1.0 Introduction The (SCI) is a not-for-profit collaboration between the Hospital for Sick Children (SickKids), Toronto, Canada, and seven Caribbean health care institutions across six countries that strive to improve the outcomes and quality of life for children with cancer and blood disorders. The initiative has established a strong and formal partnership between SickKids, represented by key healthcare professionals, and six countries in the Caribbean: The Bahamas, Barbados, Jamaica, St. Lucia, St. Vincent and the Grenadines and Trinidad and Tobago. Inter-professional leaders from government, hospitals and academia are working collaboratively to implement a comprehensive strategy to build sustainable capacity in the identification and management of children with cancer and blood disorders in the Caribbean. This Guidance Document outlines the recommendations for the prevention and management of chemotherapy and /or radiation-induced nausea and vomiting in children diagnosed with cancer in the Caribbean. It was developed by adapting the guidelines listed in Section 5.0 to reflect the resources available in the partnering Caribbean countries. 1.1 Disclaimer This guidance document ( Guidance Document ) is intended solely for healthcare providers who are collaborators in the ( Collaborators ). The Guidance Document is a general guide to appropriate practice, to be followed only subject to the judgment of a patient's attending physician, taking into consideration all available information related to the condition of the patient and after review of the benefits and risks of the proposed course of action with the patient (if of an appropriate age) and/or the patient s parents or guardians. The Guidance Document has been specifically tailored for use at Collaborators institutions taking into consideration available health care resources and other relevant contextual factors in Collaborators countries. The Guidance Document is NOT intended for use by patients or their families and is not designed or intended to constitute medical advice or to be used for diagnosis. The Guidance Document is NOT a substitute for the personalized judgment and care provided by trained medical professionals. Every effort has been made to ensure that the information provided in the Guidance Document is accurate and in accordance with the standards accepted at the time it was created, however new research and experience may result in changes to these standards. In all cases, you, in your role as the patient s physician and the SCI lead physician for the relevant participating SCI country, are responsible for ensuring that the recommendations detailed below comply with all applicable local laws, statutes and regulations. By viewing and using any information derived from the Guidance Document, you, in your role as the patient s responsible physician, hereby waive any claims, causes of action and demands, whether in tort or contract, against any of the Collaborators (including their employees, physicians, directors and agents) in any way related to use of the Guidance Document or the information derived from it. Page 1 of 14
2.0 Definitions and Abbreviations CINV: chemotherapy induced nausea and vomiting IV: Intravenous PO: oral Chemotherapy block: series of consecutive days that chemotherapy is given within a treatment plan or protocol 3 phases of CINV: a. Acute - begins with the first dose of chemotherapy and continues for 24 hours following the last dose of chemotherapy of the chemotherapy block b. Delayed - begins at the end of the acute phase and may persist for up to 7 days c. Anticipatory - any nausea or vomiting which occurs within 24 hours prior to the first chemotherapy dose of a chemotherapy block. Breakthrough CINV: vomiting, retching or significant nausea during the acute or delayed phases that occurs despite appropriate antiemetic prophylaxis Failure: of acute CINV prophylaxis - patient experiences more than 2 vomits or retches within a 24 hour period or 3 or more hours of significant nausea despite appropriate antiemetic prophylaxis Classfication of emetogenic potential of antineoplastic or radiation therapy: a. ly emetogenic - vomiting occurs in more than 90% of patients who are not given antiemetic prophylaxis b. ly emetogenic - vomiting occurs in 30 to 90% of patients who are not given antiemetic prophylaxis c. emetogenicity - vomiting occurs in 10 to less than 30% of patients who are not given antiemetic prophylaxis d. ly emetogenic - vomiting occurs in less than 10% of patients who are not given antiemetic prophylaxis. 3.0 Recommendations 3.1 Assessment of the emetogenicity potential of single and multiple antineoplastic agents and based on site of radiotherapy Refer to Table 1 and Table 2 respectively. This assessment is most relevant in patients who are naïve to antineoplastic agents or radiotherapy. The emetogenicity of multiple day antineoplastic therapy is classified based on the most highly emetogenic agent (see Table 1) given on each day of therapy. Assessment of regimen emetogenicity in patients who have received antineoplastic agents or radiotherapy in the past should incorporate an evaluation of the patient s nausea and vomiting experience during prior chemotherapy blocks. Page 2 of 14
3.2 Selection of Antiemetic Interventions For a chemotherapy-naïve patient, the emetogenicity of therapy should be ranked based on Table 1 and or Table 2, then the initial antiemetic regimen selected as outlined in Figure 1. Ondansetron IV/PO and granisetron IV/PO are considered to be equivalent. Choice of agent and formulation should be based on relative acquisition cost and availability. The use of dexamethasone may be contraindicated or recommended to be avoided in certain patients. This may be re-evaluated based on patient response after discussion with the patient s primary physician. 3.3 Adjunctive non-pharmacological interventions Dietary interventions may be effective in helping to control CINV. Consider recommending the following: eat smaller, more frequent meals reduce food aromas and other stimuli with strong odours avoid foods that are spicy, fatty or highly salty take antiemetics prior to meals use measures and foods (e.g. comfort foods ) that helped to minimize nausea in the past If available, the following may be effective: acupuncture, acupressure (e.g. Seabands ), guided imagery, music therapy, progressive muscle relaxation and psycho-educational support and information and virtual reality. 3.4 Interventions to treat breakthrough acute CINV Children who experience breakthrough acute nausea and vomiting: exclude other possible causes of nausea and vomiting administer lorazepam to treat episodes of nausea and vomiting (see Table 2) ensure that the prescribed antiemetic agents are appropriate based on the emetogenicity ranking of the antineoplastic therapy being administered.if not, adjust antiemetic prophylaxis accordingly. select antiemetic prophylaxis based on the emetogenicity ranking PLUS one level. For example, give antiemetic prophylaxis recommended for children receiving highly emetogenic chemotherapy to a child receiving moderately emetogenic chemotherapy. 3.5 Interventions to treat children who have experienced failure of acute CINV prophylaxis in past chemotherapy blocks For patients who have experienced failure of antiemetic prophylaxis, consider the following interventions the next time chemotherapy or radiotherapy is administered: incorporate the interventions which were successful to treat breakthrough nausea/vomiting during the last treatment cycle in children who failed while receiving ondansetron, administer granisetron select antiemetic prophylaxis based on the emetogenicity ranking PLUS one level Page 3 of 14
3.6 CINV in the Delayed Phase Patients who are at higher risk of developing CINV in the delayed phase include those who: experience nausea or vomiting during the acute phase are known to have experienced nausea or vomiting during the delayed phase of past cycles and/or have received highly or moderately emetogenic therapy Ondansetron and granisetron are not effective in preventing or treating CINV in the delayed phase. Consider dexamethasone (See Table 2) in patients at risk of delayed phase CINV. Patients at risk of delayed CINV who cannot receive dexamethasone and who are older than 1 year should receive metoclopramide (see Table 2). If metoclopramide is given, consider giving diphenhydramine concurrently to prevent extrapyramidal reactions. Antiemetics should be given on a round-the-clock basis until the patient is symptom-free for at least 24 hours and should be reinstituted should symptoms reappear within the first 5 to 7 days following antineoplastic therapy. If nausea and vomiting increase in severity or persist beyond 5 to 7 days following antineoplastic administration, exclude other possible causes of nausea and vomiting. 3.7 Anticipatory CINV Complete control of acute and delayed CINV best minimizes the risk of developing anticipatory CINV. Psychological interventions such as hypnosis or systematic desensitization may be offered if available. Lorazepam (see Table 2) once at bedtime and once on the day prior to the administration of chemotherapy may also be used to prevent or treat anticipatory CINV. 3.8 Nausea and Vomiting due to Radiation Guidance regarding the selection of antiemetic prophylaxis for radiation-induced nausea and vomiting is presented in Table 3. 3.8.1 Radiation Somnolence Syndrome This is an early to delayed adverse effect of cranial radiation which presents as extreme lethargy and signs of increased intracranial pressure including nausea and vomiting. It may be difficult to distinguish radiation somnolence syndrome from acute and delayed phase CINV. Page 4 of 14
4.0 References 1. Antiemetic Selection for Children Receiving Antineoplatics and/or Radiotherapy. In Chen, J and Lau, E. (Eds.). (2015) The Hospital for Sick Children Drug Handbook and Formulary. Toronto, ON. Lexicomp. 2. Guideline for classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. 2010. (Accessed July 14, 2015, at http://www.pogo.ca/healthcare/practiceguidelines/pogoemetogenicitycla/) 3. Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication in Pediatric Cancer Patients. 2012. (Accessed July 14, 2015, at http://www.pogo.ca/healthcare/practiceguidelines/acuteainvguideline/) 4. Guideline for the Prevention and Treatment of Anticipatory Nausea and Vomiting due to Chemotherapy in Pediatric Cancer Patients. 2014. (Accessed July 14, 2015 at http://www.pogo.ca/healthcare/practiceguidelines/anticipatorycinv/) 5. Basch E, Prestrud A, Hesketh P, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology 2011; 29: 4189-98. 6. Salvo N, Doble B, Khan L, et al. Prophylaxis of radiation-induced nausea and vomiting using 5- hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials. Int J Radiation Oncology Biol Phys 2012: 82: 408-17. 5.0 Guidance Document Group This Guidance Document is adapted from the SickKids Clinical Practice Guideline Antiemetic Selection for Children Receiving Antineoplastics and/or Radiotherapy (2013) 1 ; the Pediatric Oncology Group of Ontario (POGO) Guideline for the Classification of the Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients 2 ; POGO Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication in Pediatric Cancer Patients 3 ; POGO Guideline for the Prevention and Treatment of Anticipatory Nausea and Vomiting due to Chemotherapy in Pediatric Cancer Patients 4 and Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update 5. The individuals included below have participated in the development of this Guidance Document: L. Lee Dupuis, RPh, ACPR, FCSHP, PhD, Health Clinician Scientist, Research Institute, The Hospital for Sick Children, Toronto, Canada Alicia Koo, RPh, PharmD, ACPR, BScPhm, HonBSc, Clinical Pharmacy Manager, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada Page 5 of 14
6.0 Reviewers Strategic input to guide the development of this Guidance Document was solidified from and provided by the following Caribbean physicians. List of reviewers: Dr. Paula Michele Lashley, Queen Elizabeth Hospital, Barbados Dr. Corrine SinQuee-Brown, Paediatric Haematologist/Oncologist, Princess Margaret Hospital, The Bahamas Dr. Sharon McLean-Salmon, Bustamante Hospital for Children, Jamaica Dr. Michelle Reece-Mills, University Hospital of the West Indies, Jamaica Dr. Curt Bodkyn, Eric Williams Medical Sciences Complex, Trinidad and Tobago Dr. Sanjay Lalchandani, Eric Williams Medical Sciences Complex, Trinidad and Tobago Dr. Pauline Balkaransingh, Eric Williams Medical Sciences Complex, Trinidad and Tobago Page 6 of 14
Figure 1: Summary of the Recommendations Regarding Prevention of Acute AINV in Children Receiving Antineoplastic Medication Corticosteroids permitted ondansetron OR granisetron + dexamethasone emetogenic risk Corticosteroids contraindicated ondansetron OR granisetron + chlorpromazine OR nabilone Antineoplastic Agents with HIGH Emetic Risk Single agent antineoplastic therapy Altretamine Carboplatin Carmustine > 250 mg/m 2 Cisplatin Cyclophosphamide 1 g/m 2 Cytarabine 3 g/m 2 /dose Dacarbazine Dactinomycin Mechlorethamine Methotrexate 12 g/m 2 Procarbazine (oral) Streptozocin Thiotepa 300 mg/m 2 Multiple agent antineoplastic therapy With the exceptions listed below, emetogenicity is classified based on the most highly emetogenic agent. The following are also classified as high emetic risk: Cyclophosphamide + anthracycline Cyclophosphamide + doxorubicin Cyclophosphamide + epirubicin Cyclophosphamide + etoposide Cytarabine 150-200 mg/m 2 + daunorubicin Cytarabine 300 mg/m 2 + etoposide Cytarabine 300 mg/m 2 + teniposide Doxorubicin + ifosfamide Doxorubicin + methotrexate 5 g/m 2 Etoposide + ifosfamide Multi-day antineoplastic therapy Emetogenicity is classified based on the most highly emetogenic agent on each day of therapy. Antiemetic Dosage Recommendations for Children receiving HIGHLY Emetogenic Antineoplastic Therapy Drug Dose Ondansetron Granisetron Dexamethasone Chlorpromazine Nabilone 5 mg/m 2 /dose (0.15 mg/kg/dose) IV/PO pre-therapy x 1 and then q8h 40mcg/kg/dose IV as a single daily dose OR 40mcg/kg/dose PO q12h < 12 yrs : 6 mg/m 2 /dose IV/PO pre-therapy x 1 and then q6h 12 yrs: 20 mg IV/PO pre-therapy and then q24h 0.5mg/kg/dose IV q6h < 18 kg: 0.5 mg/dose PO twice daily 18 to 30 kg: 1 mg/dose PO twice daily > 30 kg: 1 mg/dose PO three times daily Maximum: 0.06 mg/kg/day Page 7 of 14
emetogenic risk Corticosteroids permitted Corticosteroids contraindicated ondansetron OR granisetron + dexamethasone ondansetron + chlorpromazine OR metoclopramide OR nabilone Antineoplastic Agents with MODERATE Emetic Risk Single agent antineoplastic therapy Aldesleukin > 12 to 15 million units/m 2 Amifostine > 300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carmustine 250 mg/m 2 Clofarabine Cyclophosphamide < 1 g/m 2 Cyclophosphamide (oral) Cytarabine > 200 mg to < 3 g/m 2 Daunorubicin Doxorubicin Epirubicin Etoposide (oral) Idarubicin Ifosfamide Imatinib (oral) Intrathecal therapy (methotrexate, hydrocortisone & cytarabine) Irinotecan Lomustine Melphalan > 50 mg/m 2 Methotrexate 250 mg to < 12 g/m 2 Oxaliplatin > 75 mg/m 2 Temozolomide (oral) Vinorelbine (oral) Multiple agent antineoplastic therapy With the exceptions listed under high emetic risk, emetogenicity is classified based on the most highly emetogenic agent. Multi-day antineoplastic therapy Emetogenicity is classified based on the most highly emetogenic agent on each day of therapy. Antiemetic Dosage Recommendations for Children receiving MODERATELY Emetogenic Antineoplastic Therapy Drug Ondansetron Granisetron Dexamethasone Chlorpromazine Metoclopramide Nabilone Dose 5 mg/m 2 /dose (0.15 mg/kg/dose; maximum 8 mg/dose) IV/PO pretherapy x 1 and then q12h 40mcg/kg/dose IV as a single daily dose OR 40mcg/kg/dose PO q12h 0.6m 2 : 2mg/dose IV/PO q12h > 0.6m 2 : 4mg/dose IV/PO q12h 0.5mg/kg/dose IV q6h 1 mg/kg/dose IV pre-therapy x 1 then 0.0375 mg/kg/dose PO q6h Give diphenhydramine (1.25mg/kg/dose IV/PO up to q6h) or benztropine (children >3 years: 0.02-0.05 mg/kg/dose IV 1-2 times/day ; max 2mg/dose) concurrently. < 18 kg: 0.5 mg/dose PO twice daily 18 to 30 kg: 1 mg/dose PO twice daily > 30 kg: 1 mg/dose PO three times daily Maximum: 0.06 mg/kg/day Page 8 of 14
emetogenic risk ondansetron OR granisetron Antineoplastic Agents with LOW Emetic Risk Single agent antineoplastic therapy Amifostine 300 mg/m 2 Amsacrine Bexarotene Busulfan (oral) Capecitabine Cytarabine 200 mg/m 2 Docetaxel Doxorubicin (liposomal) Etoposide Fludarabine (oral) 5-Fluorouracil Gemcitabine Ixabepilone Methotrexate >50 mg/m 2 to <250 mg/m 2 Mitomycin Mitoxantrone Nilotinib Paclitaxel Paclitaxel-albumin Pemetrexed Teniposide Thiotepa <300 mg/m 2 Topotecan Vorinostat Multiple agent antineoplastic therapy With the exceptions listed under high emetic risk, emetogenicity is classified based on the most highly emetogenic agent. Multi-day antineoplastic therapy Emetogenicity is classified based on the most highly emetogenic agent on each day of therapy. Antiemetic Dosage Recommendations for Children receiving LOW Emetic Risk Antineoplastic Therapy Drug Ondansetron Granisetron Dose 10 mg/m 2 /dose (0.3 mg/kg/dose; maximum 16 mg/dose) IV/PO pre-therapy x 1 40mcg/kg/dose IV/PO pre therapy x 1 Page 9 of 14
emetogenic risk no routine prophylaxis Alemtuzumab Alpha interferon Aspagarinase (IM or IV) Bevacizumab Bleomycin Bortezomib Cetuximab Chlorambucil (oral) Cladribine (2-chlorodeoxyadenosine) Dasatinib Decitabine Denileukin diftitox Dexrazoxane Antineoplastic Agents with MINIMAL Emetic Risk Single agent antineoplastic therapy Erlotinib Fludarabine Gefitinib Gemtuzumab ozogamicin Hydroxyurea (oral) Lapatinib Lenalidomide Melphalan (oral low-dose) Mercaptopurine (oral) Methotrexate 50 mg/m 2 Nelarabine Panitumumab Pentostatin Rituximab Sorafenib Sunitinib Temsirolimus Thalidomide Thioguanine (oral) Trastuzumab Valrubicin Vinblastine Vincristine Vindesine Vinorelbine For multiple agent and multi-day antineoplastic therapy Please refer to recommendations in emetic risk table. Page 10 of 14
Table 1: Emetogenicity Rankings of Antineoplastic Agents in Alphabetical Order Note: All agents are given intravenously (IV) unless otherwise stated. *Pediatric evidence available Antineoplastic Agent 5-Fluorouracil Aldesleukin > 12 to 15 million units/m 2 Alemtuzumab Alpha interferon Amifostine > 300 mg/m 2 Amifostine 300 mg/m 2 Amsacrine Anthracycline + cyclophosphamide *Cyclophosphamide + doxorubicin *Cyclophosphamide + epirubicin Arsenic trioxide Aspagarinase (IM or IV) Azacitidine Bleomycin Bortezomib Busulfan Busulfan (oral) Capecitabine Carboplatin* Carmustine > 250 mg/m 2 Carmustine 250 mg/m 2* Cetuximab Chlorambucil (oral) Cisplatin* Cladribine (2-chlorodeoxyadenosine) Clofarabine* Cyclophosphamide (oral) Cyclophosphamide < 1 g/m 2* Cyclophosphamide 1 g/m 2* Cyclophosphamide + anthracycline *Cyclophosphamide + doxorubicin *Cyclophosphamide + epirubicin Cyclophosphamide + etoposide Cytarabine > 200 mg to < 3 g/m 2 Cytarabine 200 mg/m 2 Level of Emetic Risk Page 11 of 14
Cytarabine 3 g/m 2 /dose* Cytarabine 150-200 mg/m 2 + daunorubicin* Cytarabine 300 mg/m 2 + etoposide* Cytarabine 300 mg/m 2 + teniposide* Cytarabine, methotrexate + hydrocortisone: Intrathecal therapy* Dacarbazine Dactinomycin* Daunorubicin* Daunorubicin + cytarabine 150-200 mg/m 2 * Dasatinib Decitabine Dexrazoxane Docetaxel Doxorubicin (liposomal) Doxorubicin* Doxorubicin + cyclophosphamide* Doxorubicin + ifosfamide* Doxorubicin + methotrexate 5 g/m 2 Epirubicin Epirubicin + cyclophosphamide* Etoposide Etoposide (oral) Etoposide + cyclophosphamide* Etoposide + cytarabine 300 mg/m 2 * Etoposide + ifosfamide* Fludarabine Fludarabine (oral) Gemcitabine Gemtuzumab ozogamicin Hydrocortisone, cytarabine + methotrexate: Intrathecal therapy* Hydroxyurea (oral) Idarubicin Ifosfamide Ifosfamide + doxorubicin* Ifosfamide + etoposide* Imatinib (oral) Intrathecal therapy (methotrexate, hydrocortisone & cytarabine)* Irinotecan Ixabepilone Lomustine Mechlorethamine Page 12 of 14
Melphalan (oral low-dose) Melphalan > 50 mg/m 2 Mercaptopurine (oral) Methotrexate > 50 mg/m 2 to < 250 mg/m 2 Methotrexate 50 mg/m 2 Methotrexate 12 g/m 2* Methotrexate 250 mg to < 12 g/m 2 Methotrexate 5 g/m 2 + Doxorubicin Methotrexate, hydrocortisone + cytarabine: Intrathecal therapy* Mitomycin Mitoxantrone Nelarabine Nilotinib Oxaliplatin > 75 mg/m 2 Paclitaxel Paclitaxel-albumin Procarbazine (oral) Rituximab Sorafenib Streptozocin Sunitinib Temozolomide (oral) Temsirolimus Teniposide Teniposide + cytarabine 300 mg/m 2 * Thalidomide Thioguanine (oral) Thiotepa < 300 mg/m 2 Thiotepa 300 mg/m 2* Topotecan Trastuzumab Vinblastine Vincristine Vindesine Vinorelbine Vinorelbine (oral) Vorinostat Page 13 of 14
Table 2: Recommended antiemetics and doses for anticipatory CINV, breakthrough CINV, failure of CINV prophylaxis and delayed phase CINV. See text for details regarding antiemetic choice. Antiemetic Agent Therapy Emetogenicity Dose Anticipatory CINV: Lorazepam All 0.04-0.08mg/kg/dose (maximum 2mg/dose) IV/PO/SL the night before and the morning of subsequent antineoplastic therapy Breakthrough CINV or Failure of Prophylaxis in the Acute Phase: Lorazepam All 0.025 mg/kg/dose (max 2 mg/dose ) IV/PO/SL q6h PRN Delayed phase CINV: Dexamethasone All 4.5 mg/m 2 /dose (maximum 8 mg/dose) q12h PO Metoclopramide All 0.1 to 0.2mg/kg/dose PO/IV q6h Consider the concurrent use of diphenhydramine to prevent extrapyramidal effects. Table 3: Acute emetogenic potential of radiotherapy Site of Radiation Therapy Craniospinal Half-body Total body irradiation Total Nodal Irradiation Cranium Upper abdomen Upper body Head and neck er thorax region Pelvis Extremities Breast Level of Emetogenic Risk Page 14 of 14