Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

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.

Counseling and surveillance of obstetrical risks for female childhood, adolescent, and young adult cancer survivors: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female childhood, adolescent, and young adult cancer survivors have an increased risk of adverse pregnancy outcomes related to their cancer- or treatment-associated sequelae. Optimal care for childhood, adolescent, and young adult cancer survivors can be facilitated by clinical practice guidelines that identify specific adverse pregnancy outcomes and the clinical characteristics of at-risk subgroups. However, national guidelines are scarce and vary in content. Here, the International Late Effects of Childhood Cancer Guideline Harmonization Group offers recommendations for the counseling and surveillance of obstetrical risks of childhood, adolescent, and young adult survivors. A systematic literature search in MEDLINE database (through PubMed) to identify all available evidence published between January 1990 and December 2018. Published articles on pregnancy and perinatal or congenital risks in female cancer survivors were screened for eligibility. Study designs with a sample size larger than 40 pregnancies in childhood, adolescent, and young adult cancer survivors (diagnosed before the age of 25 years, not pregnant at that time) were eligible. This guideline from the International Late Effects of Childhood Cancer Guideline Harmonization Group systematically appraised the quality of available evidence for adverse obstetrical outcomes in childhood, adolescent, and young adult cancer survivors using Grading of Recommendations Assessment, Development, and Evaluation methodology and formulated recommendations to enhance evidence-based obstetrical care and preconception counseling of female childhood, adolescent, and young adult cancer survivors. Healthcare providers should discuss the risk of adverse obstetrical outcomes based on cancer treatment exposures with all female childhood, adolescent, and young adult cancer survivors of reproductive age, before conception. Healthcare providers should be aware that there is no evidence to support an increased risk of giving birth to a child with congenital anomalies (high-quality evidence). Survivors treated with radiotherapy to volumes exposing the uterus and their healthcare providers should be aware of the risk of adverse obstetrical outcomes such as miscarriage (moderate-quality evidence), premature birth (high-quality evidence), and low birthweight (high-quality evidence); therefore, high-risk obstetrical surveillance is recommended. Cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for all female survivors treated with anthracyclines and chest radiation. Female cancer survivors have increased risks of premature delivery and low birthweight associated with radiotherapy targeting the lower body and thereby exposing the uterus, which warrant high-risk pregnancy surveillance.

Hepatic late adverse effects after antineoplastic treatment for childhood cancer.

BACKGROUND: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately, the improved prognosis has been accompanied by the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors, the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies, it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. This review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate all the existing evidence on the association between antineoplastic treatment (that is, chemotherapy, radiotherapy involving the liver, surgery involving the liver and BMT) for childhood cancer and hepatic late adverse effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2018, Issue 1), MEDLINE (1966 to January 2018) and Embase (1980 to January 2018). In addition, we searched reference lists of relevant articles and scanned the conference proceedings of the International Society of Paediatric Oncology (SIOP) (from 2005 to 2017) and American Society of Pediatric Hematology/Oncology (ASPHO) (from 2013 to 2018) electronically. SELECTION CRITERIA: All studies, except case reports, case series, and studies including fewer than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection and 'risk of bias' assessment. The 'risk of bias' assessment was based on earlier checklists for observational studies. For the original version of the review, two review authors independently performed data extraction. For the update of the review, the data extraction was performed by one reviewer and checked by another reviewer. MAIN RESULTS: Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis. AUTHORS' CONCLUSIONS: The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.

Population-Based Long-Term Cardiac-Specific Mortality Among 34 489 Five-Year Survivors of Childhood Cancer in Great Britain.

BACKGROUND: Increased risks of cardiac morbidity and mortality among childhood cancer survivors have been described previously. However, little is known about the very long-term risks of cardiac mortality and whether the risk has decreased among those more recently diagnosed. We investigated the risk of long-term cardiac mortality among survivors within the recently extended British Childhood Cancer Survivor Study. METHODS: The British Childhood Cancer Survivor Study is a population-based cohort of 34 489 five-year survivors of childhood cancer diagnosed from 1940 to 2006 and followed up until February 28, 2014, and is the largest cohort to date to assess late cardiac mortality. Standardized mortality ratios and absolute excess risks were used to quantify cardiac mortality excess risk. Multivariable Poisson regression models were used to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity and trends. RESULTS: Overall, 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were 2.5 times and 5.9 times more at risk of ischemic heart disease and cardiomyopathy/heart failure death, respectively, than expected. Among those >60 years of age, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, and 15% of all excess deaths, respectively, providing clear focus for preventive interventions. The risk of both overall cardiac and cardiomyopathy/heart failure mortality was greatest among those diagnosed from 1980 to 1989. Specifically, for cardiomyopathy/heart failure deaths, survivors diagnosed from 1980 to 1989 had 28.9 times the excess number of deaths observed for survivors diagnosed either before 1970 or from 1990 on. CONCLUSIONS: Excess cardiac mortality among 5-year survivors of childhood cancer remains increased beyond 50 years of age and has clear messages in terms of prevention strategies. However, the fact that the risk was greatest in those diagnosed from 1980 to 1989 suggests that initiatives to reduce cardiotoxicity among those treated more recently may be having a measurable impact.

Risk stratification of childhood cancer survivors necessary for evidence-based clinical long-term follow-up.

BACKGROUND: Reorganisation of clinical follow-up care in England was proposed by the National Cancer Survivorship Initiative (NCSI), based on cancer type and treatment, ranging from Level 1 (supported self-management) to Level 3 (consultant-led care). The objective of this study was to provide an investigation of the risks of serious adverse health-outcomes associated with NCSI Levels of clinical care using a large population-based cohort of childhood cancer survivors. METHODS: The British Childhood Cancer Survivor Study (BCCSS) was used to investigate risks of specific causes of death, subsequent primary neoplasms (SPNs) and non-fatal non-neoplastic outcomes by NCSI Level. RESULTS: Cumulative (excess) risks of specified adverse outcomes by 45 years from diagnosis among non-leukaemic survivors assigned to NCSI Levels 1, 2 and 3 were for: SPNs-5% (two-fold expected), 14% (four-fold expected) and 21% (eight-fold expected); non-neoplastic death-2% (two-fold expected), 4% (three-fold expected) and 8% (seven-fold expected); non-fatal non-neoplastic condition-14%, 27% and 40%, respectively. Consequently overall cumulative risks of any adverse health outcome were 21%, 45% and 69%, respectively. CONCLUSIONS: Despite its simplicity the risk stratification tool provides clear and strong discrimination between survivors assigned to different NCSI Levels in terms of long-term cumulative and excess risks of serious adverse outcomes.

Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

Psychosocial factors associated with impact of cancer in longterm haematological cancer survivors.

To assess the impact of cancer (IOC) on subsequent quality of life (QOL), 718 long-term haematological cancer survivors completed validated psychosocial, functional and QOL scales, including IOC. Fifteen percent reported significant psychological distress, 18% high levels of fatigue and 10% moderate to severe functional impairment. These groups of participants also showed poorer QOL. There were no significant differences in psychological distress (P = 0·76), fatigue (P = 0·23) or functional impairment (P = 0·74) across different cancer subtypes. Two separate hierarchical regression analyses examined the combined association of disease-type, psychosocial and other factors on negative and positive IOC scores respectively. Higher negative IOC scores were significantly associated (P ≤ 0·001) with medical comorbidity, psychological distress, lower social support, high fatigue levels and functional impairment. Paediatric patients (diagnosed at <17 years) had significantly higher negative IOC scores than adult patients (P = 0·001); greater years since diagnosis was significantly (P < 0·001) associated with less negative IOC. Higher positive IOC was associated with acute leukaemia (P = 0·01); lower positive IOC with paediatric patients (P < 0·001), white ethnicity (P < 0·001), higher education (P = 0·003), no partner (P = 0·01) and lower social support (P = 0·01). Screening for medical comorbidity, psychological distress and fatigue identifies those needing most support and should allow earlier interventions to address negative and positive IOC to improve the well-being of cancer survivors.

Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were given radiation to fields that include breast tissue (ie, chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these individuals receive optimum care and to reduce the detrimental consequences of cancer treatment; however, surveillance recommendations vary among the existing long-term follow-up guidelines. We applied evidence-based methods to develop international, harmonised recommendations for breast cancer surveillance among female survivors of CAYA cancer who were given chest radiation before age 30 years. The recommendations were formulated by an international, multidisciplinary panel and are graded according to the strength of the underlying evidence.

A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence-based methods, we provide a framework for the harmonization of guidelines for the long-term follow-up of childhood and young adult cancer survivors.

Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study.

PURPOSE: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Renal tumours: long-term outcome.

Childhood cancer is rare, with an incidence of 100 new cases per million children and with renal tumours contributing 7% of cases. The introduction of multimodality treatment, surgery, radiotherapy and chemotherapy, has led to an exponential increase in the 5-year survival rate to >80%. However, this successful treatment has led to the development of late adverse effects. These treatment-related effects can cause premature deaths and increased morbidity compared with patients' peers. Radiation causes damage to tissue and organs within the radiation field, affecting growth and function, and is largely responsible for the leading cause of death, namely, second malignant neoplasms. Another important late effect is cardiac dysfunction due to anthracycline use with or without cardiac radiation. In addition, a few patients have genetic abnormalities predisposing to Wilms tumour development, which result in renal dysfunction in the long term and may be exacerbated by cancer treatment regimens. Awareness of late consequences of cancer treatment is important, as early recognition can improve outcome. When presented with a patient with a history of renal tumours, it is vital to enquire about previous treatment to understand whether it is relevant to the presenting problem.

European PanCareFollowUp Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer.

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.

Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: Recommendations from the international late effects of childhood cancer guideline harmonization group.

BACKGROUND: Survivors of childhood, adolescent and young adult (CAYA) cancer may develop treatment-induced chronic liver disease. Surveillance guidelines can improve survivors' health outcomes. However, current recommendations vary, leading to uncertainty about optimal screening. The International Late Effects of Childhood Cancer Guideline Harmonization Group has developed recommendations for the surveillance of late hepatotoxicity after CAYA cancer. METHODS: Evidence-based methods based on the GRADE framework were used in guideline development. A multidisciplinary guideline panel performed systematic literature reviews, developed evidence summaries, appraised the evidence, and formulated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance while allowing for flexibility in implementation across different health care systems. RESULTS: The guideline strongly recommends a physical examination and measurement of serum liver enzyme concentrations (ALT, AST, gGT, ALP) once at entry into long-term follow-up for survivors treated with radiotherapy potentially exposing the liver (moderate- to high-quality evidence). For survivors treated with busulfan, thioguanine, mercaptopurine, methotrexate, dactinomycin, hematopoietic stem cell transplantation (HSCT), or hepatic surgery, or with a history of chronic viral hepatitis or sinusoidal obstruction syndrome, similar surveillance for late hepatotoxicity once at entry into LTFU is reasonable (low-quality evidence/expert opinion, moderate recommendation). For survivors who have undergone HSCT and/or received multiple red blood cell transfusions, surveillance for iron overload with serum ferritin is strongly recommended once at long-term follow-up entry. CONCLUSIONS: These evidence-based, internationally-harmonized recommendations for the surveillance of late hepatic toxicity in cancer survivors can inform clinical care and guide future research of health outcomes for CAYA cancer survivors.

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.

Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study.

OBJECTIVE: In this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study. METHODS: Eight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3-5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors. RESULTS: Overall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14-30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)). CONCLUSIONS: In this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.

Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma. METHODS: Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate. RESULTS: Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above. CONCLUSIONS: Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.

Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group.

PURPOSE: As new evidence is available, the International Late Effects of Childhood Cancer Guideline Harmonization Group has updated breast cancer surveillance recommendations for female survivors of childhood, adolescent, and young adult cancer. METHODS: We used evidence-based methods to apply new knowledge in refining the international harmonized recommendations developed in 2013. The guideline panel updated the systematic literature review, developed evidence summaries, appraised the evidence, and updated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance interventions while attaining flexibility in implementation across different health care systems. The GRADE Evidence-to-Decision framework was used to translate evidence to recommendations. A survivor information form was developed to counsel survivors about the potential harms and benefits of surveillance. RESULTS: The literature update identified new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), radiation dose-volume, anthracyclines and alkylating agents in non-chest irradiated survivors, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the performance metrics of mammography and magnetic resonance imaging among survivors of Hodgkin lymphoma. Modified recommendations include the performance of mammography and breast magnetic resonance imaging for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with any type of anthracyclines in the absence of chest radiation. CONCLUSION: The newly identified evidence prompted significant change to the recommendations formulated in 2013 related to moderate-dose chest radiation and anthracycline exposure as well as breast cancer surveillance modality.

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.

Do doctors discuss fertility issues before they treat young patients with cancer?

BACKGROUND: Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS: Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS: Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS: These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.