Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium.

Late mortality of European 5-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95% CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95% CI 6.32-6.62). At 60 to 68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95% CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5-20.4) to 7.3% (95% CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P = .1105 and P = .0829, respectively). PanCareSurFup is the largest study with the longest follow-up of late mortality among European childhood and adolescent cancer 5-year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long-term care needs.

Health of children born to childhood cancer survivors: Participant characteristics and methods of the Multicenter Offspring Study.

INTRODUCTION: Research on childhood cancer survivor offspring has been limited to genetic disease occurrence, malformations or non-hereditary cancers. However, previous surveys indicated that survivors harbor fears about their (prospective) children's overall health. Our Multicenter Offspring Study examined extensive health aspects in children born to survivors and their siblings providing comprehensive information to be used in patient counseling to elucidate and alleviate existing concerns. METHODS: Using a specifically designed questionnaire, childhood cancer survivors and their siblings were surveyed on their offspring's health (Supplementary material). Recruitment strategies depended on local infrastructures and standards of participating centers, including registry-based and direct approaches. Group differences were tested non-parametrically and effect sizes were calculated. RESULTS: In total, 1126 survivors reported on 1780 offspring and 271 siblings reported on 441 offspring. Response rates ranged from 32.1% (Czech Republic) to 85.0% (Austria). Respondents were more likely to be female (p = .007), older at time of survey (p < .001), diagnosed 1980-1999 (p < .001) and treated with chemotherapy (p < .001). Compared to siblings, survivors were younger at time of survey (35 years vs. 39 years, p < .001) and at first birth (29 years vs. 30 years, p < .001). Survivor and sibling offspring only differed in terms of age at survey (6.3 years vs. 8.9 years, p < .001). CONCLUSION: The Multicenter Offspring Study investigates a wide variety of health aspects in offspring born to survivors and their siblings in five European countries. Our study cohorts form a solid basis for future analyses; yet, certain limitations, due to differences in approach among participating centers, must be considered when interpreting findings.

Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

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.

Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Clinical considerations for the treatment of secondary differentiated thyroid carcinoma in childhood cancer survivors.

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.

Evidence-based recommendations for the organization of long-term follow-up care for childhood and adolescent cancer survivors: a report from the PanCareSurFup Guidelines Working Group.

PURPOSE: To facilitate the implementation of long-term follow-up (LTFU) care and improve equality of care for childhood, adolescent, and young adult (CAYA) cancer survivors, the PanCareSurFup Guidelines Working Group developed evidence-based recommendations for the organization of LTFU. METHODS: We established an international multidisciplinary guideline panel. A systematic review of the literature published from 1999 to 2017 was completed to answer six clinical questions. The guideline panel reviewed the identified studies, developed evidence summaries, appraised the quality of the body of evidence, and formulated recommendations based on the evidence, expert opinions, and the need to maintain flexibility of application across different healthcare systems. RESULTS: We provide strong recommendations based on low level evidence and expert opinions, regarding organization of LTFU care, personnel involved in LTFU care, components of LTFU care and start of LTFU care. We recommend that risk-adapted LTFU care provided under the guidance of a cancer survivorship expert service or cancer centre should be available and accessible for all CAYA cancer survivors throughout their lifespan. CONCLUSION: Despite the weak levels of evidence, successful and effective implementation of these recommendations should improve LTFU, thereby leading to better access to appropriate healthcare services and an improvement in health outcomes for CAYA cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: To improve health outcomes and quality of survivorship of current and future survivors, continued age-adapted education of survivors about the cancer, its treatment, risk of late effects, importance of health behaviours, and necessity of LTFU is important along the cancer and survivorship trajectory.

The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer.

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.

Long-term survivors of childhood cancer: cure and care-the Erice Statement (2006) revised after 10 years (2016).

PURPOSE: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens. METHODS: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778-80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years. RESULTS: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. "Cure" refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child. CONCLUSIONS AND IMPLICATION FOR CANCER SURVIVORS: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).

Survivorship after childhood cancer: PanCare: a European Network to promote optimal long-term care.

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.

The views of European clinicians on guidelines for long-term follow-up of childhood cancer survivors.

BACKGROUND: Evidence-based guidelines are needed to guide effective long-term follow-up (LTFU) of childhood cancer survivors (CCS) at risk of late adverse effects (LAEs). We aimed to ascertain the use of LTFU guidelines throughout Europe, and seek views on the need for pan-European LTFU guidelines. PROCEDURES: One expert clinician from each of 44 European countries was invited to participate in an online survey. Information was sought regarding the use and content of LTFU guidelines in the respondent's centre and country, and their views about developing pan-European LTFU guidelines. RESULTS: Thirty-one countries (70%) responded, including 24 of 26 full EU countries (92%). LTFU guidelines were implemented nationally in 17 countries (55%). All guidelines included recommendations about physical LAEs, specific risk groups and frequency of surveillance, and the majority about psychosocial LAEs (70%), and healthy lifestyle promotion (65%). A minority of guidelines described recommendations about transition to age-appropriate LTFU services (22%), where LTFU should be performed (22%) and by whom (30%). Most respondents (94%) agreed on the need for pan-European LTFU guidelines, specifically including recommendations about surveillance for specific physical LAEs (97%), action to be taken if a specific LAE is detected (90%), minimum requirements for LTFU (93%), transition and health promotion (both 87%). CONCLUSIONS: Guidelines are not universally used throughout Europe. However, there is strong support for developing pan-European LTFU guidelines for CCS. PanCareSurFup (www.pancare.eu) will collaborate with partners to develop such guidelines, including recommendations for hitherto relatively neglected topics, such as minimum LTFU requirements, transition and health promotion. Pediatr Blood Cancer 2015;62:322-328. © 2014 Wiley Periodicals, Inc.

Transitional care of a childhood cancer survivor to adult services: facilitating the process of individual access to different models.

PURPOSE OF REVIEW: In the past 20 years, several papers have been published concerning healthcare transition from pediatric after-care to long-term follow-up in adult health service for childhood cancer survivors. Initially, the papers were optimistic and included guidelines and models of care. However, after this optimistic beginning, more recent research has found that transitional care is not a successful process. RECENT FINDINGS: Although the number of papers regarding transition in the past 2 years is few, they include revealing results about barriers and facilitators of the transition process. SUMMARY: There is some evidence that joint pediatric/adult transition clinics are more successful in providing transitional care. The use of tools to assess individual psychological factors is important for the transition process and could lead to more individualized models of transition.

Gastrointestinal stromal tumours in children and young adults: a clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Studies on gastrointestinal stromal tumours (GIST) in the paediatric population are limited to case reports or small case series. PATIENTS AND METHODS: We conducted a retrospective study to describe the long-term outcome of children and adolescents with GIST registered in the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). RESULTS: Sixteen patients (female, n = 11) were identified. Median age at diagnosis was 13.5 years. In four female patients presence of thoracic masses in addition to GIST led to the diagnosis of complete or incomplete Carney triad. Three female patients had metastatic disease at diagnosis, the remaining thirteen GIST were localised. The stomach was the most common primary site of the tumour, followed by the small bowel and colon/abdomen. All patients underwent tumour resection. Receptor tyrosine kinase inhibitors (RTKI) were administered in five patients. With a median follow-up of 96 months all patients are alive, nine of them in first CR. Four female patients developed local or distant recurrence; three of them achieved second CR and one a PR. Two individuals have extensive progressive (n = 1) or stable (n = 1) disease. Estimated progression-free survival at 5 years is 0.63 (95%CI: 0.50-0.86). CONCLUSIONS: Although long-term overall survival is favourable, approximately 30 percent of patients develop disease progression. International cooperation in registration, tissue collection and molecular studies are required to obtain reliable data on the clinical course of these rare tumours in the paediatric population. Biological studies are a prerequisite for initiation of studies with RTKI.

Natural course of HCV infection in childhood cancer survivors.

GOALS OF WORK: To describe the course of hepatitis C in a cohort of 105 survivors after childhood cancer. PATIENTS AND METHODS: Data on chemo/radiotherapy, clinical status, serial alanine aminotransferase (ALT) evaluation, and virological parameters after the end of treatment were collected for each patient. Liver biopsies, when performed, were centrally evaluated by a pathologist. MAIN RESULTS: All patients were alive at the end of follow-up and did not show hepatic insufficiency. ALT evaluation along the entire follow-up showed a moderate (87%) or a remarkable (13%) cytolytic pattern. Young age at diagnosis, hematopoietic stem cell transplantation, and duration of infection significantly correlate with a worse hepatic activity. Type of tumor and chemo and/or radiotherapy regimens did not influence the pattern of hepatic cytolysis. Liver biopsy, centrally reviewed in 30% of the cohort, showed one case of cirrhosis and mild fibrosis in 71% of the group. Higher degrees of fibrosis did not seem to be related to any exposition to chemo/radiotherapy but correlated significantly with the more remarkable cytolytic course. CONCLUSIONS: The outcome of hepatitis C in our patients is comparable to the one described in European cohorts of adult cancer survivors and perinatally infected subjects. Nevertheless, progression to high degrees of hepatic damage has to be monitored by a careful follow-up.

Quality of life in long-term childhood cancer survivors and the relation of late effects and subjective well-being.

GOALS: The purpose of the present study was the assessment of health-related quality of life in adult long-term survivors of childhood cancer and the detection of possible treatment- and cancer-related late effects. The relation of objective medical data and subjective appraisal was also examined by combining the doctor's and the patient's views of the perceived health status. PATIENTS AND METHODS: Seventy-eight young adults at the age of at least 18 years who had been diagnosed with cancer in the years 1975-1995 and were off therapy at least 5 years with no evidence of disease participated. Cancer survivors completed self-rating instruments [SF-36 Health Survey, Nottingham Health Profile (NHP), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI) trait-anxiety scale]; the doctor assessed the patient's health by means of the Common Toxicity Criteria (CTCv2). MAIN RESULTS: The cancer survivors showed a mostly higher-than-average positive subjective rating of the various areas of quality of life. In comparison to the general population, the cancer survivors showed lower extents of depression. In 64.1% of the cancer survivors, medical rating and self-assessment regarding the perceived health status corresponded. Cancer survivors who felt severely impaired regarding their subjectively perceived well-being showed worse results in some dimensions of quality of life than persons who subjectively felt mildly impaired. The so-called "unfortunate" persons showed the worst assessment of quality of life and the highest extent of depression and anxiety. CONCLUSIONS: The results of the present study may be helpful in planning an appropriate multidisciplinary, long-term follow-up of childhood cancer survivors.