Annah N. Abrams

Prospective Study of Health-Related Quality of Life for Children With Brain Tumors Treated With Proton Radiotherapy

PURPOSE We describe the health-related quality of life (HRQoL) of a cohort of children with brain tumors treated with proton radiotherapy. PATIENTS AND METHODS We recruited 142 pediatric patients with brain tumors (age 2 to 18 years) and parents of such patients treated with proton radiation at Massachusetts General Hospital from 2004 to 2010. HRQoL was assessed using the PedsQL core, brain tumor, and cancer modules (range, 0 to 100). Assessments took place during radiation and annually thereafter. We examined correlations of HRQoL with disease, treatment, and cognitive and behavioral data. RESULTS Overall reports of HRQoL during treatment were 74.8 and 78.1 for child self-report (CSR) and 67.0 and 74.8 for parent proxy report (PPR) for the core and brain tumor modules, respectively. PPR demonstrated lower HRQoL scores than CSR, but the two were highly correlated. Higher HRQoL scores were significantly associated with Wechsler Full Scale Intelligence Quotient scores (administered via the age-appropriate version) and better scores on two behavioral measures. Disease type also correlated with PPR core total HRQoL score at the beginning of treatment: medulloblastoma or primitive neuroectodermal tumors, 57.8; germ cell tumors, 63.5; ependymoma or high-grade glioma, 69.8; low-grade glioma, 71.5; and other low-grade neoplasms, 78.0 (P = .001). Craniospinal irradiation and chemotherapy were negatively correlated with HRQoL. CONCLUSION This is the first study to our knowledge of HRQoL in a cohort of children with brain tumors treated with proton radiation. This prospective study demonstrates the effect of disease type and intensity of treatment on HRQoL. It further suggests that where CSR is not possible, PPR is appropriate in most circumstances.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study

BACKGROUND Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING US National Cancer Institute and Massachusetts General Hospital.

Fluoxetine pharmacokinetics in pediatric patients.

The objective of this study was to evaluate the pharmacokinetic profile of fluoxetine (FLX) and its major metabolite, norfluoxetine (NORFLX), in children and adolescent patients undergoing psychiatric treatment. Twenty-one pediatric subjects—10 children (6–12 years) and 11 adolescents (13– 18 years)—were administered 20 mg FLX for 60 days, with sparse blood samples taken throughout the open-label study. Subjects contributed 168 plasma concentrations. Pharmacokinetic parameters were estimated using a mixed effects nonlinear model. Mean steady-state FLX and NORFLX of 127 ng/mL and 151 ng/mL, respectively, were achieved in children and adolescents after 4 weeks of treatment, with high between-patient variability. FLX was 2-fold higher and NORFLX was 1.7-fold higher in children relative to adolescents; however, when normalized to body weight, FLX and NORFLX were similar for both age groups. Age, body weight, body mass index, and body surface area, modeled independently as continuous variables, significantly improved the population pharmacokinetic model when evaluated as patient factors. Body weight was the covariate retained in the final model. In conclusion, children have 2-fold higher FLX and NORFLX relative to adolescents that appear to be related to indices of body size. The accumulation profile and steady-state concentrations in adolescents appear similar to those in adults.

Psychosocial Assessment as a Standard of Care in Pediatric Cancer

This paper presents the evidence for a standard of care for psychosocial assessment in pediatric cancer. An interdisciplinary group of investigators utilized EBSCO, PubMed, PsycINFO, Ovid, and Google Scholar search databases, focusing on five areas: youth/family psychosocial adjustment, family resources, family/social support, previous history/premorbid functioning, and family structure/function. Descriptive quantitative studies, systematic reviews, and meta‐analyses (n = 149) were reviewed and evaluated using grading of recommendations, assessment development, and evaluation (GRADE) criteria. There is high quality evidence to support a strong recommendation for multifaceted, systematic assessments of psychosocial health care needs of youth with cancer and their families as a standard of care in pediatric oncology. Pediatr Blood Cancer

Psychiatric Aspects of Pediatric Cancer

The diagnosis and treatment of children and adolescents with cancer has a tremendous and lasting effect on the patients, their families, and other individuals in their social network. It carries a host of psychological and behavioral ramifications, from questions of mortality to changes in levels of functioning in multiple domains. In this review the authors address the psychosocial and treatment-related issues that arise in children with cancer, with attention to the adjustment to cancer at different developmental stages, mood and anxiety issues, treatment-related psychiatric sequelae, and the challenges faced by childhood cancer survivors.

Posterior fossa syndrome: Review of the behavioral and emotional aspects in pediatric cancer patients

Medulloblastoma, the most common malignant brain tumor of childhood, occurs in the posterior fossa, the part of the intracranial cavity that contains the brainstem and the cerebellum. The cerebellum is involved in many complex aspects of human behavior and function, and when it is disrupted or insulted, this can lead to significant sequelae in children with posterior fossa tumors. A constellation of impairing and distressing symptoms, including mutism, ataxia/hypotonia, and emotional lability, develops in approximately 25% of children after the surgical resection of posterior fossa tumors. These symptoms may impede treatment and frequently require intervention in order for children to be able to participate in their care. The eventual recovery of speech occurs for most, but with slowly improving dysarthria over many months. Behavioral changes and emotional lability also occur. This phenomenon has been classified differently by different investigators over the past 35 years. For the purposes of this article, the term posterior fossa syndrome is used to refer to the neuropsychiatric and behavioral features that compose this condition. The current review summarizes the development of the clinical understanding of this phenomenon with a focus on near‐ and long‐term psychosocial and psychiatric implications. Also, clinical examples of the presentation, management, and lasting implications of this syndrome are provided. This review is intended to be a resource for clinicians who treat affected children. Cancer 2017;123:551–559.

Olanzapine for chemotherapy-induced nausea: Lessons learned from child and adolescent psychiatry

1Department of PsychosocialOncology andPalliativeCare, Dana–FarberCancer Institute, Boston,Massachusetts 2Department of Psychiatry, BostonChildrensHospital, Boston,Massachusetts 3HarvardMedical School, Boston,Massachusetts 4Department of Psychiatry andBehavioral Sciences,Memorial SloanKetteringCancerCenter, NewYorkCity, NewYork 5Department of Psychiatry andPediatrics, University of KentuckyCollege ofMedicine, Lexington, Kentucky 6KentuckyChildrensHospital, Lexington, Kentucky 7Department of Pediatric Psychosocial Oncology,MassachusettsGeneral Hospital, Boston,Massachusetts 8Department of Psychiatry andPalliativeCare, University of California SanDiego School ofMedicine, SanDiego, California Correspondence ChaseSamsel,DepartmentofPsychosocialOncologyandPalliativeCare,Dana–FarberCancer Institute, SW360A,450BrooklineAvenue,Boston,MA,02115. Email: chase_samsel@dfci.harvard.edu

Reply to: Comment on: Olanzapine for chemotherapy-induced nausea: Lessons learned from child and adolescent psychiatry

To the Editor: We thankDrsDupuis et al for their letter and for enhancing the discussion regarding the use of Olanzapine for refractory chemotherapyinduced nausea and vomiting (CINV).1 The intent of our commentary was to foster collaboration among pediatric oncology, pharmacy, and psychiatry in the novel use of this medication.2 We applaud the development of guidelines to provide effective relief of CINV in children and adolescents and are encouraged by the role that olanzapine can play. There are important distinctions between the long-term use of antipsychotic medications in the treatment of acute and chronic psychiatric illness and the short-term targeted use of olanzapine for refractory CINV. Our commentary is meant to contribute additional information to concurrently reduce risk and allay concerns, and we do not intend to create barriers to the use of potentially effective antiemetic therapy. We are especially enthusiastic about the use of olanzapine for children and adolescents with comorbid CINV and psychiatric symptoms such as severe anxiety, mood instability, or delirium. We agree the existing pediatric and psychiatric consensus guidelines regarding metabolic and waist circumference monitoring in long-term use of atypical antipsychotics may not be applicable for short-term use in pediatric oncology.3,4 It is important background information to have should prolonged treatment be considered or become necessary, as olanzapine has the strongest metabolic effects of its class.5,6 We agree that severe QTc prolongation is not an acute risk with olanzapine monotherapy in children without other cardiac risk factors or QTc prolonging polypharmacy. However, in clinical oncology practice, many children are on concomitant QTc prolonging medications and may need a reference electrocardiogram, often available from their baseline medical work-up.7 In terms of dosing, we agree that 0.1 mg/kg/dose (max: 10 mg/dose) is a reasonable rule of thumb, though dosage forms of oral and disintegrating tablets may limit the increments for dosing. Doses of greater than 5 mg may be too sedating and should only be considered for older children or adolescents who do not respond to lower doses. Intramuscular administration is only used for acute psychiatric emergencies. We are hopeful that prospective research can be done regarding the efficacy and side effects of olanzapine for refractory CINV in children and adolescents.8 Some of our own institutions are rolling out evidence-based guidelines based on those developed by Pediatric Oncology Group of Ontario and endorsed by The Childrens Oncology Group,9,10 with olanzapine as a treatment for refractory CINV. We appreciate the multidisciplinary efforts that can contribute to supportive care and symptom relief for our young patients with cancer,