The microbiome in pediatric oncology

The human microbiome comprises a diverse set of microorganisms, which play a mostly cooperative role in processes such as metabolism and host defense. Next-generation genomic sequencing of bacterial nucleic acids now can contribute a much broader understanding of the diverse organisms composing the microbiome. Emerging evidence has suggested several roles of the microbiome in pediatric hematology/oncology, including susceptibility to infectious diseases, immune response to neoplasia, and contributions to the tumor microenvironment as well as changes to the microbiome from chemotherapy and antibiotics with unclear consequences. In this review, the authors have examined the evidence of the role of the microbiome in pediatric hematology/oncology, discussed how the microbiome may be modulated, and suggested key questions in need of further exploration.     

Barriers to accessing palliative care for pediatric patients with cancer: A review of the literature

Although many of the 16,000 children in the United States diagnosed who are with cancer each year could benefit from pediatric palliative care, these services remain underused. Evidence regarding the barriers impeding access to comprehensive palliative care is dispersed in the literature, and evidence specific to pediatric oncology remains particularly sparse. The purpose of the current review was to synthesize the existing literature regarding these barriers and the strategies offered to address them. The authors completed a literature search using the PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science databases. In total, 71 articles were reviewed. Barriers to accessing pediatric palliative care were categorized according to the 4 levels of a modified socioecological model (ie, barriers related to policy/payment, health systems, organizations, and individuals). Major themes identified at each level included: 1) the lack of consistent and adequate funding mechanisms at the policy/payment level, 2) the lack of pediatric palliative care programs and workforce at the health systems level, 3) difficulties integrating palliative care into existing pediatric oncology care models at the organizational level, and 4) the lack of knowledge about pediatric palliative care, discomfort with talking about death, and cultural differences between providers and patients and their families at the individual level. Recommendations to address each of the barriers identified in the literature are included. Cancer 2018;124:2278‐88 . © 2018 American Cancer Society.     

Pilot study of a pediatric metronomic 4-drug regimen

Background

Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC is gaining interest as an alternative strategy to fight resistant cancer.

Objective

to assess the safety of 4 drug MC regimen in pediatric patients with refractory or relapsing various tumors types.

Setting

From November 2008 to December 2010, in three academic pediatric oncology centers, 16 children (median age 12 years old; range 5.5-20) were included in this pilot study. This treatment was proposed to children with refractory disease for whom no further effective treatments were available. Most frequent diagnosis were medulloblastoma/cerebral PNET (5) osteosarcoma (5), and one case each of nephroblastoma, high grade glioma, Hodgkin lymphoma, rhabdomyosarcoma, neuroblastoma and kidney rhabdoid tumour. The MC regimen consisted in cycles of 56 days (8 weeks) with weekly vinblastine 3 mg/m² (week 1-7), daily cyclophosphamide 30 mg/m² (days 1-21), and twice weekly methotrexate 10 mg/m²; (days 21-42), and daily celecoxib 100 mg to 400 mg twice daily (days1-56) followed by a 2-weeks chemotherapy break. Adverse events were determined through laboratory analysis and investigator observations.

Results

One objective response was observed in a patient with Hodgkin lymphoma, and 4 patients experienced disease stabilization and continued their treatment for 3 cycles (24 weeks) or more. At last follow-up, 7 patients (43%) are alive including 1 still undergoing treatment. During the overall 36 cycles of treatments received by patients, 4 grade IV toxicities and 24 grade III toxicities were observed in 11 cycles in only 10 different patients.

Conclusion

The metronomic regimen we report here was well tolerated and associated with disease stabilization. This regimen is currently being evaluated in a national multicenter phase II study.     

Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy

BackgroundTreatment for pediatric ependymoma includes surgical resection followed by local radiotherapy (RT). Proton RT (PRT) enables superior sparing of critical structures compared with photons, with potential to reduce late effects. We report mature outcomes, patterns of failure, and predictors of outcomes in patients treated with PRT.MethodsOne hundred fifty patients (<22 y) with World Health Organization grades II/III ependymoma were treated with PRT between January 2001 and January 2019 at Massachusetts General Hospital. Demographic, tumor, and treatment-related characteristics were analyzed. Event-free survival (EFS), overall survival (OS), and local control (LC) were assessed.ResultsMedian follow-up was 6.5 years. EFS, OS, and LC for the intracranial cohort (n = 145) at 7 years were 63.4%, 82.6%, and 76.1%. Fifty-one patients recurred: 26 (51.0%) local failures, 19 (37.3%) distant failures, and 6 (11.8%) synchronous failures. One hundred sixteen patients (77.3%) underwent gross total resection (GTR), 5 (3.3%) underwent near total resection (NTR), and 29 (19.3%) underwent subtotal resection (STR). EFS for the intracranial cohort at 7 years for GTR/NTR and STR was 70.3% and 35.2%. With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location. There was no adverse effect on disease control if surgery to RT interval was within 9 weeks of GTR/NTR.ConclusionPRT is effective and safe in pediatric ependymoma. Similar to previous studies, GTR/NTR was the most important prognostic factor. Intervals up to 9 weeks from surgery to PRT did not compromise disease outcomes. There was no LC benefit between patients treated with >54 Gray relative biological effectiveness (Gy_RBE) versus ≤54 Gy_RBE.     

Fertility preservation options in pediatric and adolescent patients with cancer

The incidence of childhood cancer has steadily increased since the 1950s, with approximately 16,000 children diagnosed each year. However, with the advent of more effective multimodal therapies, childhood cancer survival rates have continued to improve over the past 40 years, with >80% of patients now surviving into adulthood. Fertility preservation (FP) has become an important quality‐of‐life issue for many survivors of childhood cancer. As a result, the therapeutic options have become less gonadotoxic over time and more patients are being offered FP options. This review examines the indications for consultation, male and female FP options both in the prepubertal patient and adolescent patient, and the unique ethical issues surrounding FP in this vulnerable population. Cancer 2018;124:1867‐76 . © 2018 American Cancer Society.     

Psychological interventions with siblings of pediatric cancer patients: a systematic review

Objective: Siblings of pediatric cancer patients have been shown to be at risk for developing emotional, behavioral, and social problems. There is a need for psychological interventions in this population. Several researchers have previously documented and evaluated their interventions with siblings. This paper aimed at reviewing the existing reports of evaluated psychological interventions with siblings of pediatric cancer patients and at outlining future directions. Methods: Research was conducted on several online bibliographic databases. Articles were selected on the basis of predefined criteria. If possible, effect sizes (ES) were calculated. Results: Fourteen studies representing 11 different sibling interventions met criteria for inclusion. One individual intervention, three camps, and seven groups were found. Objectives of interventions concentrated mainly on enhancing siblings' coping and improving their medical knowledge. In terms of outcome measures, most of the studies focused on psychological adjustment variables. Findings showed significant improvements in siblings' depression symptomatology, medical knowledge, and health‐related quality of life. Findings were inconsistent with regard to anxiety, behavioral problems, social adjustment, self‐esteem, and posttraumatic stress symptoms. Depending on the outcome variables, small to large ES were found. Satisfaction with the intervention was high in both siblings and parents. Conclusion: There is tentative evidence that psychological interventions with siblings of childhood cancer patients can effectively reduce psychological maladjustment and improve medical knowledge about cancer. However, the number of studies is small, and several methodological shortcomings have to be noted. In future, more randomized controlled trials need to be conducted in larger samples to extend the evidence base. Copyright © 2009 John Wiley & Sons, Ltd.     

A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study

BackgroundWe sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.MethodsEnzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m²) and twice daily at 440 mg/m²/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples.ResultsThirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m² given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m² dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.ConclusionEnzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m²/day administered once daily.     

Molecular biology of pediatric gliomas

The genes involved in the genesis and progression of adult astrocytic tumors have been an area of considerable investigation. The tumor suppressor gene, p53, has been implicated, as has the epidermal growth factor receptor gene. Additional currently unidentified genes lie on chromosomes 10 and 19. Interestingly, work on pediatric astrocytomas suggests that the genes involved are different. p53 is rarely mutated in pediatric tumors, the epidermal growth factor receptor gene is rarely amplified or mutated, and chromosome 10 deletions are rare. The only pediatric tumor that seems to mimic the findings in adult tumors is brainstem glioma, perhaps explaining the uniformly grim prognosis in this type of tumor. In the pilocytic astrocytoma of childhood, mutations in the neurofibromatosis type I gene have been implicated in tumor development. In this review, the oncogenesis of pediatric gliomas is discussed and compared and contrasted to what is known about tumors.     

Agreement between pediatric brain tumor patients and parent proxy reports regarding the Pediatric Functional Assessment of Cancer Therapy–Childhood Brain Tumor Survivors questionnaire,version 2

BACKGROUND:

This study investigated the agreement between self‐reports from pediatric brain tumor patients and proxy reports from their parents regarding the patients' quality of life (QOL), as assessed using a brain tumor‐specific QOL assessment tool, the Pediatric Functional Assessment of Cancer Therapy‐Childhood Brain Tumor Survivors (pedsFACT‐BrS) questionnaire. The authors expected moderate correlation and similar mean scores between patient and parent reports.

METHODS:

The pedsFACT‐BrS for those aged 7 to 18 years was completed by 351 brain tumor patients (166 children and 185 adolescents), and the parent proxy reports were completed by 351 mother proxies and 37 father proxies. Statistical analyses, including the Pearson product‐moment correlation coefficient, intraclass correlation, and comparison of group means, were used to compare the 33 items shared by all 4 versions of the pedsFACT‐BrS.

RESULTS:

The correlation between reports completed by pediatric patients and their parent proxies was significant (P = .59‐.84), whereas that between the reports of adolescent patients and their parent proxies was slightly weaker (P = .47‐.78). The patient and parent proxy reports showed moderate‐to‐good agreement and yielded similar mean scores in both the child and adolescent brain tumor patient groups; the sole exception was a difference in emotional well‐being scores.

CONCLUSIONS:

The results indicate that proper use of the pedsFACT‐BrS for patients and their parent proxies can provide clinicians with valid information about the overall QOL of child and adolescent brain tumor patients, including both their general health and their brain tumor‐specific well‐being. Cancer 2010. © 2010 American Cancer Society.     

Parental optimism in poor prognosis pediatric cancers

Objective: The objectives were to describe parent‐rated and physician‐rated prognosis in a wide range of pediatric cancers and to describe the prevalence and predictors of parental prognostic optimism in poor prognosis pediatric cancer patients. Methods: This Canadian multi‐institutional cross‐sectional study included children with cancer receiving any type of active treatment. The primary caregiver rated child prognosis on a 5‐point categorical rating scale. For each child, five pediatric oncologists rated prognosis according to child‐ and disease‐related characteristics. Results: Of the 395 included families, 42 (10.6%) of parents rated prognosis as excellent or very good for children in whom physicians rated prognosis as poor. In multiple regression analysis, in comparison to parents of children with leukemia and lymphoma, parents of children with solid tumors (odds ratio (OR) 11.3, 95% CI 4.6, 27.8; P=0.0009) and brain tumors (OR 7.5, 95% CI 2.7, 21.1; P=0.09), parents of children with relapsed disease (OR 10.7, 95% CI 3.6, 31.3; P<0.0001) and parents with greater dispositional optimism (OR 1.1, 95% CI 1.0, 1.2; P=0.008) were more likely to have optimistic prognostic estimates in the setting of physician‐rated poor prognosis. Conclusion: Approximately 10% of parents have optimistic prognostic estimates in the setting of physician‐rated poor prognosis. Families of children with solid tumors and relapsed cancer and parents who were more optimistic were more likely to be optimistic in the poor prognosis setting. More research is needed to understand the impact of such discrepancies in prognosis on processes and outcomes. Copyright © 2008 John Wiley & Sons, Ltd.