The chemotherapy agent cisplatin is essential for treatment of many paediatric and adolescent malignancies but in a large proportion of patients results in cisplatin-induced hearing loss, a ...debilitating and permanent late effect, with consequences for neurocognition, academic achievement, employment, and social and psychological outcomes.1,2 In The Lancet Oncology, we previously reported the results of the Children's Oncology Group study ACCL0431, an international, randomised, controlled trial of sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents.3 Participants were randomly assigned to sodium thiosulfate or observation in addition to their planned cisplatin-containing chemotherapy. In ACCL0431, we found compelling evidence for hearing protection from sodium thiosulfate, a finding replicated by the concurrent International Childhood Liver Tumours Strategy Group 6 trial (SIOPEL-6) in standard-risk (ie, localised) hepatoblastoma.4 As described in the initial ACCL0431 report, survival was a prespecified secondary outcome to assess for potential interference with chemotherapy efficacy by sodium thiosulfate. ...future research designed specifically to explore safety of sodium thiosulfate use or alternative approaches to otoprotection is warranted to address the risk for severe ototoxicity also facing children with disseminated tumours.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adolescent and young adult (AYA) enrollment in cancer clinical trials (CCT) is suboptimal. Few studies have explored site level barriers and facilitators to AYA enrollment on CCTs and the efficacy of ...interventions to enhance enrollment. A cross sectional survey was developed by the COG AYA Oncology Discipline Committee Responsible Investigator (RI) Network to identify perceived barriers and facilitators to enrollment, as well as opportunities to improve enrollment. Associations of barriers and facilitators to enrollment with program demographics were assessed. The survey was sent to all AYA RI Network members (n = 143) and quantitative and thematic analyses were conducted. The overall response rate was 42% (n = 60/143). Participants represented diverse institutions based on size, presence or absence of dedicated AYA programs, and proximity and relationship between pediatric and medical oncology practices within the institution. The most frequently cited barriers to enrolling AYAs in CCTs were administrative logistical issues (45%), disparate enrollment practices (42%) and communication issues (27%) between pediatric and medical oncology and perceived limited trial availability (27%). The most frequently reported facilitators to enrollment included having strong communication between pediatric and medical oncology (48%), having a supportive research infrastructure (35%) and the presence of AYA champions (33%). Many barriers and facilitators were similar across institutions and AYA program types. Shared barriers and facilitators to AYA CCT enrollment exist across the landscape of cancer care settings. Interventions aimed at increasing coordination between pediatric and medical oncology clinical trials offices and providers have high potential to improve site-level AYA enrollment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Adolescents and young adults (AYAs) form a unique group of patients with newly diagnosed acute myeloid leukemia (AML). They differ in terms of disease biology, psychosocial challenges, survival, and ...in other important respects from children as well as from middle-aged and older adults. AYAs may be treated using pediatric protocols developed in trials composed primarily of younger patients, or using adult protocols developed in trials composed primarily of older patients. After reviewing the distinguishing characteristics of AYAs with AML, we compare and contrast the chemotherapy approaches and argue that neither the pediatric nor adult approaches may be ideally suited for AYAs and the development of AYA-specific approaches merits further consideration. We finish by putting forth ideas for future research to optimize chemotherapy treatment of AYAs with AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective: This study investigated profiles of emotional distress and growth in adolescents and young adults (AYAs) with cancer. Clinical, demographic, and psychosocial factors were examined for ...their potential to distinguish these profiles and predict health-related quality of life (HRQoL) of AYAs with cancer. Method: This was a multicenter, longitudinal study of AYAs diagnosed with cancer at 14-39 years of age. Participants were assessed 3 times over 24 months following a baseline survey administered at diagnosis. Four profiles (resilient, resilient growth, distressed, distressed growth) were derived using published cutoff points on standardized measures of depression, anxiety, posttraumatic stress disorder, and posttraumatic growth. Mixed-effects models were used to examine profile correlates and the extent to which profiles were associated with HRQoL. Results: Among 179 participants at Time 1, the proportion of profiles ranged from 18.8% for the resilient profile to 30.4% for the distressed-growth profile. These proportions remained consistent over time. Factors that appeared to distinguish these profiles included work or school status, sex, race, age at diagnosis, treatment status, prognosis, and personality characteristics. When compared to AYAs with resilient-growth profiles, HRQoL was significantly worse for AYAs reporting distressed and distressed-growth profiles, controlling for demographic, clinical, and social characteristics. Conclusion: The current study found 4 patterns of psychological adjustment in AYAs with cancer. The resilient-growth profile was associated with better HRQoL, whereas distressed and distressed-growth profiles were associated with worse HRQoL.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
Within the Children's Oncology Group and the ...Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m
across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m
ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m
). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% 95% CI, 0.3 to 2.5) and ejection fraction (absolute difference, +1.6% 95% CI, 0.0 to 3.2), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL 95% CI, -10.6 to -2.8). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 95% CI, 0.07 to 0.81). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m
.
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Purpose
Cisplatin-induced hearing loss (CIHL) is a common late effect after childhood cancer treatment having profound, lifelong consequences that lower quality of life. The recent identification of ...intravenous sodium thiosulfate (STS) as an effective agent for preventing pediatric CIHL represents a paradigm shift that has created new opportunities for expanding STS usage and developing additional otoprotectants. The purpose of this paper is to discuss key considerations and recommendations for the design and implementation of future pediatric otoprotection trials.
Methods
An approach synthesizing published data and collective experience was used.
Results
Key issues were identified in the categories of translational research, trial designs for systemic and intratympanic agents, measurement of ototoxicity, and biostatistical challenges.
Conclusions
Future pediatric otoprotection trials should emphasize (1) deep integration of preclinical and early-phase studies; (2) an embedded or free-standing design for systemic agents based on mechanistic considerations; (3) use of suitable audiologic testing batteries for children, SIOP grading criteria, and submission of raw audiologic data for central review; and (4) novel endpoints and innovative study designs that maximize trial efficiency for limited sample sizes. Additional recommendations include routine collection of DNA specimens for assessing modifying effects of genetic susceptibility and meaningful inclusion of patient/family advocates for informing trial development.
Implications for Cancer Survivors
Changing the historical paradigm from acceptance to prevention of pediatric CIHL through expanded research with existing and emerging otoprotectants will dramatically improve quality of life for future childhood cancer survivors exposed to cisplatin.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Given concerns that dexrazoxane may reduce treatment efficacy, induce second cancers, and thus compromise overall survival among children, we examined long-term overall and cause-specific mortality ...and disease relapse rates from three randomized clinical trials.
Children's Oncology Group trials P9404 (T-cell acute lymphoblastic leukemia/lymphoma; n = 537), P9425 (intermediate/high-risk Hodgkin lymphoma; n = 216), and P9426 (low-risk Hodgkin lymphoma; n = 255) were conducted between 1996 and 2001. Each trial randomly assigned patients to doxorubicin with or without dexrazoxane. The dexrazoxane:doxorubicin dose ratio was 10:1, and the cumulative protocol-specified doxorubicin dose was 100 to 360 mg/m(2). Dexrazoxane was given as an intravenous bolus before each doxorubicin dose. Data from all three trials were linked with the National Death Index to determine overall and cause-specific mortality by dexrazoxane status.
Among 1,008 patients (507 received dexrazoxane) with a median follow-up of 12.6 years (range, 0 to 15.5 years), 132 died (67 received dexrazoxane). Overall mortality did not vary by dexrazoxane status (12.8% with dexrazoxane at 10 years v 12.2% without; hazard ratio HR, 1.03; 95% CI, 0.73 to 1.45). Findings were similar when each trial was examined separately. Dexrazoxane also was not significantly associated with differential causes of death. The original cancer caused 76.5% of all deaths (HR, 0.90; 95% CI, 0.61 to 1.32) followed by second cancers (13.6% of deaths; HR, 1.24; 95% CI, 0.49 to 3.15). Specifically, dexrazoxane was not associated with deaths from acute myeloid leukemia/myelodysplasia or cardiovascular events.
Among pediatric patients with leukemia or lymphoma, after extended follow-up, dexrazoxane use did not seem to compromise long-term survival.
Obesity as defined by body mass index percentile (BMI%) is strongly associated with relapse and poorer survival in childhood ALL. Whether BMI% accurately reflects body fat percentage (BF%) in this ...population is unknown. We conducted a prospective study assessing body composition during frontline ALL therapy. Dual-energy X-ray absorptiometry measured BF% and lean muscle mass (LMM) at diagnosis, end of Induction, and end of Delayed Intensification. Sarcopenic obesity (gain in BF% with loss of LMM) was surprisingly common during ALL treatment, resulting in poor correlation between changes in BMI% (expressed as Z-score) and BF% overall (r = −0.05) and within patients (r = −0.09). BMI Z-score and BF% changed in opposite directions in >50% of interval assessments. While BMI% at diagnosis is a suitable predictor of obesity/BF% for epidemiological studies, change in BMI% (as expressed as Z-score) does not reflect body composition. Studies evaluating obesity in leukemia should consider using direct measures of body composition.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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