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.     

Guideline for the Treatment of Breakthrough and the Prevention of Refractory Chemotherapy‐Induced Nausea and Vomiting in Children With Cancer

This clinical practice guideline provides an approach to the treatment of breakthrough chemotherapy‐induced nausea and vomiting (CINV) and the prevention of refractory CINV in children. It was developed by an international, interprofessional panel and is based on systematic literature reviews. Evidence‐based interventions for the treatment of breakthrough and prophylaxis of refractory CINV are recommended. Gaps in the evidence used to support the recommendations made in this clinical practice guideline were identified. The contribution of these recommendations to breakthrough and refractory CINV control in children requires prospective evaluation.     

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.     

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.     

Aprepitant for the control of chemotherapy induced nausea and vomiting in adolescents

Nausea and vomiting are common side effects of chemotherapy in adult and pediatric patients. Even with standard antiemetic therapy, a significant number of patients continue to experience acute and delayed symptoms. When used in combination with standard antiemetic therapy, a new class of antiemetics, the neurokinin-1 (NK-1) receptor antagonists, have been shown to improve both acute and delayed nausea and vomiting in adults. In this report, we describe the NK-1 receptor antagonist aprepitant in two adolescent patients receiving highly emetogenic chemotherapy who had experienced refractory nausea and vomiting with previous chemotherapy courses. The addition of aprepitant to the antiemetic regimen in the patients resulted in significant subjective improvement in nausea and vomiting as well as quality of life. These results in our adolescent patients are promising, but there is a need for well-designed studies to determine the efficacy, dosing, and safety of aprepitant in children of all ages.     

Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients

This guideline provides clinicians caring for children with an approach to assessing the acute emetogenic potential of antineoplastic therapies. It was developed by an international, inter-professional panel of clinicians and researchers using AGREE and CAN-ADAPTE methods. The emetogenicity of antineoplastic agents was evaluated and ranked as high, moderate, low, or minimal. The emetogenicity of multiple-agent and multiple-day antineoplastic therapy was also classified. Gaps in the evidence used to underpin the guideline recommendations were identified. The contribution of this guideline to the prevention of antineoplastic-induced nausea and vomiting in individual children about to receive antineoplastic therapy requires prospective evaluation.     

Prophylaxis of acute chemotherapy‐induced nausea and vomiting in children with cancer: What is the evidence?

BACKGROUND: Nausea and vomiting are preventable side effects of cancer chemotherapy for children. Antiemetics are essential, especially as treatment becomes more intensive. Many drugs are available, but adequate evidence-based recommendations are lacking. We aimed (1) to consider an evidence-based approach for pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in children, and (2) to compare this approach with antiemetic prescribing in two paediatric oncology centres. PROCEDURE: Relevant publications (Medline, Embase, CancerLit:1966-2002) were critically evaluated using pre-defined criteria. Evidence-based statements summarising their findings were formulated, and evidence basis proposed. Current prescribing practice was then compared with this evidence basis in Welsh children under 16 receiving chemotherapy at Llandough Hospital, Cardiff or Alder Hey Children's Hospital, Liverpool between 1 January 2001 and 31 December 2001. RESULTS: Of 213 studies retrieved, 82 provided evidence. Our evidence basis recommends combination 5HT3-antagonist/corticosteroid for highly emetogenic chemotherapy, 5HT3-antagonist alone for moderate emetogenicity, and no antiemetic for other chemotherapy. Forty-four children in Cardiff (0.6-16.9 yrs) and 14 in Liverpool (0.8-16.2 yrs) were included in the audit. Differences in prescribing practice between the centres were not significant. In 109/159 (69%) of chemotherapy courses (35, 87 and 100% of high, moderate and low emetogenicity, respectively), antiemetics were selected in accordance with evidence basis. Seventy percent of prescribed doses were as evidence basis recommended. CONCLUSIONS: We present an evidence basis for prescribing prophylactic antiemetics to children undergoing chemotherapy. Prescribing practices in these two centres treating Welsh children were similar. Both differed from the evidence basis we propose. Deviations were greatest for regimens of high emetogenicity, where effective emetic control is most crucial.     

Prevention of Emesis by Tropisetron in Children Receiving Combined Chemotherapy with Cisplatin

We evaluated the antiemetic efficacy of tropisetron, a 5-HT3 receptor antagonist, during its use in 15 children with malignant disease who received cisplatin (CDDP) either alone (1/15) or in combination (14/15) with other cytostatic drugs. Tropisetron was given to 15 children (8 boys and 7 girls, ranging from 6 months to 17 years of age) with miscellaneous neoplasms. Generally, tropisetron (5 mg/m²/day, maximum 5 mg/day) was administered intravenously the first day of CDDP-based chemotherapy and orally for 4 subsequent days of chemotherapy. The dose of tropisetron was reduced to 0.2 mg/kg/day in children less than 1 year of age and/or those weighing less than 10 kg. Vomiting and nausea were controlled completely in 8 of 15 (53.3%) children on day 1 with a single intravenous infusion of tropisetron. Partial control was observed in 40% of patients on day 1. Complete control of delayed nausea and vomiting ranged between 40% and 80% in patients over days 2 to 5. The results obtained during administration of tropisetron confirm that it is a valid, safe, and manageable antiemetic for the treatment of malignant disease in pediatric patients.     

Delayed nausea and vomiting in children receiving antineoplastics

BACKGROUND: The nature and prevalence of delayed antineoplastic-induced nausea and vomiting have not been well-described in children. This study describes the extent of delayed nausea and vomiting in children receiving antineoplastic agents as well as the drug therapies initiated in an attempt to prevent or manage it. PROCEDURE: All children receiving antineoplastics were eligible for study entry. The date and time of each emetic episode were recorded on each day antineoplastics were given and for 3 days thereafter. Nausea was self-assessed daily by children who were older than 3 years and were not developmentally delayed. Diet was also assessed daily. The emetic response, median nausea rating and median diet achieved were described. RESULTS: The emetic response of 124 children who received 174 antineoplastic cycles was evaluated. Most cycles (137/174;79%) were not associated with delayed vomiting. Cycles which included cisplatin, carboplatin, or cyclophosphamide; involved antineoplastic therapy given over 2 or more consecutive days; or were accompanied by vomiting during the acute phase were associated with a significantly higher incidence of delayed vomiting. Moderate to severe nausea was reported on 58% (267/459) of study days. No antiemetics were given on most study days (412/522;79%); nevertheless, most of the study days (381/412;93%) which were unaccompanied by antiemetic support during the delayed phase were completely free from vomiting. Antiemetics were most often given as single agents (ondansetron: 54 study days; dimenhydrinate: 17 study days; dexamethasone: 6 study days). Diet was largely unaffected during the study period. CONCLUSIONS: Antineoplastic-induced delayed nausea and vomiting may be less prevalent in children than in adults. Routine antiemetic administration during the delayed phase may not be warranted in all patients. Med Pediatr Oncol 2001;37:115-121.     

Single-Dose Oral Granisetron Versus MultiDose Intravenous Ondansetron for Moderately Emetogenic Cyclophosphamide-Based Chemotherapy in Pediatric Outpatients with Acute Lymphoblastic Lukemia

This prospective study was designed to compare the efficacy of ondansetron with granisetron in terms of complete emesis control and time spent in an ambulatory care setting in children with acute lymphoblastic leukemia (ALL) undergoing moderately emetogenic cyclophosphamide-based chemotherapy.The costs for both treatments are also examined. A total of 33 children (mean age: 7.8 ± 4.9 year) were studied during 66 chemotherapy cycles. Analysis was based on 33 courses of a single oral dose of granisetron and 33 courses of ondansetron incorporating 2 intravenous doses of ondansetron 0.15 mg/kg followed by 1 dose of the same dosage orally. There was no significant difference between the 2 treatments in terms of overall efficacy (McNemar's chi-square test). Twenty of 33 patients (60.6%) receiving granisetron and 15 of 33 patients (45.5%) receiving ondansetron experienced no emesis 24 h after chemotherapy (p = .227). Boys experienced greater rates of vomiting than did girls despite antiemetic treatment; however, no apparent reason for the gender discrepancy was noted. Both antiemetic regimens have similar antiemetic efficacy for treating the moderately emetogenic effects associated with cyclophosphamide-based chemotherapy. It is possible that the granisetron regimen may be preferable because it is simpler to administer and more cost-effective.     

Single-dose oral granisetron versus multidose intravenous ondansetron for moderately emetogenic cyclophosphamide-based chemotherapy in pediatric outpatients with acute lymphoblastic leukemia

This prospective study was designed to compare the efficacy of ondansetron with granisetron in terms of complete emesis control and time spent in an ambulatory care setting in children with acute lymphoblastic leukemia (ALL) undergoing moderately emetogenic cyclophosphamide-based chemotherapy.The costs for both treatments are also examined. A total of 33 children (mean age: 7.8 ± 4.9 year) were studied during 66 chemotherapy cycles. Analysis was based on 33 courses of a single oral dose of granisetron and 33 courses of ondansetron incorporating 2 intravenous doses of ondansetron 0.15 mg/kg followed by 1 dose of the same dosage orally. There was no significant difference between the 2 treatments in terms of overall efficacy (McNemar's chi-square test). Twenty of 33 patients (60.6%) receiving granisetron and 15 of 33 patients (45.5%) receiving ondansetron experienced no emesis 24 h after chemotherapy (p = .227). Boys experienced greater rates of vomiting than did girls despite antiemetic treatment; however, no apparent reason for the gender discrepancy was noted. Both antiemetic regimens have similar antiemetic efficacy for treating the moderately emetogenic effects associated with cyclophosphamide-based chemotherapy. It is possible that the granisetron regimen may be preferable because it is simpler to administer and more cost-effective.     

Electrocardiographic findings after 5-HT3 receptor antagonists and chemotherapy in children with cancer

BACKGROUND: The antiemetic efficacy of serotonin-type 3 (5-HT3) receptor antagonists has been found to be superior to older antiemetic drugs in cancer patients. Following the administration of these agents, changes in ECG parameters and increased or decreased heart rates have been demonstrated, but there is no sufficient data in children with cancer who are treated with cytotoxic agents. The objective of this study is to evaluate the ECG changes after administration of 5-HT3 receptor antagonists and chemotherapeutic agents in children with cancer. PROCEDURE: Thirty-eight patients with an age range between 2 and 19 years receiving chemotherapy for solid tumors were included in the study. The patients received 5-HT3 receptor antagonists 30 min before antineoplastic agents in 83 chemotherapy days. Antiemetic therapy consisted of ondansetron in 43 and granisetron in 40 chemotherapy days. Twelve-leads ECGs were obtained four times at the first day of each chemotherapy: just before 30, 90 min, and 24 hr after 5-HT3 receptor antagonists were given. Rate, rhythm, PR interval, QRS duration, ST segment, the shortest (QTca) and the longest (QTcb) QTc intervals with QTc dispersion (QTcd) were all evaluated. RESULTS: We found a significant shortening of the PR interval and QRS complex durations in the granisetron group at 90th min and at 24th hr, respectively. Also, granisetron infusion caused a significant prolongation of the QTca interval at 90 min. CONCLUSION: Although we observed minor ECG changes after 5-HT3 receptor antagonists and chemotherapy, neither dangerous rhythm disturbances nor serious ECG changes were seen.     

Children's Oncology Group's 2013 blueprint for research: Central nervous system tumors

In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5‐year survival ranges from >80% (standard‐risk) to 60% (high‐risk). For those with high‐grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5‐year survival remains <10%. Sixty‐five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk‐based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma. Pediatr Blood Cancer 2013; 60: 1022–1026. © 2012 Wiley Periodicals, Inc.     

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a “well‐controlled level” for an extended period in which the child patient can lead a trouble‐free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti‐inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well‐controlled level refers to a symptom‐free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.     

The duration of anthracycline infusion should be at least one hour in children with cancer: A clinical practice guideline

We aimed to provide recommendations on the infusion duration of anthracycline chemotherapy agents in children with cancer. This study also serves as a practice example of the essential steps that need to be taken when using a previously published systematic review to develop a high‐quality clinical practice guideline. Although evidence was scarce and included adult studies, the panel was able (using the Grading of Recommendations Assessment, Development and Evaluation evidence‐to‐decision framework) to recommend in favor of an anthracycline infusion duration of at least 1 hr (strong recommendation, very low to moderate quality of evidence). Recommending a precise optimal prolonged infusion duration was currently not possible.     

Safety and efficacy of a continuous infusion, patient-controlled antiemetic pump for children receiving emetogenic chemotherapy

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects of moderately or highly emetogenic chemotherapy. Diphenhydramine, lorazepam, and dexamethasone have been used individually to treat CINV. The objective of this study was to evaluate the safety and potential efficacy of those drugs administered via a patient controlled pump (BAD pump) to control CINV. PROCEDURE: A retrospective chart review was conducted of all pediatric oncology patients who received the BAD pump. Emetic episodes, doses of rescue medications to treat breakthrough nausea or vomiting, and occurrence of adverse events were recorded. Complete response (CR) was defined as no emesis or rescue medications, partial response (PR) as emesis but no rescue medications, and failure (F) as rescue medications required. RESULTS: Thirty patients received a total of 141 courses. Adverse events occurred in 4.2% of the courses; confusion (n = 2), depressed mood (n = 1), dysphoria (n = 1), agitation (n = 1), and restlessness (n = 1). All side effects resolved after decreasing the infusion rate, and the pump was not discontinued in any patients. Eighteen patients failed conventional prophylaxis and received BAD pump for identical subsequent chemotherapy cycles; they spent more days in CR with BAD pump than without it, 21 versus 45 days (P = .003) respectively. Patients receiving BAD pump had significantly shorter hospital stay with BAD pump than those not receiving it, 68 days versus 76 (P = .046). CONCLUSIONS: BAD pump is well tolerated in pediatric patients receiving chemotherapy and may be more effective than conventional prophylaxis in controlling CINV in some patients.     

Oral Ondansetron: An Effective Ambulatory Complement to Intravenous Ondansetron in the Control of Chemotherapy-Induced Nausea and Vomiting in Children

One hundred children with non-central nervous system malignancies received ondansetron at initiation of chemotherapy and every 8 hours for 5 days after cisplatin-containing therapy and for 3 days after other chemotherapy. Ondansetron was administered orally except with the intravenous chemotherapy. For the chemotherapy days, 72 of 93 children (76%) had complete or major control of vomiting on their worst day, 25% with cisplatin-containing protocols, 60% with ifosfamide-containing protocols, and 82% with other protocols. For the overall period, 71 of 93 children (76%) reported complete or major control of vomiting on the worst day, 14% with cisplatin, 60% with ifosfamide, and 83% with other chemotherapy. All had mild or no nausea. Of the 355 chemotherapy days, 228 children (64%) were emesisfree, 40% with cisplatin, 60% with ifosfamide, and 68% with other regimens. Of the overall period (541 days), 393 days were emesisfree, 45% with cisplatin, 71% with ifosfamide, and 86% with other regimes. Sixty-nine patients were not hospitalized, and oral ondansetron was given when chemotherapy was completed. Of the 241 ambulatory chemotherapy days, 178 (74%) were emesisfree. No significant toxicity was encountered. Oral ondansetron reduced hospitalization without reducing antiemetic efficiency in children.     

Children's Oncology Group's 2013 blueprint for research: Soft tissue sarcomas

In the US, approximately 850–900 children are diagnosed each year with soft tissue sarcomas (STS). Key findings from recent Children's Oncology Group (COG) clinical trials include safe reduction in therapy for low risk rhabdomyosarcoma (RMS), validation of FOXO1 fusion as a prognostic factor, a modest improvement in outcome for high‐risk RMS, and a biologically designed non‐cytotoxic therapy for pediatric desmoid tumor. Planned Phase 2 trials include targeted agents for VEGF/PDGF, mTOR, and IGF‐1R for children with RMS and VEGF for children with non‐RMS STS (NRSTS). For RMS, COG Phase 3 trials potentially will explore VEGF/mTOR inhibition or chemotherapy interval compression. For NRSTS, a COG Phase 3 trial will explore VEGF inhibition. Pediatr Blood Cancer 2013; 60: 1001–1008. © 2012 Wiley Periodicals, Inc.     

COMPARISON OF TROPISETRON AND GRANISETRON IN THE CONTROL OF NAUSEA AND VOMITING IN CHILDREN RECEIVING COMBINED CANCER CHEMOTHERAPY

Tropisetron and granisetron are selective serotonin (5-HT 3 ) antagonists that have been proven effective in the prevention of nausea and vomiting in adults and children receiving cancer chemotherapy. This prospective, randomised study was designed to compare the efficacy of the two agents in the prevention of vomiting and nausea in children receiving highly emetogenic chemotherapy for various malignancies. A total of 51 children (mean age: 7.7 &#45 4.8 year) were studied in 133 chemotherapy cycles. In 66 chemotherapy cycles, the children received tropisetron as an antiemetic agent in a dose of 0.2 mg/kg/24 h intravenously and, in 67 cycles, they received granisetron 40 &#119 g/kg/24 h intravenously before cytotoxic drug administration during the days they received chemotherapy. The response per 24 h of chemotherapy was defined as complete (no nausea and vomiting), partial (1-4 events of vomiting and/or nausea), and failure (more than 4 events o fvomiting and/or nausea). Efficacy of antiemetic therapy was evaluatedas acute (Day 1) and overall was based on the worst day during the chemotherapy. Complete control of acute vomiting was achieved in 74% of tropisetron and 88% of granisetron patients ( P = 0.04), and complete control of acute nausea in 56% and 82% respectively ( p = 0.002). Overall response by means of complete control of both vomiting and nausea during the whole therapy period was 29% of tropisetron group and 55% of granisetron group ( p = 0.007). The statistical analysis (depending on the emetogenicity of the chemotherapy cycles) showed increased efficacy of granisetron in highly (grade 3) emetogenic chemotherapy cycles ( p = 0.002), whereas there was no differencein the very highly emetogenic cycles ( p = 0.7). Also, granisetron was found to be more effective than tropisetron, especially in patients heavier than 25 kg ( p = 0.02). The adverse reactions were few and mild. There were no differences in the tolerability of the two antiemetic therapy modalities. In conclusion, granisetron was found to be more effective than tropisetron in controlling nausea and vomiting in children receiving highly emetogenic chemotherapy. This increased antiemetic efficacy of granisetron might have been related to maximal dose differences according to body weight.