Supportive Care in Pediatric Oncology: Opportunities and Future Directions.

The optimization of outcomes for pediatric cancer patients relies on the successful advancement of supportive care to ease the treatment burden and mitigate the long-term impacts of cancer therapy. Advancing pediatric supportive care requires research prioritization as well as the development and implementation of innovations. Like the prevailing theme throughout pediatric oncology, there is a clear need for personalized or precision approaches that are consistent, evidence-based, and guided by clinical practice guidelines. By incorporating technology and datasets, we can address questions which may not be feasible to explore in clinical trials. Now is the time to listen to patients' voices by using patient-reported outcomes (PROs) to ensure that their contributions and experiences inform clinical care plans. Furthermore, while the extrapolation of knowledge and approaches from adult populations may suffice in the absence of pediatric-specific evidence, there is a critical need to specifically understand and implement elements of general and developmental pediatrics like growth, nutrition, development, and physical activity into care. Increased research funding for pediatric supportive care is critical to address resource availability, equity, and disparities across the globe. Our patients deserve to enjoy healthy, productive lives with optimized and enriched supportive care that spans the spectrum from diagnosis to survivorship.

Yoga versus iPad active control for fatigue in paediatric cancer therapy: a randomised controlled trial.

OBJECTIVES: The primary objective was to determine if individualised yoga for hospitalised children receiving intensive chemotherapy was associated with less fatigue using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL MFS) compared with iPad control. METHODS: This was a multicentre randomised controlled trial of individualised yoga in paediatric patients aged 8-18 years who were inpatients receiving intensive chemotherapy for leukaemia, lymphoma or haematopoietic cell transplantation. Participants were randomised to yoga or iPad groups; allocated programme was delivered individually by trained yoga instructors 5 days/week for 21 days. The primary outcome was day 21 guardian-reported general fatigue using the PedsQL MFS. Secondary outcomes included day 21 PedsQL sleep/rest and cognitive fatigue, Fatigue Scale and PedsQL Acute Cancer Module, and systemic opioid administration. RESULTS: The study was closed early for poor accrual when 125/210 planned participants had been enrolled and randomised to yoga (n=62) or iPad (n=63). Guardian-reported PedsQL MFS general fatigue scores on day 21 were not significantly different between groups (adjusted difference 7.2, 95% CI -2.6 to 16.9) in favour of yoga. However, day 21 cognitive fatigue (adjusted difference 9.0, 95% CI 0.9 to 17.1), cognitive problems (adjusted difference 11.2, 95% CI 3.5 to 19.0) and communication (adjusted difference 10.6, 95% CI 0.8 to 20.4) were significantly better in the yoga compared with the iPad group. There were no significant differences in the other secondary outcomes including PedsQL sleep/rest fatigue (adjusted difference 4.9, 95% CI -3.5 to 13.3). CONCLUSIONS: The effect of individualised yoga on general fatigue is uncertain in paediatric patients receiving intensive chemotherapy. However, yoga significantly improved cognitive fatigue and cognitive problems. TRIAL REGISTRATION NUMBER: NCT02134782.

Thrombocytopenia Associated with Elemental Mercury Poisoning in Two Siblings - Connecticut, July 2022.

Two siblings aged 5 and 15 years from Connecticut were hospitalized with petechial rash, oral mucositis, and severe thrombocytopenia approximately 10 days after they played with a jar of elemental mercury they found in their home. Before the mercury exposure was disclosed, the siblings were treated with platelet transfusions, intravenous immune globulin (IVIG) for possible immune thrombocytopenic purpura, and antibiotics for possible infectious causes. When their conditions did not improve after 6 days, poison control facilitated further questioning about toxic exposures including mercury, testing for mercury, and chelation with dimercaptosuccinic acid. The older sibling soon recovered, but the younger child required a prolonged hospitalization for severe thrombocytopenia, ultimately receiving repeated doses of IVIG, steroids, and romiplostim, a thrombopoietin receptor agonist. Close collaboration among multiple agencies was required to identify the extent of mercury contamination, evaluate and treat the other family members, and decontaminate the home. These cases demonstrate the importance of ongoing public health outreach to promote early detection of elemental mercury toxicity, and the need to evaluate for environmental exposures when multiple close contacts experience similar signs and symptoms.

Treatment of breakthrough and prevention of refractory chemotherapy-induced nausea and vomiting in pediatric cancer patients: Clinical practice guideline update.

This clinical practice guideline update provides recommendations for treating breakthrough chemotherapy-induced nausea and vomiting (CINV) and preventing refractory CINV in pediatric patients. Two systematic reviews of randomized controlled trials in adult and pediatric patients informed the recommendations. In patients with breakthrough CINV, escalation of antiemetic agents to those recommended for chemotherapy of the next higher level of emetogenic risk is strongly recommended. A similar recommendation to escalate therapy is made to prevent refractory CINV in patients who did not experience complete breakthrough CINV control and are receiving minimally or low emetogenic chemotherapy. A strong recommendation to use antiemetic agents that controlled breakthrough CINV for the prevention of refractory CINV is also made.

v-SYMPHONY career development series: A collaboration to enhance professional awareness for pediatric hematology oncology trainees.

BACKGROUND: A recent survey of pediatric hematology oncology (PHO) physicians identified that a majority believe fellows are struggling to find jobs that align with their goals. Career development for trainees has historically been home institution-specific, limiting fellows' exposures to career path possibilities. The "virtual-Symposium of Pediatric Hematology/Oncology of New York (v-SYMPHONY)" instituted a tristate Career Development Series for PHO trainees to better address their needs and increase awareness of the variety of PHO career opportunities. PROCEDURE: The v-SYMPHONY Career Development Series incorporated three sessions: (a) institutional perspective, (b) individual perspectives, and (c) nuts and bolts of job search. Pre- and post-series surveys were administered to participants to measure impact. RESULTS: Forty-one fellows registered for the series and completed a pre-survey. Over half (54%) were in their third or later year of fellowship. Careers with a clinical focus were the most commonly desired career path (59%). Most had received career development advice only from faculty within their institutions (90%). Post-surveys were completed by 11 PHO fellows. Overall, 100% of respondents reported benefiting from the career sessions and recommended the series should be repeated annually. Over 90% learned new information to prepare for the job search. CONCLUSIONS: The v-SYMPHONY Career Development Series for PHO fellows across multiple institutions was established and was extremely well received by its participants. PHO fellows agreed that these sessions were beneficial in helping prepare them for the job search process. An annual regional Career Development Series is feasible and is strongly suggested to support PHO fellows.

Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: A clinical practice guideline.

This clinical practice guideline provides recommendations for preventing acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. The recommendations are based on two systematic reviews of randomized controlled trials evaluating interventions to prevent (1) acute phase CINV and (2) delayed phase CINV. Recommendations for acute phase and delayed phase CINV prophylaxis are made for patients receiving chemotherapy of varying emetogenicity, as well as for patients not able to receive dexamethasone or a neurokinin-1 receptor antagonist. Evidence gaps, including antiemetic safety and optimal dosing, were identified.

Interventions for the prevention of acute phase chemotherapy-induced nausea and vomiting in adult and pediatric patients: a systematic review and meta-analysis.

PURPOSE: To identify effective and safe interventions to prevent acute phase chemotherapy-induced nausea and vomiting (CINV) in adult and pediatric patients. METHODS: We conducted a systematic review of randomized trials evaluating interventions to prevent acute CINV. Outcomes assessed were complete chemotherapy-induced vomiting (CIV) control, complete chemotherapy-induced nausea (CIN) control, complete CINV control, and discontinuation of antiemetics due to adverse effects. RESULTS: The search identified 65,172 citations; 744 were evaluated at full-text, and 295 (25 pediatric) met eligibility criteria. In patients receiving highly emetogenic chemotherapy (HEC), complete CIV (risk ratio (RR) 1.23, 95% confidence interval (CI) 1.05-1.44) and CIN (RR 1.34, 95% CI 1.10-1.62) control improved when olanzapine was added. The addition of a neurokinin-1 receptor antagonist (NK1RA) to a corticosteroid plus a serotonin-3 receptor antagonist (5HT3RA) also improved complete CIV (RR 1.11, 95% CI 1.08-1.14) and CIN (RR 1.05, 95% CI 1.01-1.08) control. Compared to granisetron/ondansetron, palonosetron provided improved complete CIV control when the 5HT3RA was given alone or when combined with dexamethasone. In patients receiving moderately emetogenic chemotherapy (MEC), dexamethasone plus a 5HT3RA improved complete CIV control compared to a 5HT3RA alone (RR 1.29, 95% CI 1.21-1.39). Only a single meta-analysis evaluating the safety outcome was possible. CONCLUSIONS: For patients receiving HEC, various antiemetic regimens improved CIV and CIN control. For patients receiving MEC, administration of a 5HT3RA plus dexamethasone improved CIV control. Analysis of antiemetic safety was constrained by lack of data.

Feeling scared or worried self-report in children receiving cancer treatments using the Symptom Screening in Pediatrics Tool (SSPedi).

INTRODUCTION: The objectives of this study were to describe reports of bother for feeling scared or worried among children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients, and to identify factors associated with it. METHODS: We included children receiving cancer treatments who were 8-18 years of age. Three patient types were enrolled: inpatients receiving active cancer treatment, outpatients receiving maintenance acute lymphoblastic leukemia chemotherapy, and outpatients in survivorship. Amount of bother due to feeling scared or worried yesterday or today was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi) on a 0-4 scale. Risk factors were evaluated using logistic regression. RESULTS: Among the 502 children included, 225 (45.0%) reported any degree of bother (score ≥ 1) and 29 (5.8%) reported severe bother (score ≥ 3) for feeling scared or worried. In multiple regression evaluating any bother, boys were less likely to be bothered (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41-0.87) and inpatients receiving active cancer treatment were more likely to be bothered compared to outpatients in survivorship (OR 3.58, 95% CI 2.00-6.52). The only factor associated with being severely bothered by feeling scared or worried was clinic visit or admission due to fever (OR 4.57, 95% CI 1.24-13.60). DISCUSSION: We found 45% of children receiving cancer treatments reported being bothered by feeling scared or worried. Girls and inpatients receiving active treatment experienced more bother of any degree, while visiting the hospital due to fever was associated with being severely bothered. Future work should identify interventions to prevent or alleviate this symptom.

Classification of the acute emetogenicity of chemotherapy in pediatric patients: A clinical practice guideline.

This clinical practice guideline (CPG) provides clinicians with recommendations regarding chemotherapy emetogenicity classification in pediatric oncology patients. This information is critically important for the appropriate selection of antiemetic prophylaxis. Recommendations are based on a systematic review limited to pediatric patients and a framework for classification when antiemetic prophylaxis is provided. Findings of 87 publications informed the emetogenicity classification of 49 single-agent and 13 combination-agent regimens. Information required for the classification of many chemotherapies commonly administered to pediatric patients is lacking. In the absence of pediatric data, consultation of methodologically sound CPGs aimed at adult oncology patients may be appropriate.

Taste changes in children with cancer and hematopoietic stem cell transplant recipients.

BACKGROUND: Objectives were to describe bothersome self-reported changes in taste in pediatric oncology and hematopoietic stem cell (HSCT) patients and to identify patient and treatment-related factors associated with bothersome taste changes. METHODS: We prospectively enrolled children and adolescents with cancer or pediatric HSCT recipients 8-18 years of age from three groups: inpatients receiving cancer treatments; outpatients in maintenance therapy for acute lymphoblastic leukemia (ALL); and outpatients in survivorship. Bothersome changes in taste was self-reported using the Symptom Screening in Pediatrics Tool (SSPedi); nausea was self-reported using the Pediatric Nausea Assessment Tool (PeNAT). RESULTS: Among the 502 children included, 226 (45.0%) reported bothersome taste changes and 48 (9.6%) reported severely bothersome taste changes. In multiple regression, factors independently associated with severely bothersome taste changes were: inpatients receiving cancer treatments vs outpatients in survivorship (odds ratio (OR) 12.28, 95% confidence interval (CI) 2.50-222.27), ALL in maintenance vs outpatients in survivorship (OR 7.43, 95% CI 1.06-147.77), current nausea (OR 1.59, 95% CI 1.04-2.42), vomiting (OR 2.18, 95% CI 1.06-4.38), and first language not English (OR 2.09, 95% CI 0.97-4.28). CONCLUSIONS: We found that 45% of children with cancer and pediatric HSCT recipients reported bothersome changes in taste and these were severely bothersome in 9.6% of children. Inpatients receiving cancer treatment, those experiencing more nausea and vomiting and children whose first language was not English were at greater risk of severely bothersome changes in taste. Future work should evaluate systematic symptom screening in clinical practice and identify interventions focused on addressing bothersome taste changes.

Severely bothersome fatigue in children and adolescents with cancer and hematopoietic stem cell transplant recipients.

BACKGROUND: Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. METHODS: We included children ages 8-18 years treated for cancer or HSCT recipients from three groups: [1] receiving active cancer treatment and admitted to hospital for at least 3 days, [2] attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and [3] attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi); severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3-4 on 0-4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. RESULTS: Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1-4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11-14 and 15-18 years vs 8-10 years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21-3.77 and OR 2.96, 95% CI 1.66-5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17-7.27). CONCLUSIONS: We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue.

Validation of the Proxy Version of Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments.

OBJECTIVES: Primary objectives were to evaluate the interrater reliability and validity of proxy-report Symptom Screening in Pediatrics Tool (SSPedi) in children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Secondary objective was to describe the interrater reliability of each SSPedi item. METHODS: Respondents were children aged eight to 18 years with cancer or HSCT recipients, and their parents or guardians. We enrolled two pediatric respondent groups. The more symptomatic group was receiving active treatment for cancer, admitted to hospital, and expected to be in a hospital three days later. The less symptomatic group either was in maintenance therapy for acute lymphoblastic leukemia or had completed cancer treatments. Convergent validity was evaluated by comparing proxy-reported mucositis, nausea and vomiting, pain, and total SSPedi scores, with child self-reported validated scales, and we hypothesized fair correlations. Discriminant validity was evaluated by comparing proxy-reported total SSPedi scores between groups. Interrater reliability of each SSPedi item was evaluated. RESULTS: Four hundred thirty-nine child and parent or guardian pairs were recruited. Mean difference in proxy-reported SSPedi scores between the more and less symptomatic groups was 8.2, 95% CI 6.6-9.8. All hypothesized relationships among measures were observed. Intraclass correlation coefficients for SSPedi items ranged from 0.34 (problems with thinking) to 0.80 (diarrhea). CONCLUSION: Proxy-report SSPedi is reliable and valid in children aged 8 years to 18 years with cancer and HSCT recipients. Future work should support proxy-reported symptom assessment in clinical settings where children are not able to self-report or communicate bothersome symptoms.

Describing symptoms using the Symptom Screening in Pediatrics Tool in hospitalized children with cancer and hematopoietic stem cell transplant recipients.

Objectives were to describe any bothersome symptom and severely bothersome symptoms in inpatient children with cancer and hematopoietic stem cell transplant (HSCT) recipients. We included children 8-18 years of age with cancer or HSCT recipients who were receiving active treatment for cancer, admitted to hospital, and expected to be in hospital 3 days later. We administered the self-report Symptom Screening in Pediatrics Tool (SSPedi). We described those who identified any degree of symptom bother (at least "a little") and those who rated the degree of bother as severe ("a lot" or "extremely"). Factors associated with severe symptoms and total SSPedi scores were examined using multiple logistic and linear regression. Among the 302 patients, 298 (98.7%) reported having any bothersome symptom and 181 (59.9%) had at least one severely bothersome symptom. In multiple regression, older children were significantly more likely to have at least one severely bothersome symptom (15-18 and 11-14 years vs. 8-10 years; P = 0.008) and to have higher total SSPedi scores (P = 0.0003). Those with relapsed disease were more likely to have at least one severely bothersome symptom (odds ratio 2.1, 95% confidence interval 1.1-4.3; P = 0.037) and HSCT recipients were more likely to have higher symptom scores (ß = 3.48, standard error = 1.6; P = 0.030). Almost all children receiving cancer therapies experience bothersome symptoms and 60% have at least one severely bothersome symptom. Older children experienced more severely bothersome symptoms and higher symptom scores. Future studies should follow children longitudinally to better understand the symptom trajectory and should institute interventions to manage symptoms.

Validation of the Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments.

Background: The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods: In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results: Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions: SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update.

This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including the inclusion of palonosetron to the 5-HT3 antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children 6 months of age or older receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.

2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children.

PURPOSE: To update the 2009 recommendations for the prevention of acute chemotherapy-induced emesis in children. METHODS: We updated the original systematic literature search. Randomized studies were included in the evidence to support this guideline if they were primary studies fully published in full text in English or French; included only children less than 18 years old or, for mixed studies of adults and children, reported the pediatric results separately or the median or mean age was no more than 13 years; evaluated acute chemotherapy-induced nausea and vomiting (CINV) prophylaxis; provided sufficient information to permit determination of the emetogenicity of the antineoplastic therapy administered or the study investigators stated the emetogenicity of the chemotherapy administered; included an implicit or explicit definition of complete acute CINV response; described the antiemetic regimen in full; and reported the complete acute CINV response rate as a proportion. RESULTS: Twenty-five randomized studies, including eight published since 2009, met the criteria for inclusion in this systematic review. Prophylaxis with a 5-HT3 antagonist (granisetron or ondansetron or palonosetron or tropisetron) ± dexamethasone ± aprepitant is recommended for children receiving highly or moderately emetogenic chemotherapy. For children receiving chemotherapy of low emetogenicity, a 5-HT3 antagonist is recommended. CONCLUSIONS: The findings of several randomized trials were used to update recommendations for the prevention of acute CINV. However, significant research gaps remain and must be addressed before CINV control in children can be optimized.

Does socioeconomic status impact physical activity and sleep among children with cancer?

BACKGROUND: Compared with healthy children, pediatric oncology patients have impaired sleep and engage in less physical activity (PA). Socioeconomic status (SES) may be one determinant of PA and sleep among pediatric oncology patients. PROCEDURE: Between November 12, 2009 and March 27, 2013, 50 pediatric oncology patients between the ages of 8 and 18 years were recruited from an urban children's hospital. PA and sleep were assessed by actigraphy and diaries over 7 days. Fatigue was assessed using the Fatigue Scale. SES was defined by primary payer status of insurance (state or private) and by Median Household Income (MHI) obtained from 2010 U.S. Census block data for residences. MHI was compared to Connecticut state median income ($67,000). Multivariate regression models examined the relationship between SES and PA, sleep and fatigue. RESULTS: PA and sleep efficiency were strongly correlated (r = 0.31, P = 0.03). Children with state insurance had higher average PA (P = 0.004) than children on private insurance. There were no significant differences in PA or sleep efficiency by block MHI. The 7-day fatigue score was lower among the participants aged 8-12 years in the group with MHI less than $67,000 (P = 0.03), although there was no significant difference among participants aged 13-18 years in the group. There was no difference in mean fatigue scores by insurance status. CONCLUSIONS: Participants on state insurance had higher PA than those with private insurance. Although block MHI did not influence PA or sleep efficiency among children with cancer, participants aged 8-12 years in a lower MHI block had less fatigue. Future research is needed to further understand how SES influences PA.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis: Practice Within the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group (COG) has endorsed a clinical practice guideline (CPG) for acute chemotherapy-induced nausea and vomiting (CINV) prophylaxis in children with cancer. This project aims to describe current acute CINV prophylaxis practice at COG sites and the gap between this practice and CPG recommendations. PROCEDURE: Two surveys were developed. The first survey, sent to 94 cancer control and supportive care responsible individuals (CCL RIs) at 94 COG institutions, asked if the institution had a standardized approach to practice and focused on antiemetic agent choice. The second survey, sent to 54 pharmacists at COG sites where the CCL RI indicated that there was a standardized approach to CINV prophylaxis practice, focused on antiemetic dosing. Survey results were described and analyzed for consistency with the CPG recommendations. RESULTS: Among the 69 respondents to the first survey, 54 (78%) stated that their institutions have a standardized approach to CINV prophylaxis practice. However, antiemetic choice varied widely among respondents. Results from the 36 respondents to the second survey also demonstrated significant antiemetic dosing practice variability. Frequent sources of deviation from CPG recommendations were as follows: antiemetic choice when corticosteroids are contraindicated, dexamethasone dosing, aprepitant use in children less than 12 years, and aprepitant use in the presence of a known or suspected drug interaction. CONCLUSIONS: There is a great diversity in the CINV prophylaxis provided to children with cancer at COG sites. Concerted strategies are required to improve awareness of the current CINV prophylaxis CPG and to facilitate CPG-consistent CINV prophylaxis.

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy.

BACKGROUND: Subacute cardiotoxicity, consisting of acute myocyte damage and associated left ventricular dysfunction, occurs early during anthracycline therapy. We investigated the impact of myocardial dysfunction, defined herein by a shortening fraction (SF) < 29 % at any time during or after anthracycline therapy, on late onset cardiomyopathy and all-cause mortality, among childhood cancer survivors exposed to anthracyclines. In addition, we sought to identify subpopulations of subjects at highest risk for cardiomyopathy and death from all causes. METHODS: Five hundred thirty-one childhood cancer survivors exposed to anthracyclines were enrolled and studied on average 10 (1.4-27.3) years following their initial exposure. The medical records were reviewed to identify known risk factors associated with cardiotoxicity, including cumulative anthracycline dose, length of post-therapy interval, administration of other cardiotoxic medications (vinca alkaloids), previous heart disease, radiation dose to the heart, history of bone marrow transplantation, age at treatment, gender, systolic dysfunction, and history of congestive heart failure during anthracycline therapy. RESULTS: Ninety subjects (16.9 %) developed SF < 29 % and 71 patients (13.4 %) died on average 10 years after initial exposure (range 1.4-27.3 years). Total cumulative dose (OR 3.27, 95 % CI 1.94, 5.49, p < 0.001) and bone marrow transplantation (OR 2.57, 95 % CI 1.24, 5.30, p = 0.01) were found to be statistically significant risk factors for development of myocardial dysfunction. There was a 3-fold increase in the odds of having a SF < 29 % at any point during or following cancer therapy if a subject underwent bone marrow transplantation or had a total cumulative dose anthracycline therapy ≥ 240 mg/m2. The all-cause mortality ratio was almost seven-fold higher (95 % CI, 2.40-fold to 17.81-fold higher) if a subject developed systolic dysfunction, defined by a previous SF < 29 % anytime during or after anthracycline therapy. Nine deaths (12.7 %) were attributed to cardiovascular disease. The risk of dying as a result of cardiac disease also was significantly higher in individuals who had a SF < 29 % at any time during or after therapy. CONCLUSIONS: This study demonstrates an almost seven-fold increase in all cause mortality in pediatric cancer survivors with a history of anthracycline induced myocardial dysfunction defined as SF < 29 %.