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Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of dexrazoxane, and little guidance is available on its use in children. To facilitate global consensus, a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the existing literature and used evidence-based methodology to develop a guideline for dexrazoxane administration in children with cancer who are expected to receive anthracyclines. Recommendations were made in consideration of evidence supporting the balance of potential benefits and harms, and clinical judgement by the expert panel. Given the dose-dependent risk of anthracycline-induced cardiotoxicity, we concluded that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m 2 (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m 2 , due to insufficient evidence to determine whether the risk of cardiotoxicity outweighs the possible risk of subsequent neoplasms. Further research is encouraged to determine the long-term efficacy and safety of dexrazoxane in children with cancer., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment., Methods: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk., Findings: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; p mediation =0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; p mediation =0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001)., Interpretation: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population., Funding: National Cancer Institute and the American Lebanese-Syrian Associated Charities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

More than 80% of children and 60% of adults with cancer will become long-term survivors, emphasizing the importance of late effects of cancer therapy. Cardiotoxicity due to chemotherapy and radiation is a frequent cause of serious morbidity and premature mortality in survivors. Anthracyclines, a core component of many treatment regimens, have been implicated as a principal cause of irreversible cardiomyopathy. Approximately 60% of anthracycline-treated children will develop echocardiographic evidence of cardiac dysfunction, and 10% of those treated with high-dose anthracyclines will develop congestive heart failure within the 20 years after therapy. Adults treated with trastuzumab are at risk of a cardiomyopathy that is usually reversible. As many as 12% of adults treated with trastuzumab and 20% of those who have also received an anthracycline will develop cardiotoxicity within 5 years. Risk factors for cardiomyopathy include patient (eg, age, sex, genetic predisposition) and treatment characteristics (eg, cumulative anthracycline dose). Radiotherapy to a field involving the heart increases the risk of cardiomyopathy, coronary artery disease, valvular dysfunction, arrhythmias, and pericardial disease. Surveillance guidelines are available to guide long-term cardiac follow-up of childhood cancer survivors, but not for survivors of adult cancers; however, periodic follow-up to detect cardiac dysfunction may be reasonable. Modifiable cardiac risk factors such as hypertension, smoking, and dyslipidemia interact with cancer therapies to increase the risk of cardiac disease, emphasizing the importance of risk-factor control. Coordination of care between oncologists and cardiologists would optimize care for those individuals at high risk of cardiotoxicity who would benefit from appropriate surveillance and treatment strategies., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Chemotherapy emetogenicity is the most important known determinant of chemotherapy-induced vomiting (CIV) in children. However, direct evidence regarding the emetogenic potential of chemotherapeutic agents in children is limited. This study describes the prevalence of complete control of acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in children receiving methotrexate. The prevalence of anticipatory CINV is described, and risk factors for CINV are explored., Methods: English-speaking children (4 to 18 years) receiving intermediate-dose (ID-MTX: >1 to <12 g/m(2)/dose) or high-dose methotrexate (HD-MTX: ≥12 g/m(2)/dose) participated in this prospective study. Emetic episodes, nausea severity, and antiemetic administration were documented for 24 h from the start of the methotrexate infusion (acute phase) and for up to a further 168 h (delayed phase). CINV prophylaxis was provided at the discretion of the treating physician. Anticipatory CINV was assessed in the 24 h preceding chemotherapy. Complete CINV control was defined as no emetic episodes and no nausea., Results: Thirty children (mean age, 11.8 ± 4 years; ID-MTX, 20; HD-MTX, 10) completed the study. CINV prophylaxis included the following: ondansetron/granisetron plus dexamethasone or nabilone. Few patients experienced complete CINV control (ID-MTX: acute phase 20%, delayed phase 5%; HD-MTX: acute phase 0%, delayed phase 30%). Complete emesis control was higher (ID-MTX: acute phase 70%, delayed phase 50%; HD-MTX: acute phase 70%, delayed phase 60%). Anticipatory CINV was reported by 6/28 patients (21%). Patient age, sex, and history of motion sickness were not significant predictors of CINV., Conclusions: The poor complete CINV control rate in children receiving methotrexate confirms the classification of HD-MTX as highly emetogenic chemotherapy (HEC) and suggests that ID-MTX be reclassified as HEC.

Effective cancer therapies have resulted in significant improvement in survival. However, treatment-related acute and subacute complications are a cause of significant morbidity and mortality. Effects of cancer therapy in children can be seen early in the survival period or later in life in almost all organ systems of the body. Many of these conditions are evaluated by imaging and some are diagnosed based on characteristic imaging features. This article aims to discuss acute and subacute toxicities of cancer therapy in children involving multiple organ systems, pulmonary, gastrointestinal, hepatobiliary, genitourinary and musculoskeletal systems with emphasis on those in which imaging plays a role in diagnosis or management. We also discuss the role of imaging and choice of imaging modalities in these conditions.

Both the kidneys and lungs are susceptible to the toxic effects of cancer therapy, with specific chemotherapy agents, as well as radiation therapy, leading to acute toxicities and the risk for long-term dysfunction. The kidneys also are vulnerable to the direct impact of the cancer itself and to supportive care drugs such as certain anti-infectives and immunosuppressive agents, nonsteroidal anti-inflammatories, and radiocontrast media. The lungs are especially vulnerable after hematopoietic stem cell transplantation (HSCT), particularly in patients who develop chronic graft-versus-host disease. This article will discuss the epidemiology, specific risk factors, pathogenesis, natural history, recommended screening, preventive strategies, treatment, and areas for future research into renal and pulmonary toxicity in survivors of cancer., (© 2013 Elsevier Inc. All rights reserved.)

Background: While cisplatin is considered superior to carboplatin for the treatment of malignant germ cell tumors (MGCTs) in adults, pediatric oncology collaborative groups still remain concerned about the late effects of cisplatin in children., Methods: We performed a literature search to identify randomized controlled trials (RCTs) that used carboplatin for MGCTs in adults. Since no RCTs were available in children, we identified cohort studies of pediatric MGCTs treated with carboplatin. We compared the adult and pediatric studies in terms of characteristics, doses of chemotherapy, and outcomes., Results: Of 2,131 publications retrieved, five RCTs in adults (1,340 patients) and four cohort studies in children (219 patients) met criteria for inclusion. All adult RCTs evaluated carboplatin versus cisplatin regimens in men with good-prognosis metastatic MGCTs. Carboplatin regimens had a higher risk of events (RR 2.51, P < 0.001) and of deaths (RR 2.21, P < 0.001) than cisplatin regimens. Across all five RCTs, 497/654 (76%) of adults who received carboplatin remained event-free. Compared to the adult trials, three pediatric studies used carboplatin at a higher dose, frequency, and number of cycles. Across these three studies, 158/179 (88%) of children remained event-free., Conclusions: Cisplatin is superior to carboplatin at the studied doses for the treatment of adult metastatic MGCTs. However, we observe that carboplatin is associated with good outcomes for children with MGCT when used at the higher doses. We hypothesize that a risk-adapted approach utilizing both platinum agents may achieve the optimal balance between cure and late effects., (Copyright © 2012 Wiley Periodicals, Inc.)

Existing guidelines for the prevention of antineoplastic chemotherapy-induced nausea and vomiting (CINV) in children are constrained by the lack of robust evidence. Current guidelines recommend the use of a serotonin 5-HT(3) receptor antagonist plus a corticosteroid to prevent acute CINV. Consequently, antiemetic agents that are recommended for use in adult cancer patients do not appear in the current pediatric guidelines. In addition, there is no information to guide the selection of alternative antiemetic agents for children who either cannot receive the recommended agents or who do not respond adequately to the treatment. Possible barriers to adherence to the pediatric antiemetic selection guidelines that are currently available are discussed, and published pediatric experience with antiemetic agents recommended in the current adult antiemetic selection guidelines (dolasetron, tropisetron, palonosetron, aprepitant) is summarized in this review. The use of novel and emerging antiemetic therapeutic interventions {metopimazine, diphenhydramine (Benadryl)-lorazepam (Avitan)-dexamethasone (Decadron) [BAD], nabilone, acupuncture, midazolam, olanzapine, mirtazapine, gabapentin, droperidol} in children are explored.

The current standard of care with respect to preventing acute chemotherapy-induced nausea and vomiting (CINV) in children includes the administration of a 5-HT(3) antagonist with or without a corticosteroid, depending on the emetogenicity of the chemotherapy to be given. Problems in assessing the emetogenicity of chemotherapy regimens and nausea severity in children may influence the degree of success of CINV prophylaxis. Nevertheless, the majority of children who receive chemotherapy today experience moderate to complete control of acute CINV when given appropriate antiemetic prophylaxis. If children vomit or experience nausea despite appropriate prophylaxis, then measures must be taken to treat these symptoms since these children are likely to go on to experience delayed or anticipatory CINV. However, appropriate selection of interventions to treat acute CINV in children is limited by the lack of rigorous evidence to support one approach over another. Lorazepam is suggested as an immediate agent for the treatment of acute CINV. Doses and frequencies of the 5-HT(3) antagonist and corticosteroid administered for initial prophylaxis should also be maximized. Further treatment must be tailored to the circumstances and preferences of each child and family. Options include crossover to another 5-HT(3) antagonist, or administration of an adjunctive antiemetic such as metopimazine, low dose metoclopramide, domperidone, alizapride, nabilone, scopolamine, prochlorperazine, or chlorpromazine. Complementary interventions such as acupuncture, hypnosis, counseling, or ginger may also be of benefit. Further study is required to establish optimal antiemetic strategies in children.

Background: Anthracycline-induced cardiac toxicity is a cause of significant morbidity and early mortality in survivors of childhood cancer. Current strategies for predicting which children are at greatest risk for toxicity are imperfect and diagnosis of cardiac injury is usually made relatively late in the natural history of the disease. This study aims to identify genomic, biomarker and imaging parameters that can be used as predictors of risk or aid in the early diagnosis of cardiotoxicity.Methods: This is a prospective longitudinal cohort study that recruited two cohorts of pediatric cancer patients at six participating centres: (1) an Acute Cohort of children newly diagnosed with cancer prior to starting anthracycline therapy (n = 307); and (2) a Survivor Cohort of long-term survivors of childhood cancer with past exposure to anthracycline (n = 818). The study team consists of three collaborative cores. The Genomics Core is identifying genomic variations in anthracycline metabolism and in myocardial response to injury that predispose children to treatment-related cardiac toxicity. The Biomarker Core is identifying existing and novel biomarkers that allow for early diagnosis and prognosis of anthracycline-induced cardiac toxicity. The Imaging Core is identifying echocardiographic and cardiac magnetic resonance (CMR) imaging parameters that correspond to early signs of cardiac dysfunction and remodeling and precede global dysfunction and clinical symptoms. The data generated by the cores will be combined to create an integrated risk-prediction model aimed at more accurate identification of children who are most susceptible to anthracycline toxicity.Discussion: We aim to identify genomic risk factors that predict risk for anthracycline cardiotoxicity pre-exposure and imaging and biomarkers that facilitate early diagnosis of cardiac injury. This will facilitate a personalized approach to identifying at-risk children with cancer who may benefit from cardio- protective strategies during therapy, and closer surveillance and earlier initiation of medications to preserve heart function after cancer therapy.Trial Registration: NCT01805778 . Registered 28 February 2013; retrospectively registered. [ABSTRACT FROM AUTHOR]