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking., Aim: To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers., Methods: A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations., Results: 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations., Conclusion: These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors., Competing Interests: Conflict of interest statement None declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines., Methods: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries., Results: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10)., Conclusions: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF., Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public., Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors., Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Evidence-based clinical practice guidelines are essential to ensure that childhood cancer survivors at risk of chronic health conditions receive effective long-term follow-up care. However, adult survivors of childhood cancer are not always engaged in recommended health promotion and follow-up practices, as many centres do not have a formal transition programme that prepares survivors and their families for successful transfer from child-centred to adult-oriented healthcare. The need for a specific pan-European guideline for the transition of care for childhood cancer survivors has been recognised. The first step is to define the concept of transition of care for survivors of childhood cancer based on existing evidence., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure., Methods: Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts., Results: Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90)., Conclusions: Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Survival after childhood cancer has improved substantially over recent decades. Although cancer in childhood is rare increasingly effective treatments have led to a growing number of long-term survivors. It is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe. Such good survival prospects raise important questions relating to late effects of treatment for cancer. Research has shown that the majority will suffer adverse health outcomes and premature mortality compared with the general population. While chronic health conditions are common among childhood cancer survivors, each specific type of late effect is very rare. Long-term effects must be considered particularly when addressing complex multimodality treatments, and taking into account the interaction between aspects of treatment and genotype. The PanCare Network was set up across Europe in order to effectively answer many of these questions and thereby improve the care and quality of life of survivors. The need for a structured long-term follow-up system after childhood cancer has been recognised for some time and strategies for implementation have been developed, first nationally and then trans-nationally, across Europe. Since its first meeting in Lund in 2008, the goal of the PanCare Network has been to coordinate and implement these strategies to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. This paper will outline the structure and work of the PanCare Network, including the results of several European surveys, the start of two EU-funded projects and interactions with relevant stakeholders and related projects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Wilms' tumour is the second most common paediatric solid tumour. Prognosis is good although higher stage disease carries significant mortality and treatment related morbidity. In the UK, risk stratification is based on histological response to pre-operative chemotherapy. F(18)-Fluorodeoxyglucose Positron Emission Tomography (F(18)FDG-PET) is an emerging functional imaging technique in paediatric oncology. Little is known about the relationship between F(18)FDG-PET images and the disease process of Wilms' tumour. We performed F(18)FDG-PET/CT scans in seven children with Wilms' tumour after induction chemotherapy, immediately before surgery. The standard uptake values (SUV) of F(18)FDG-PET/CT images were related to conventional imaging and histopathological findings. In total seven children were studied. F(18)FDG-PET/CT was consistently safely performed. All tumours showed F(18)FDG activity. Four tumours had activity with SUV/bw max >5 g/ml. Histological examination of these active areas revealed viable anaplastic Wilms' tumour. Furthermore, in these four tumours GLUT-1 and Ki67 immunostaining was strongly positive. Three further tumours demonstrated lower uptake (SUV/bw max <5 g/ml), which represented areas of microscopic foci of residual viable tumour mixed with post chemotherapy change. Metastatic disease was F(18)FDG avid in two of four children with stage four diseases. In conclusion, following chemotherapy, active Wilms' tumour is F(18)FDG avid and higher SUV was seen in histologically high risk disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Childhood cancer patients now have an excellent survival rate. Anthracyclines and radiation have contributed to this success, unfortunately at a cost. Both modalities are cardiotoxic and in some cases this is fatal unless treated by cardiac transplantation. This population-based study investigates the requirement for transplantation, patient demographics and transplant outcomes. Childhood cancer survivors requiring a subsequent cardiac or cardiopulmonary transplant were identified by record linkage between the National Registry Childhood Tumours (NRCT) and United Kingdom Transplant registry (UKT). The clinical details were obtained from the treatment centres for confirmed matches. Forty-three patients were identified as requiring cardiac transplantation: 36 underwent transplantation, 4 died while waiting and 3 were removed from the list. Their childhood cancers included 21 haematopoietic and 22 solid tumours diagnosed at a median age of 3.00 years (range 0.11-13.92 years). All patients were treated with anthracyclines (210-750 mg/m(2)) and 15 received cardiac radiation. The median age at cardiac transplantation was 14.80 years (range 3.26-23.92 years) and actuarial survival for the 36 who underwent cardiac transplantation was 74% and 67% at 5 and 10 years, respectively. A further three patients underwent heart/lung transplantation: all three died from transplant-related causes. Cardiac transplantation is a realistic option for cancer survivors, with survival rates comparable with those of other cardiac recipients. This study demonstrates that, over three decades, there has been an increased requirement for cardiac transplantation among childhood cancer survivors. Future planning for long term survivors needs to take this into account.

Aim: To evaluate the effectiveness of cardiac markers to quantify anthracycline-induced cardiotoxicity in children with cancer., Methods: Systematic review using a priori methods., Results: Seven studies, all with methodological limitations, were identified. One RCT suggests that cardiac troponin can be used to assess the effectiveness of the cardio-protective agent dexrazoxane. Cohort studies suggest that atrial natriuretic peptide and brain (B-type) natriuretic peptide are elevated in some subgroups of patients compared with healthy children; NT-pro-BNP levels are significantly elevated in children with cardiac dysfunction compared with those without; serum lipid peroxide is higher in children who have received doxorubicin compared with children not receiving doxorubicin; there are no differences in carnitine levels between children treated with doxorubicin and a healthy control group., Conclusions: The limited evidence makes conclusions difficult. Research is needed to fill this important evidence gap and link short-term changes in cardiac markers to longer-term cardiac damage.

Though cure from cancer is not guaranteed, children's chances of survival have increased significantly. As a result the paediatric oncology community is focused on providing appropriate follow-up care to an increasing number of young cancer survivors. How this care should be designed and delivered however remains the centre of ongoing discussion and was the focus of this review. The aims of the review were to (1) gain an understanding of current follow-up practices from studies involving health care professionals, (2) identify and evaluate studies presenting views of survivors, (3) examine commentaries on both the current and future design of long-term follow-up services and (4) evaluate existing follow-up guidelines. Empirical research, commentary papers and published guidelines were reviewed. Twenty-eight papers and five guidelines were analysed. Empirical papers were examined in relation to sample, design, findings and limitations. Commentary papers were assessed in relation to key issues about follow-up care. Guidelines were assessed on how far they were evidence-based, peer-reviewed and involved users in their development. Varying models of care were illustrated, and were dependent upon personnel and centre orientation. Variability in the level and degree to which long-term survivors were followed up was also reported. Inconsistencies in practice were noted. Nonetheless requirements for an effective service were highlighted in the majority of publications, these included communication and information. Although young people and professionals had a shared view on many aspects of follow-up care, these preferences were not consistently mirrored in service provision.

Background: Langerhans' cell histiocytosis, a clonal multisystem disorder, can affect children or adults resulting in long term sequelae. However, the overall morbidity for survivors has not been formally determined., Patients and Methods: We performed a cross-sectional study of 40 unselected long term survivors of childhood multisystem Langerhans cell histiocytosis, involving clinical examination, health-related quality of life assessment, brain imaging, neuropsychometry, endocrine assessment, respiratory function tests and audiometry. A specific 'morbidity score' was devised to measure outcome., Results: Seventy-five percent of patients had detectable long term sequelae, hypothalamic-pituitary dysfunction (50%), cognitive dysfunction (20%) and cerebellar involvement (17.5%) being the most common. Half had moderate to severe morbidity, and the worst-affected patients were unable to lead an independent adult life. Health-related quality of life, which correlated well with the morbidity score (p<0.001), was adversely affected in >50% of patients., Conclusion: Organ damage from multisystem Langerhans cell histiocytosis causes long term morbidity extending into adult life. Carefully planned, multidisciplinary follow up is essential to ensure early recognition of problems with appropriate interventions to reduce the impact on patients' 'quality of life'.

Purpose: To determine if patients receiving preoperative chemotherapy with vincristine and actinomycin D for non-metastatic Wilms' tumour have a more advantageous stage distribution and so need less treatment compared to patients who have immediate nephrectomy, without adversely affecting outcome., Methods: Between 1991 and 2001, a total of 205 patients with newly diagnosed non-metastatic renal tumours, of which 186 had Wilms' histologies, were randomly assigned either to immediate surgery or to 6 weeks preoperative chemotherapy and then delayed surgery. Both groups of children received postoperative chemotherapy according to tumour stage and histology determined at the time of nephrectomy., Results: There was a significant improvement in the stage distribution for patients with Wilms' histologies receiving delayed surgery compared to those having immediate nephrectomy (stage I: 65.2% versus 54.3%; stage II: 23.9% versus 14.9%; stage III: 9.8% versus 29.8%, chi2 test for trend=7.02, p=0.008). This improvement resulted in 20% fewer children receiving radiotherapy or doxorubicin yet event-free and overall survivals at 5 years of 79.6% and 89.0%, respectively, were similar in the two groups., Conclusion: Six weeks of preoperative chemotherapy with vincristine and actinomycin D results in a significant shift towards a more advantageous stage distribution and hence reduction in therapy, while maintaining excellent event free and overall survival in children with non-metastatic Wilms' tumour. Around 20% of survivors were therefore spared the late-effects of doxorubicin or radiotherapy. Our results suggest that all children with non-metastatic Wilms' tumour should receive chemotherapy prior to tumour resection.

The aim of this study was to identify patients treated in Great Britain for childhood cancer and subsequently referred for cardiopulmonary transplantation in order to assess diagnosis, cancer treatment, management and outcome. Computerised record linkage between the National Registry of Childhood Tumours and the national transplant database held and maintained by the United Kingdom Transplant Support Service Authority (UKTSSA) was used to identify patients. Verification and clinical details were then obtained from the oncology and transplant centres. 16 patients were identified from the 31992 cases of childhood malignancy diagnosed in Britain since 1970. These comprised 13 heart transplants, 2 heart/lung transplants and 1 patient who died while on the heart transplantation waiting list. All 14 potential heart transplant patients had cardiomyopathy presumed secondary to anthracycline therapy. The original diagnoses were acute myeloblastic leukaemia (3), Wilms' tumour (4), rhabdomyosarcoma (2) and one each of five different solid tumours. Median age at diagnosis was 44 months (range 4-165 months). Median anthracycline dose was 413 mg/m2 (range 240-680 mg/m2). 13 of the 14 potential cardiac transplantation patients were more than 2 years from end of their cancer treatment before requiring transplantation and the transplantation was performed 2-126 months after onset of cardiac failure at a median age of 163 months. Five year actuarial survival from transplantation was 74%. There was no recurrence of the original malignancy in any of these patients. Both heart/lung patients died, 3 and 11 months after the transplant. These heart transplantation data suggest that, in Britain, survival compares favourably with that of patients whose heart transplant was required for other causes of cardiomyopathy. This indicates that patients successfully treated for childhood cancer should not be excluded from transplant programmes.