A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.

Palliative care for children: methodology for the development of a national clinical practice guideline.

BACKGROUND: Provision of paediatric palliative care for children with life-threatening or life-limiting conditions and their families is often complex. Guidelines can support professionals to deliver high quality care. Stakeholders expressed the need to update the first Dutch paediatric palliative care guideline with new scientific literature and new topics. This paper provides an overview of the methodology that is used for the revision of the Dutch paediatric palliative care guideline and a brief presentation of the identified evidence. METHODS: The revised paediatric palliative care guideline was developed with a multidisciplinary guideline panel of 72 experts in paediatric palliative care and nine (bereaved) parents of children with life-threatening or life-limiting conditions. The guideline covered multiple topics related to (refractory) symptom treatment, advance care planning and shared-decision making, organisation of care, psychosocial care, and loss and bereavement. We established six main working groups that formulated 38 clinical questions for which we identified evidence by updating two existing systematic literature searches. The GRADE (CERQual) methodology was used for appraisal of evidence. Furthermore, we searched for additional literature such as existing guidelines and textbooks to deal with lack of evidence. RESULTS: The two systematic literature searches yielded a total of 29 RCTs or systematic reviews of RCTs on paediatric palliative care interventions and 22 qualitative studies on barriers and facilitators of advance care planning and shared decision-making. We identified evidence for 14 out of 38 clinical questions. Furthermore, we were able to select additional literature (29 guidelines, two textbooks, and 10 systematic reviews) to deal with lack of evidence. CONCLUSIONS: The revised Dutch paediatric palliative care guideline addresses many topics. However, there is limited evidence to base recommendations upon. Our methodology will combine the existing evidence in scientific literature, additional literature, expert knowledge, and perspectives of patients and their families to provide recommendations.

Pain monitoring app leads to less pain in children with cancer at home: Results of a randomized controlled trial.

BACKGROUND: The authors developed a pain monitoring app offering educational information, and real-time health care professional feedback on clinically significant pain (>4 numeric rating scale [NRS]-11) for children with cancer to reduce pain at home. METHODS: This monocenter, nonblinded randomized controlled trial enrolled Dutch children (0-18 years old) receiving cancer treatment (≥3 months after diagnosis, ≥2 months treatment remaining). Children were randomly assigned to use the app or receive usual care (two parallel groups). We assessed whether use of the app yielded less clinically significant pain (aim 1) and whether it affected pain severity, duration, interference, pain management strategies, and parental emotional well-being (aim 2). The app was also evaluated by families (aim 3). RESULTS: A total of 94 children were randomized to use the app (15 drop-outs), and 90 were to receive care as usual (11 drop-outs). The app group (n = 79, mean age: 7.5 [5.1] years, 48% girls, 63% hemato-oncology diagnosis) reported significantly less clinically significant pain compared to usual care (n = 79, mean age: 7.5 [5.4] years, 52% girls, 65% hemato-oncology diagnosis) (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.198-0.734]) (aim 1), as well as significantly lower pain severity (ß = -0.27; 95% CI, -0.407 to -0.142). No differences were found for duration, interference, or management strategies. Parents in the app group reported significantly less distress compared to usual care (ß = -0.84; 95% CI, -1.61 to -0.03]) (aim 2). Families generally evaluated the app positively (aim 3). CONCLUSIONS: Use of the app resulted in less clinically significant pain at home. The exact working mechanisms of the app should be further elucidated.

Palliative Care for Childhood Cancer.

Cure rates for children with cancer are improving, but often at the cost of quality of life during treatment [...].

Reducing pain in children with cancer at home: a feasibility study of the KLIK pain monitor app.

PURPOSE: This study assessed adherence to, feasibility of, and barriers and facilitators of implementation of an app developed to monitor and follow-up with pain in children with cancer at home. METHODS: Children (8-18 years) receiving cancer treatment (all diagnoses) or their parents (of children aged 0-7 years) used the KLIK Pain Monitor app for 3 weeks. Pain was assessed twice daily using an 11-point numeric rating scale (NRS-11) (ranging from 0 to 10). Healthcare professionals (HCP's) from the hospital's Pediatric Pain Service were instructed to follow-up with clinically significant pain scores (≥ 4) within 120 min (scores 4-6) or 30 min (scores 7-10). Adherence, feasibility, and implementation outcomes were assessed using questionnaires, app log data, and interviews. RESULTS: Twenty-seven children (M age = 7.3 years, 51.8% male) and six HCP's participated. Sixty-three percent (N = 17) of families used the app on a daily basis during three weeks, and 18.5% (N = 5) reported pain scores twice daily during that time (family adherence). Twelve out of 27 children (44.4%) reported a clinically significant pain score at least once. In 70% (14/20) of clinically significant pain scores, HCP's followed-up with families within the set timeframe (HCP adherence). Outcomes reveal feasibility for the majority of app functions (i.e., positive evaluation by ≥ 70% families/HCP's), and non-feasible aspects could be resolved. Identified barriers and facilitators were used to improve future implementation efforts. CONCLUSION: Use of the KLIK Pain Monitor app seems feasible. Future research will determine its effectiveness in reducing pain in children with cancer at home.

High Prevalence of Weight Gain in Childhood Brain Tumor Survivors and Its Association With Hypothalamic-Pituitary Dysfunction.

PURPOSE: Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS. METHODS: Prevalence of and risk factors for significant weight gain (body mass index [BMI] change ≥ +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors. RESULTS: Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS. CONCLUSION: Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance.

Pain at home during childhood cancer treatment: Severity, prevalence, analgesic use, and interference with daily life.

BACKGROUND: Pain is a common symptom in childhood cancer. Since children spend more time at home, families are increasingly responsible for pain management. This study aimed at assessing pain at home. PROCEDURE: In this longitudinal observational study (April 2016-January 2017), pain severity and prevalence, analgesic use, and pain interference with daily life (Brief Pain Inventory Short Form) were assessed for 4 consecutive days around the time of multiple chemotherapy appointments. Descriptive statistics (frequencies and percentages) were used to report pain severity (with clinically significant pain defined as: score ≥ 4 on "worst pain" or "average pain in the last 24 h"), pain prevalence, and analgesic use. Mixed models were estimated to assess whether patient characteristics were associated with pain severity, and whether pain severity was associated with interference with daily life. RESULTS: Seventy-three children (50.7% male) participated (1-18 years). A majority (N = 57, 78%) experienced clinically significant pain at least once, and 30% reported clinically significant pain at least half the time. In 33.6% of scores ≥ 4, no medication was used. We found an association between pain severity and interference with daily life: the higher the pain, the bigger the interference (estimated regression coefficient = 1.01 [95% CI 0.98-1.13]). CONCLUSIONS: The majority of children experienced clinically significant pain at home, and families frequently indicated no medication use. A stronger focus on education and coaching of families seems essential, as well as routine screening for pain in the home setting.

Declining free thyroxine levels over time in irradiated childhood brain tumor survivors.

OBJECTIVE: The incidence of cranial radiotherapy (cRT)-induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS. DESIGN: Nationwide, 10-year retrospective study of irradiated CBTS. METHODS: TSHD was defined as 'diagnosed' when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as 'presumed' when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test). RESULTS: Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9-9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P < 0.01) to diagnosis of TSHD and 12.4% (P = 0.02) in GH-deficient CBTS without diagnosed TSHD. CONCLUSIONS: FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.

Very long-term sequelae of craniopharyngioma.

OBJECTIVE: Studies investigating long-term health conditions in patients with craniopharyngioma are limited by short follow-up durations and generally do not compare long-term health effects according to initial craniopharyngioma treatment approach. In addition, studies comparing long-term health conditions between patients with childhood- and adult-onset craniopharyngioma report conflicting results. The objective of this study was to analyse a full spectrum of long-term health effects in patients with craniopharyngioma according to initial treatment approach and age group at craniopharyngioma presentation. DESIGN: Cross-sectional study based on retrospective data. METHODS: We studied a single-centre cohort of 128 patients with craniopharyngioma treated from 1980 onwards (63 patients with childhood-onset disease). Median follow-up since craniopharyngioma presentation was 13 years (interquartile range: 5-23 years). Initial craniopharyngioma treatment approaches included gross total resection (n = 25), subtotal resection without radiotherapy (n = 44), subtotal resection with radiotherapy (n = 25), cyst aspiration without radiotherapy (n = 8), and 90Yttrium brachytherapy (n = 21). RESULTS: Pituitary hormone deficiencies (98%), visual disturbances (75%) and obesity (56%) were the most common long-term health conditions observed. Different initial craniopharyngioma treatment approaches resulted in similar long-term health effects. Patients with childhood-onset craniopharyngioma experienced significantly more growth hormone deficiency, diabetes insipidus, panhypopituitarism, morbid obesity, epilepsy and psychiatric conditions compared with patients with adult-onset disease. Recurrence-/progression-free survival was significantly lower after initial craniopharyngioma treatment with cyst aspiration compared with other therapeutic approaches. Survival was similar between patients with childhood- and adult-onset craniopharyngioma. CONCLUSIONS: Long-term health conditions were comparable after different initial craniopharyngioma treatment approaches and were generally more frequent in patients with childhood- compared with adult-onset disease.

Home-Based Palliative Care for Children With Incurable Cancer: Long-term Perspectives of and Impact on General Practitioners.

CONTEXT: Although a large percentage of children with advanced-stage cancer die at home, remarkably little information is available regarding the experience of general practitioners (GPs) with respect to providing home-based palliative care to children with incurable cancer. OBJECTIVES: The objective of this study was to explore the perspectives of GPs who care for children with advanced-stage cancer in a home-based setting. METHODS: In this cross-sectional study, 144 GPs who provided home-based palliative care to 150 children with incurable cancer from 2001 through 2010 were invited to complete a questionnaire addressing their perspectives regarding: 1) symptom management, 2) collaboration with other health care professionals, 3) the child's death and care after death, and 4) impact of having provided palliative care, scored on distress thermometer (range 0-10). RESULTS: A total of 112 GPs (78%) responded, and 91 GPs completed the questionnaire for 93 patients. The median interval between the child's death and completing the questionnaire was seven years. The most prevalent symptoms reported in the patients were fatigue (67%) and pain (61%). Difficulties with communicating with (14%), coordinating with (11%), collaborating with (11%), and contacting (2%) fellow members of the multidisciplinary treatment team were rare. Hectic (7%) and shocking (5%) situations and panic (2%) around the child's death were rare. GPs reported feelings of sadness (61%) and/or powerlessness (43%) around the time of the patient's death, and they rated their own distress level as relatively high during the terminal phase (median score 6, range 0-9.5). The majority of GPs (94%) reported that they ultimately came to terms with the child's death. CONCLUSION: In general, GPs appear to be satisfied with the quality of home-based palliative care that they provide pediatric patients with incurable cancer. Communication among health care professionals is generally positive and is considered important. Finally, although the death of a pediatric patient has a profound impact on the GP, the majority of GPs eventually come to terms with the child's death.

Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study.

Purpose To evaluate the prevalence of, and risk factors for, early endocrine disorders in childhood brain tumor survivors (CBTS). Patients and Methods This nationwide study cohort consisted of 718 CBTS who were diagnosed between 2002 and 2012, and who survived ≥ 2 years after diagnosis. Patients with craniopharyngeoma or a pituitary gland tumor were excluded. Results of all endocrine investigations, which were performed at diagnosis and during follow-up, were collected from patient charts. Multivariable logistic regression was used to study associations between demographic and tumor- and treatment-related variables and the prevalence of early endocrine disorders. Results After a median follow-up of 6.6 years, 178 CBTS (24.8%) were diagnosed with an endocrine disorder. A total of 159 CBTS (22.1%) presented with at least one endocrine disorder within the first 5 years after diagnosis. The most common endocrine disorders were growth hormone deficiency (12.5%), precocious puberty (12.2%), thyroid-stimulating hormone deficiency (9.2%), and thyroidal hypothyroidism (5.8%). The risk of hypothalamic-pituitary dysfunction (n = 138) was associated with radiotherapy (odds ratio [OR], 15.74; 95% CI, 8.72 to 28.42), younger age at diagnosis (OR, 1.09; 95% CI, 1.04 to 1.14), advanced follow-up time (OR, 1.10; 95% CI, 1.02 to 1.18), hydrocephalus at diagnosis (OR, 1.77; 95% CI, 1.09 to 2.88), and suprasellar (OR, 34.18; 95% CI, 14.74 to 79.29) and infratentorial (OR, 2.65; 95% CI, 1.48 to 4.74) tumor site. Conclusion The prevalence of early endocrine disorders among CBTS is high. The observation that 22.1% of CBTS developed at least one endocrine disorder within the first 5 years after diagnosis stresses the importance of early and regular assessment of endocrine function in CBTS who are at risk for endocrine damage.

Current variations in childhood cancer supportive care in the Netherlands.

BACKGROUND: Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers. METHODS: Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in ≥ 5 of 6 centers), partly concordant (highly overlapping in ≥ 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines. RESULTS: The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence-based guidelines varied but was generally low. CONCLUSIONS: Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer.

Risk-adapted approach for fever and neutropenia in paediatric cancer patients--a national multicentre study.

BACKGROUND: In this national multicentre study, we examined the safety of reducing antibiotics in selected paediatric cancer patients with febrile neutropenia. METHODS: Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk and received antibiotic therapy. Remaining patients were allocated to low- or medium risk, depending on their interleukin-8 level. Low-risk patients did not receive any antibiotics and were discharged from the hospital after having been afebrile for 12 h. Medium-risk patients were re-evaluated after 72 h of antibiotic treatment and, in selected patients, antibiotics were stopped. RESULTS: Two hundred thirty-three febrile neutropenic episodes in 141 paediatric cancer patients were included in the study. Sixty-four episodes were classified high risk (28%), 122 medium risk (52%), and 47 (20%) low risk. In the medium-risk group, antibiotics were stopped after 72 h in 50 in 122 episodes (41%). Median duration of antibiotic treatment and hospital admission was significantly lower in low- and medium-risk episodes with early discharge. No failures were observed in the medium-risk group with early discharge. In the low-risk group, six failures were observed (12.8%), due to coagulase-negative staphylococci-positive blood cultures and recurrent fever. CONCLUSION: We showed that it is safe to shorten antibiotic treatment to 72 h in selected medium-risk patients with febrile neutropenia, regardless of the neutrophil count. The safety of withholding antibiotics in selected low-risk paediatric cancer patients with febrile neutropenia requires further investigation, using more suitable definitions for safety. Reduction in hospital admissions allows children with cancer more time at home and consequently improves their quality of life.

Talking about Death with Children with Incurable Cancer: Perspectives from Parents.

OBJECTIVE: To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer. STUDY DESIGN: We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conversation regarding death occurred. The data were analyzed qualitatively using a framework approach. RESULTS: Of the 86 parents of 56 children who answered the questions regarding discussing death with their child, 55 parents of 35 children did not discuss the impending death with their child. The following themes were identified: the parents' inability to discuss the impending death; the parents' desire to protect their child; views regarding talking with children; parents' views of child characteristics; the child's unwillingness to discuss the subject; lack of opportunity to talk; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they had brief, direct conversations regarding death. The majority of parents felt positive regarding their decision about whether to talk with their child about his/her impending death. CONCLUSION: Most parents in this study cited several reasons for not discussing death with their child. Our findings highlight the sensitive and complex issues surrounding these conversations, indicating that there may be a role for clinicians in supporting parents.

Chemotherapy for children with medulloblastoma.

BACKGROUND: Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children. PRIMARY OBJECTIVES: 1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment. SECONDARY OBJECTIVES: to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results. MAIN RESULTS: The search identified seven RCTs, including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The meta-analysis of EFS/DFS not including disease progression during therapy as an event in the definition showed a difference in favour of treatment including chemotherapy (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54 to 0.91; P value = 0.007; 2 studies; 465 children). However, not including disease progression as an event might not be optimal and the finding was not confirmed in the meta-analysis of EFS/DFS including disease progression during therapy as an event in the definition (HR 1.02; 95% CI 0.70 to 1.47; P value = 0.93; 2 studies; 300 children). Two individual studies using unclear or other definitions of EFS/DFS also showed no clear evidence of difference between treatment arms (one study with unclear definition of DFS: HR 1.67; 95% CI 0.59 to 4.71; P value = 0.34; 48 children; one study with other definition of EFS: HR 0.84; 95% CI 0.58 to 1.21; P value = 0.34; 233 children). In addition, it should be noted that in one of the studies not including disease progression as an event, the difference in DFS only reached statistical significance while the study was running, but due to late relapses in the chemotherapy arm, this significance was no longer evident with longer follow-up. There was no clear evidence of difference in OS between treatment arms (HR 1.06; 95% CI 0.67 to 1.67; P value = 0.80; 4 studies; 332 children). Out of eight reported adverse effects, of which seven were reported in one study, two (severe infections and fever/neutropenia) showed a difference in favour of treatment not including chemotherapy (severe infections: risk ratio (RR) 5.64; 95% CI 1.28 to 24.91; P value = 0.02; fever/neutropenia: RR not calculable; Fisher's exact P value = 0.01). There was no clear evidence of a difference between treatment arms for other adverse effects (acute alopecia: RR 1.00; 95% CI 0.92 to 1.08; P value = 1.00; reduction in intelligence quotient: RR 0.78; 95% CI 0.46 to 1.30; P value = 0.34; secondary malignancies: Fisher's exact P value = 0.5; haematological toxicity: RR 0.54; 95% CI 0.20 to 1.45; P value = 0.22; hepatotoxicity: Fisher's exact P value = 1.00; treatment-related mortality: RR 2.37; 95% CI 0.43 to 12.98; P value = 0.32; 3 studies). Quality of life was not evaluated. In individual studies, the results in subgroups (i.e. younger/older children and high-risk/non-high-risk children) were not univocal.The search found one RCT comparing standard-dose RT with reduced-dose RT plus chemotherapy. There was no clear evidence of a difference in EFS/DFS between groups (HR 1.54; 95% CI 0.81 to 2.94; P value = 0.19; 76 children). The RCT did not evaluate other outcomes and subgroups.The presence of bias could not be ruled out in any of the studies. AUTHORS' CONCLUSIONS: Based on the evidence identified in this systematic review, a benefit of chemotherapy cannot be excluded, but at this moment we are unable to draw a definitive conclusion regarding treatment with or without chemotherapy. Treatment results must be viewed in the context of the complete therapy (e.g. the effect of surgery and craniospinal RT), and the different chemotherapy protocols used. This systematic review only allowed a conclusion on the concept of treatment, not on the best strategy regarding specific chemotherapeutic agents and radiation dose. Several factors complicated the interpretation of results including the long time span between studies with important changes in treatment in the meantime. 'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The fact that no significant differences between treatment arms were identified could, besides the earlier mentioned reasons, also be the result of low power or too short a follow-up period. Even though RCTs are the highest level of evidence, it should be recognised that data from non-randomised studies are available, for example on the use of chemotherapy only in very young children with promising results for children without metastatic disease. We found only one RCT addressing standard-dose RT without chemotherapy versus reduced-dose RT with chemotherapy, so no definitive conclusions can be made. More high-quality research is needed.

Parents' Faith and Hope during the Pediatric Palliative Phase and the Association with Long-Term Parental Adjustment.

BACKGROUND: The loss of a child is associated with an increased risk for developing psychological problems. However, studies investigating the impact of parents' faith and hope for a cure during the palliative phase on long-term parental psychological functioning are limited. OBJECTIVE: The study's objective was to explore the role of faith and hope as a source of coping and indicator of long-term parental adjustment. METHODS: Eighty-nine parents of 57 children who died of cancer completed questionnaires retrospectively, exploring faith, hope, and sources of coping, and measuring parents' current level of grief and depression. RESULTS: For 19 parents (21%) faith was very important during the palliative phase. The majority of parents remained hopeful for a meaningful time with their child (n=68, 76%); a pain-free death (n=58, 65%); and a cure (n=30, 34%). Their child (n=70, 79%) was parents' main source of coping. Twelve parents (14%) suffered from traumatic grief, and 22 parents (25%) showed symptoms of depression. Parents' faith was not associated with less long-term traumatic grief (OR=0.86, p=0.51) or symptoms of depression (OR=0.95, p=0.74), and parents' hope for a cure was not related to more long-term traumatic grief (OR=1.07, p=0.71) or symptoms of depression (OR=1.12, p=0.47). CONCLUSIONS: Faith was important for a minority of parents and was not associated with less long-term traumatic grief or symptoms of depression. The majority of parents remained hopeful. Hope for a cure was not associated with more long-term traumatic grief or symptoms of depression.

Cytogenetic prognostication within medulloblastoma subgroups.

PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Parents' experiences of pediatric palliative care and the impact on long-term parental grief.

CONTEXT: Approximately 25% of children diagnosed with cancer eventually die. Losing a child puts parents at increased risk for developing psychological problems. OBJECTIVES: To explore parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement) and symptom management during the pediatric palliative phase, and to investigate the influence on long-term grief in parents who lost a child to cancer. METHODS: A total of 89 parents of 57 children who died of cancer between 2000 and 2004 participated in this retrospective cross-sectional study by completing a set of questionnaires measuring grief (Inventory of Traumatic Grief), parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement), and symptom management during the palliative phase. Care was assessed on a five point Likert scale (1=disagree and 5=agree). RESULTS: Parents highly rated communication (4.6±0.6), continuity of care (4.3±0.6), and parental involvement (4.6±0.7) during the palliative phase. Parents' most often reported physical and psychological symptoms of their child during the palliative phase were fatigue (75%), pain (74%), anxiety to be alone (52%), and anger (48%). Higher ratings of parents on communication (ß=-9.08, P=0.03) and continuity of care (ß=-11.74, P=0.01) were associated with lower levels of long-term parental grief. The severity of the child's dyspnea (ß=2.96, P=0.05), anxiety to be alone (ß=4.52, P<0.01), anxiety about the future (ß=5.02, P<0.01), anger (ß=4.90, P<0.01), and uncontrolled pain (ß=6.60, P<0.01) were associated with higher levels of long-term parental grief. Multivariate models combining the interaction with health care professionals and symptom management showed a significant influence of both aspects on long-term parental grief. CONCLUSION: Both interaction with health care professionals, especially communication and continuity of care, and symptom management in children dying of cancer are associated with long-term parental grief levels.

Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children.

BACKGROUND: Minimally invasive surgery (MIS) is an accepted surgical technique for the treatment of a variety of benign diseases. Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Diagnostic MIS to obtain biopsy specimens for pathology has been accepted as a technique in paediatric surgical oncology, but there is limited experience with the use of MIS for the resection of malignancies. OBJECTIVES: To ascertain the differences in outcome between the minimally invasive and open approach in the treatment of solid intra-thoracic and intra-abdominal neoplasms in children, regarding overall survival, event-free survival, port-site metastases, recurrence rate and surgical morbidity. SEARCH METHODS: We searched the electronic databases of MEDLINE/PubMed (from 1966 to February 2011), EMBASE/Ovid (from 1980 to February 2011) and CENTRAL (The Cochrane Library 2011, Issue 1) with pre-specified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing MIS and open surgery for the treatment of solid intra-thoracic or intra-abdominal neoplasms in children (aged 0 to 18 years). DATA COLLECTION AND ANALYSIS: Two authors performed the study selection independently. MAIN RESULTS: No studies that met the inclusion criteria of this review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs evaluating MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children could be identified, therefore no definitive conclusions could be made about the effects of MIS in these patients. Based on the currently available evidence we are not able to give recommendations for the use of MIS in the treatment of solid intra-thoracic or intra-abdominal neoplasms in children. More high quality studies (RCTs and/or CCTs) are needed. To accomplish this, centres specialising in MIS in children should collaborate.

Biological background of pediatric medulloblastoma and ependymoma: a review from a translational research perspective.

Survival rates of pediatric brain tumor patients have significantly improved over the years due to developments in diagnostic techniques, neurosurgery, chemotherapy, radiotherapy, and supportive care. However, brain tumors are still an important cause of cancer-related deaths in children. Prognosis is still highly dependent on clinical characteristics, such as the age of the patient, tumor type, stage, and localization, but increased knowledge about the genetic and biological features of these tumors is being obtained and might be useful to further improve outcome for these patients. It has become clear that the deregulation of signaling pathways essential in brain development, for example, sonic hedgehog (SHH), Wnt, and Notch pathways, plays an important role in pathogenesis and biological behavior, especially for medulloblastomas. More recently, data have become available about the cells of origin of brain tumors and the possible existence of brain tumor stem cells. Newly developed array-based techniques for studying gene expression, protein expression, copy number aberrations, and epigenetic events have led to the identification of other potentially important biological abnormalities in pediatric medulloblastomas and ependymomas.