Summary

The guideline drafted by an international panel of paediatric oncologists provides:

• Recommendations to deal with the consequential risk of acute emetogenicity- chemo-induced vomiting only in paediatric patients
• A framework for classification of 49 single-agent and 13 combination-agent chemotherapy regimens, so that clinicians can make the right choice of antiemetic prophylaxis for such patients

Chemotherapy-induced Nausea and Vomiting (CINV) is an unavoidable adverse effect observed in cancer patients being treated with chemotherapy. For chemotherapy-naïve paediatric patients, the potential emetogenicity of the prescribed chemotherapy regimen becomes one of the important factors of CINV and the choice of CINV prophylaxis. However, this CPG focuses on the prevention of CIV only.

This clinical practice guideline (CPG) addresses the risk of acute CIV in paediatric oncology patients when they are prescribed a type of chemotherapy, administered alone or as a combination.

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Scope of the clinical practice guideline

This CPG is one of the many in a series written on prevention and management of CIV in paediatric oncology patients but is not an update on any of the previous publications. It reflects evidence derived from a systematic review of a new set of paediatric oncology cases.

The scope of the recommendations given in this CPG can be described as under:

• Covers ages 1 month to 18 years
• Limited to Chemotherapy-induced vomiting (CIV) that occurs during the acute phase (first 24 hours after administering chemotherapy; most applicable to chemotherapy-naïve paediatric patients)
• Excludes anticipatory, breakthrough, delayed or refractory CIV
• Does not include vomiting due to radiotherapy or surgery or that, which may occur towards the end of a patient’s life
• Does not apply to chemotherapy-induced nausea

The scope of the classification framework can be described as under:

• The framework for classification is for when antiemetic prophylaxis is provided
• Does not include all types of commonly administered chemotherapy
• For the absent classifications, one may refer to a high-quality, methodical CPG meant for adult oncology patients

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Basis of emetogenicity classification framework

This classification framework, based on the reviewed evidence, denotes the assigned emetogenicity to chemotherapy when antiemetic prophylaxis is administered to paediatric oncology patients.

1. The traditional emetogenicity classifications based on the incidences of vomiting, in absence of CINV prophylaxis are included in this classification, where:

High is >90%, Moderate is 30 to 90%, Low is 10 to 30% and Minimal is <10%

2. For cases where antiemetic prophylaxis was provided, it was judged as either CPG-consistent or CPG-inconsistent depending upon a specific chemotherapy emetogenicity classification
3. When CIV incidence was 10% or more, prophylaxis was considered a failure. The recommendation therefore was to provide antiemetic prophylaxis for the next higher chemotherapy emetogenicity classification.

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The emetogenicity classification framework

1. Levels of chemotherapy emetogenicity classification as per the percentage of incidences of emesis in the absence of prophylaxis

• High: >90% incidence of emesis in the absence of prophylaxis
• Moderate: 30% to 90%
• Low: 10% to 30%
• Minimal: <10%

2. Determining the emetogenicity of chemotherapy regimens:

• Emetogenicity of multiple-agent chemotherapy regimens is determined as per the most highly emetogenic chemotherapy of the regimen, unless there is evidence to prove otherwise
• Emetogenicity of multiple-day chemotherapy regimens is determined by the most highly emetogenic chemotherapy given each day

3. Antiemetic prophylaxis type, the resulting incidences and classifications:

• CPG-consistent antiemetic prophylaxis should result in an incidence of acute emesis of < 10%
• For example, chemotherapy that results in <10% emesis in patients given
• CPG-consistent CIV prophylaxis for MEC is classified as MEC.
• When antiemetic prophylaxis is provided and the emesis is ≥ 10%, it is considered as a failure of prophylaxis and thus, requires an upgrade in chemotherapy emetogenicity classification
• Use of single-agent palonosetron prophylaxis is considered equivalent to prophylaxis with first-generation 5-HT3 receptor antagonist plus dexamethasone
• When chemotherapy given at a specific dose is classified as HEC, all higher doses are also classified as HEC
• When a chemotherapy at a specific dose is classified as minimally emetogenic, all lower doses are also classified as minimally emetogenic

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Interpretation of individual included studies

1. The emetogenicity of the chemotherapy administered is determined by the CIV prophylaxis chosen and given to the maximum number of cases/patients and the reported number of incidences of vomiting during the acute phase.
2. Chemotherapy that was minimally emetogenic did not contribute to the emetogenicity of a combination chemotherapy regimen.
3. Where antiemetics are not specified, it was assumed that antiemetics were not given.

Note: All classifications were arrived at by the CPG panel after logical discussions, including those where the classifications for chemotherapy regimens differed among case studies. Cost was not considered while formulating recommendations.

 

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Chemotherapy emetegenicity classification algorithm

Source: Classification of the acute emetogenicity of chemotherapy in pediatric patients: A clinical practice guideline (PediatrBloodCancer.2019;e27646)

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Recommendations by the panel

An evidence denoted that CIV risk factors of chemotherapy emetogenicity may be different in adult and paediatric patients. Hence, the panel behind this CPG has given recommendations based on evidence found in the paediatric patients/cases drawn for this study.

All emetogenic classifications arrived at through this study are strong recommendations. These classifications are most applicable to chemotherapy-naïve paediatric patients.

1. Chemotherapy regimens that are highly emetogenic

Single-agent regimens

Asparaginase (Erwinia) IV ≥ 20 000 IU/m2/dose Busulfan IV ≥ 0.8 mg/kg/dose Busulfan PO ≥ 1 mg/kg/dose Carboplatin IV ≥ 175 mg/m2/dose Cisplatin IV ≥ 12 mg/m2/dose Cyclophosphamide IV ≥ 1200 mg/m2/dose Cytarabine IV ≥ 3 g/m2/day Dactinomycin IV ≥ 1.35 mg/m2/dose Doxorubicin IV ≥ 30 mg/m2/dose Idarubicin PO ≥ 30 mg/m2/dose Melphalan IVb Methotrexate IV ≥ 12 g/m2/dose

Multiple-agent regimens

Cyclophosphamide ≥ 600 mg/m2/dose + dactinomycin ≥ 1 mg/m2/dose Cyclophosphamide ≥ 400 mg/m2/dose + doxorubicin ≥ 40 mg/m2/dose Cytarabine ≥ 90 mg/m2/dose IV + methotrexate IV ≥ 150 mg/m2/dose Cytarabine IV + teniposide IVb Dacarbazine ≥ 250 mg/m2/dose IV + doxorubicin IV ≥ 60 mg/m2/dose Dactinomycin 900 𝜇g/m2/dose IV + ifosfamide 3 g/m2/dose Etoposide IV ≥ 60 mg/m2/dose + ifosfamide IV ≥ 1.2 g/m2/dose Etoposide IV ≥ 250 mg/m2/dose + thiotepa IV ≥ 300 mg/m2/dose

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2. Single-agent and multiple-agent chemotherapy regimens that are moderately emetogenic

Single-agent regimens	Cyclophosphamide IV 1000 mg/m2/dose Cytarabine IV 75 mg/m2/dose Dactinomycin IV 10 𝜇g/kg/dose Doxorubicin IV 25 mg/m2/dose Gemtuzumab IV 3–9 mg/m2/dose Imatinib PO > 260 mg/m2/day Interferon alpha IV 15–30 million U/m2/day Ixabepilone IV 3–10 mg/m2/dose Methotrexate IV 5 g/m2/dose Methotrexate IT Topotecan PO 0.4–2.3 mg/m2/day
Multiple-agent regimens	Cytarabine IV 100 mg/m2/dose + daunorubicin IV 45 mg/m2/dose + Etoposide IV 100 mg/m2/dose + prednisolone PO + thioguanine PO 80 mg/m2/dose Cytarabine 60 or 90 mg/m2/dose + methotrexate 120 mg/m2/dose Liposomal doxorubicin IV 20–50 mg/m2/dose + topotecan PO 0.6 mg/m2/day

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3. Single-agent and multiple-agent chemotherapy regimens that are of low emetogenicity

Single-agent regimens

Cyclophosphamide IV 500 mg/m2/dose Cyclophosphamide PO 2–3 mg/kg/dose Dasatinib PO 60–120 mg/m2/dose Erlotinib PO 35–150 mg/m2/day Everolimus PO 0.8–9 mg/m2/day Gefitinib PO 150–500 mg/m2/day Imatinib PO 260 mg/m2/day Mafosfamide IT 1–6.5 mg/dose Melphalan PO 0.2 mg/kg/dose Mercaptopurine PO ≤ 4.2 mg/kg/dose Methotrexate 38–83 mg/m2/dose IV Mitoxantrone IV ≤ 33 mg/m2/dose Procarbazine PO 50–100 mg/m2/day Ruxolitinib PO 15–21 mg/m2/dose Selumetinib PO 20–30 mg/m2/dose Sorafenib PO 150–325 mg/m2/dose Temozolomide PO 200 mg/m2/dose

Multiple-agent regimens

Cytarabine IV 60 mg/m2/dose + Methotrexate IV 90 mg/m2/dose

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4. Single-agent and multiple-agent chemotherapy regimens that are minimally emetogenic

Single-agent regimens	Asparaginase (E. coli) IM ≤ 6000 IU/m2/dose Asparaginase (Erwinia) IM ≤ 25 000 IU/m2/dose Chlorambucil ≤ 0.2 mg/kg/day PO Doxorubicin IV 10 mg/m2/dose Liposomal doxorubicin IV ≤ 50 mg/m2/dose Mercaptopurine PO ≤ 4.2 mg/kg/dose Methotrexate PO/SC ≤ 10 mg/m2/dose Pracinostat 25–45 mg/m2/dose PO Vincristine IV ≤ 1.5 mg/m2/dose
Multiple-agent regimens	Cisplatin ≤ 60 mg/m2/dose intra-arterially + doxorubicin ≤ 30 mg/m2/dose intra-arterially Cisplatin ≤ 60 mg/m2/dose intra-arterially + pirarubicin ≤ 30 mg/m2/dose intra-arterially Mercaptopurine PO ≤ 2.5 mg/kg/dose + methotrexate PO ≤ 0.1 mg/kg/day

Note: Frequency of emesis in the absence of prophylaxis: I= >90%; II= 30% to <90%; III- 10% to <30%; and IV= <10%.

Among cases where the period of CIV assessment may have exceeded the acute phase, only those studies, which reported no emesis were included. This may have led to a systematic bias to under-classification. The panel could not distinguish between the contributions of acute and delayed CIV in multiple-day chemotherapy regimens.