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Anti-emetic guidelines for the prophylaxis of and Radiotherapy induced and vomiting in ADULTS (for use by Haematologists and Oncologists)

Introduction Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most frequently experienced side effects encountered by chemotherapy patients. Patients will often find the symptoms distressing, and develop anxiety about the potential for such symptoms to recur on future cycles of chemotherapy. Modern drug treatment can successfully control CINV for the majority of patients.1

Scope The purpose of this document is to provide guidance on the rationale use of anti-emetics for prevention and treatment of chemotherapy and radiotherapy induced nausea and vomiting in adult patients. They are not intended to address nausea and vomiting in palliative care. These guidelines are intended to provide a framework to support clinical practice, they cannot cover every clinical situation and good common clinical sense and clinical experience will be required when approaching the management of individual patients.

It should be noted that the definitions for low, moderate, high and very high are in line with ASCO, MASCC and NCCN definitions. The definition of “moderate” in these sources is 30-90% which will encompass most of the chemotherapy drugs/regimens. This has been sub-categorised as low-moderate and high moderate to assist when choosing appropriate treatment for anti-emetic failure. 1

Definitions1,2,3,4 Acute N&V experienced during the first 24-hour period immediately after chemotherapy administration. Delayed N&V that occurs more than 24 hours after chemotherapy and may continue for up to 6 or 7 days after chemotherapy. Anticipatory N&V that occurs prior to the beginning of a new cycle of chemotherapy. It is either a learned response following chemotherapy induced N&V on a previous cycle or an anxiety response. It is most common after 3 to 4 cycles of chemotherapy with very badly controlled acute or delayed symptoms. Breakthrough Development of symptoms (nausea or vomiting), despite standard anti-emetic therapy, which require treatment with an additional pharmacological agent. Refractory Patients who have failed on both standard and rescue medication.

Grading of Nausea and Vomiting1,5 Grade Grade 1 Grade 2 Grade 3 Grade 4 5 Nausea Loss of appetite Oral intake decreased Inadequate oral caloric or Life- Death without without significant weight fluid intake; IV fluids, tube threatening alteration in loss, dehydration or feedings, or TPN consequences eating habits malnutrition; IV fluids indicated ≥24 h indicated <24 h Vomiting 1 episode in 24 2–5 episodes in 24 h; IV ≥6 episodes in 24 h; IV Life- Death h fluids indicated <24 h fluids, or TPN indicated threatening ≥24 h consequences

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Other causes of nausea and vomiting to be considered: Radiotherapy, radiosensitizers, infection, metabolic disorders, electrolyte disturbances (hypercalcaemia, hyperglycaemia, hyponatraemia), uraemia, constipation, gastrointestinal obstruction, gastroparesis induced by a tumour or chemotherapy (e.g. ), cachexia syndrome, metastases (brain, liver, bone), paraneoplasia, other emetogenic medication (e.g. opioids, antibiotics, antifungals, amifostine), psychophysiologic factors including anxiety and anticipatory nausea and vomiting, vestibular dysfunction. Patient Risk Factors which predict poor control of nausea and vomiting Patients with 3 or more risk factors should be considered to receive additional anti-emetics at the outset.

Female sex <30 years old History of sickness: in pregnancy / travel sickness/ with surgery Poor control with prior chemotherapy Underlying nausea and vomiting Anxiety

N.B. Previous high alcohol intake can have a protective effect and reduce risk of emesis

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Guidance

Antiemetic recommendations for Chemotherapy and Radiotherapy1,2,3,4  Always commence anti-emetics before chemotherapy and radiotherapy.  Anti-emetics should be administered regularly, prophylactically, and orally during chemotherapy administration and for at least 3 days after cessation of chemotherapy for highly and moderately emetic chemotherapy. Patients must be protected throughout the full period of risk.  Oral and IV formulations of anti-emetics are equally effective.  Give oral doses at least 30 minutes before chemotherapy is initiated.  Optimal emetic control in the acute phase is essential to prevent nausea and vomiting in the delayed phase and to prevent anticipatory nausea and vomiting.  Dexamethasone should be given prophylactically where indicated.  Dexamethasone should be given no later than 2pm to minimise wakefulness in the night. Patients should be informed of the adverse effect when scheduled to receive IV doses after 2pm, for example should their chemotherapy be initiated later in the day.  5HT-3 receptor antagonists are equally efficacious and should be administered orally, and only in the acute setting (i.e. only administer on days of chemotherapy administration). There is only evidence for the use of 5HT-3 receptor antagonists for one additional day in the delayed phase for and .  5HT-3 receptor antagonists can be administered i.v. instead of orally if necessary.  The toxicity of the specific anti-emetic(s) should be considered.  Anti-emetics should be chosen based on the emetogenic potential of the , previous patient experience with anti-emetics, and patient-specific risk factors.  Dexamethasone is not required when steroids are included in a chemotherapy regimen, nor for most haematology regimens (refer to specific haematology protocols).  Metoclopramide can be replaced with e.g. cyclizine or prochlorperazine if patient is already on regular anti- emetics.  For patients < 30 years old or if patient experiences extrapyramidal side effects, consider domperidone instead of metoclopramide or prochlorperazine.  Fosaprepitant is an intravenous preparation of aprepitant that can be substituted for aprepitant in patients unable to tolerate oral medication. Fosaprepitant is administered in a dose of 150mg IV over 20-30 minutes (see SPc available at www.medicines.org.uk ).  If lorazepam is prescribed, ensure patients are warned not to drive or drink alcohol due to high risk of drowsiness.  Domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death6. The risk may be higher in patients older than 60 years and at daily doses of more than 30mg6. Domperidone should be avoided in patients taking concomitant medication known to cause QT prolongation6. Domperidone should therefore be used at a maximum dose of 10mg tds orally. As per the MHRA recommendation, the lowest effective dose should be used for the shortest possible time6. Alternative anti-emetics should be considered in patients with severe hepatic impairment, cardiac conduction conditions or underlying cardiac disease, or receiving other medications known to prolong QT or potent CYP3A4 inhibitors6. The MHRA recommendations state that the maximum treatment duration should not usually exceed one week6. Refer to SPc for further information (www.medicines.org.uk) .  Metoclopramide should be prescribed at the lowest effective dose. Doses above 10mg tds increase the risk of extrapyramidal side effects and should be used with caution in line with MHRA guidance7. For the prophylaxis of chemotherapy induced nausea and vomiting, the network have agreed to continue to use doses of up to 20mg qds.  Ondansetron may increase the risk of QT prolongation, leading to an abnormal and potentially fatal heart rhythm. Patients at particular risk include those with an underlying heart condition, those predisposed to low serum potassium and magnesium levels, and those taking other medications that lead to QT prolongation. Ondansetron should be avoided in patient with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval.8,9 Refer to SPc for further information (www.medicines.org.uk).  Patients should only be prescribed ondansetron to prevent acute nausea and vomiting for the days of receiving highly emetic chemotherapy and up to 24 hours after.  Adult patients who receive high-dose chemotherapy with stem cell or bone marrow transplantation should be offered a three-drug combination of an NK1 , a 5-HT3 receptor antagonist, and dexamethasone as per local trust funding.

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Choice of Antiemetics1  Consult Table 1 for the emetogenic potential of individual cytotoxic drugs.  Refer to Appendix 2 and 3 for the emetogenic potential of individual protocols.  For combination chemotherapy use the following algorithm. Identify the most emetogenic agent in the combination then – - for high and moderate: increase the emetogenicity by one level per agent. - Low – increase the emetogenicity by one level regardless of the number of agents. - Rare – do not contribute.  For haematology patients, where a steroid is not a desirable antiemetic, substitute for a short course of a 5HT3 inhibitor (preferably 1 day).  For multi-day regimens choose appropriate pre-chemotherapy regimen for each day and on discharge give the anti-emetics suggested for the day with the highest emetogenic potential.  Drugs acting on the same receptor e.g. domperidone and metoclopramide or metoclopramide and prochlorperazine/ levomepromazine should not be used together as the risk of side effects will be increased without additional clinical benefit.  Cyclizine should not be used in patients with severe heart failure as it can cause a reduction in cardiac output and an increase in heart rate.  Cyclizine should not be combined with the pro-kinetics as the former will inhibit the action of the latter.  Haloperidol can be considered in patients with renal failure.  Metoclopramide, prochlorperazine, levomepromazine, haloperidol must not be used in patients with Parkinson’s.  Lorazepam maximum dose 4mg/24 hours in adults or 2mg/24 hours for the elderly.  Carefully consider the risks and benefits of the use of steroids in diabetic patients and in patients who are immunocompromised.  Omit dexamethasone pre-chemotherapy if patient is on a high dose steroid-containing regimen e.g. CHOP, ESHAP or if the patient is on high dose steroids for another medical reason.  Consider alternative 5HT3 antagonist receptor antagonist formulations if patient cannot tolerate tablets eg ondansetron film (Setofilm) or melts as per local Trust formulary.  To ensure absorption in vomiting patients, consider route of administration eg. subcutaneous, intravenous, rectal, buccal, sublingual ( Do NOT use suppositories in neutropenic patients)  Consider Akynzeo (netupitant/ palonosetron) as an option for patients receiving 3 drug combinations for highly emetogenic chemotherapy as per local Trust availability.  Ondansetron may increase the risk of arrhythmia and Torsade de pointes in patients: - with congenital long QT syndrome - with pre-existing hypokalaemia, hypomagnesemia or using medications that prolong interval 8,9.

Anti-emetic failure1  This is defined as prolonged, distressing nausea or 2 or more episodes of vomiting in 24 hours.  Move onto suggested regimen for next level of emetogenic potential. See Table 4. On completion of chemotherapy1  Omit oral dexamethasone if the patient is on a steroid-containing chemotherapy regimen e.g. CHOP or if the patient is receiving regular low dose steroid doses.  Consider omitting the steroid or reducing length of course if the patient is on a weekly regimen or an oral cytotoxic course longer than 3 days.  Consider gradual reducing dose for dexamethasone for patients who experience adverse events on stopping high dose steroids.

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Action of anti-emetics on main receptor sites1,27 Drug D2 H1 Muscarinic 5HT2 5HT3 5HT4 NK1 antagonist antagonist antagonist antagonist antagonist agonist inhibitor Metoclopramide ++ + ++ Domperidone ++ Cyclizine ++ ++ Hyoscine +++ hydrobromide Haloperidol +++ +/- Levomepromazine ++ +++ ++ +++ Aprepitant +++ Fosaprepitant +++ Ondansetron +++ Granisetron +++ Olanzapine ++ + ++ ++ + Prochlorperazine +++ ++ + +/++ Table adapted from Twycross R, Wilcock A, - Palliative Care Formulary Fifth Edition (2014)

Anti-emetic information1 Please refer to BNF/SPC for more information Ondansetron & Patients may complain of constipation and headaches. Patients need to be advised accordingly, e.g. macrogol +/- senna to Granisetron relieve constipation and paracetamol to relieve headache. If severe, consider an alternative anti-emetic. Long acting second 5HT3 antagonist generation 5HT3 antagonists are available and may be used if locally approved. The MHRA (July 2013) have issued guidance regarding ondansetron infusion dilution and rates9: - In patients aged 75 years or older, a single dose of intravenous ondansetron for the prevention of CINV must not exceed 8mg (infused over at least 15mins). - In adult patients under 75 years, a single dose of intravenous ondansetron for prevention of CINV must not exceed 16mg (infused over at least 15mins. - Repeat intravenous dosing should be given no less than 4 hours apart. Aprepitant & Aprepitant and fosaprepitant are NK-1 receptor antagonists and have been shown to inhibit emesis induced by cytotoxic Fosaprepitant chemotherapeutic agents, such as , via central actions. In addition, studies show that aprepitant augments the NK-1 Receptor antiemetic activity of the 5-HT3-receptor antagonist and dexamethasone and inhibits both the acute and delayed phases of antagonists cisplatin-induced emesis When given in combinations with corticosteroids, the SPC suggests: reduce oral dexamethasone dose by 50%, reduce methylprednisolone IV dose by 25% and oral dose by 50%. NB for practical reasons it is not necessary to halve post chemotherapy dexamethasone doses as confirmed in the aprepitant trial data. Common side effects include headaches, hiccups and . Cyclizine Cyclizine may cause antimuscarinic side effects such as dryness of the mouth and drowsiness. Children and the elderly are more susceptible to these effects. Cyclizine should not be used in patients with severe heart failure as it can cause a reduction in cardiac output and an increase in heart rate. Cyclizine should not be combined with the pro-kinetics as the former will inhibit the action of the latter. Dexamethasone Corticosteroids can cause sleep disturbances, hyperactivity and excessive appetite. They also produce glucose-intolerance, use with care in patients with diabetes mellitus. Patients may experience perineal discomfort if the drug is given by iv bolus. This can be avoided by administration via IV infusion. Domperidone Domperidone should not be used when stimulation of the gastric motility could be harmful e.g. gastro-intestinal haemorrhage, mechanical obstruction or perforation. Levomepromazine Avoid in patients with liver dysfunction. Inhibits cytochrome P-450. Common side effects are somnolence, asthenia, dry mouth, hypotension, photosensitivity and skin reactions. Lorazepam Can cause drowsiness and may affect performance of skilled tasks (driving). Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents. Therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents. Maximum dose 4mg/24 hours for adults or 2mg/24 hours for the elderly. Metoclopramide Can rarely cause agitation or the development of extra-pyramidal symptoms particularly in the young female patients. These can occur up to 24 hours after a dose and may vary from facial grimacing and dystonic movements to odd feelings in the mouth, restlessness, somnolence and irritability. Bowel transit time may be reduced and some patients experience diarrhoea. The MHRA (August 2013) have issued guidance relating to the maximum dose and duration: For adults, the maximum dose in 24 hours is 30mg. The usual dose is 10mg tds. Prochlorperazine Prochlorperazine should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostatic hypertrophy. A mild leukopenia occurs in up to 30% of patients on prolonged high dosage. May cause drowsiness.

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Emetic Risk of Chemotherapy The emetic risk of chemotherapy is shown in Table 1. Drug combinations have an additive emetic effect. If drugs from the same category are combined, the regimen is classified at a higher emetic risk. If drugs are from different categories, the emetic risk is according to the most emetic drug in the combination. Table 1.Emetic Risk of Chemotherapy (1,2,3,4,10) High Emesis Risk (>90% Moderate Emesis Risk Low Emesis Risk Minimal Emesis Risk incidence) (30% to 90% incidence) (10% to 30% incidence) ( <10% incidence) IV chemotherapy IV chemotherapy IV chemotherapy IV chemotherapy AC combination Actinomycin-D () Aflibercept Bevacizumab (/ + Alemtuzumab Alemtuzumab cyclophosphamide) Amifostine <300mg/m2 Busulfan <10mg Busulfan high doses Amsacrine Asparaginase Carboplatin ≥ 4AUC Atezolizumab (oral) >250mg/m2 Axitinib Daratumumab Cisplatin > 70mg/m2 Cyclophosphamide >1500 Blinatumomab Nivolumab mg/m2 Carboplatin ≤ 4AUC Obinituzumab Carmustine <250mg/m2 Brentuximab vedotin Ofatumumab Doxorubicin >60mg/m2 Cisplatin <70mg/m2 Cabazitaxel Pembrolizumab Epirubicin >90mg/m2 Clofaribine >2g/m2 Cyclophosphamide <1500mg/m2 Catumaxumab Pralatrexate Mechlorethamine >1000mg/m2 Cetuximab Ramucirumab Streptozocin Cytarabine ≤1000mg/m2 Doxorubicin <60mg/m2 Decitabine Trastuzumab Oral chemotherapy Epirubicin <90mg/m2 Denileukin Vinblastine Hexamethylmelamine Estramustine Dasatinib Vincristine >120mg/m2 Daunorubicin (liposomal) Dexrazoxane Ifosfamide <2g/m2 Docetaxel Oral chemotherapy Irinotecan Doxorubicin (liposomal) Cabozantinib liposomal injection Elotuzumab Chlorambucil Erlotinib Etoposide Gefitinib >100mg/m2 >250 mg/m2 Melphalan Mifamurtide Gemtuzumab Methotrexate Ipilimumab Pomalidomide Ixabepilone Ruxolitinib Sorafenib Methotrexate <250mg/m2 Vemurafenib Tegafur Uracil Mitomycin C Vismodegib Mitoxantrone Necitumumab Nivolumab Omacetaxine Oral chemotherapy Pembrolizumab Bosutinib Ceritinib Paclitaxel-albumin Crizotinib Panitumumab Cyclophosphamide Pazopanib Lenvatinib Trifluridine-tipiracil Vinorelbine Pertuzumab Romidepsin Temsirolimus

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Trastuzumab-Emantasine

Oral chemotherapy Afatinib Alectinib Axitinib Cobimetinib Dabrafenib Dasatinib Everolimus Etoposide <120mg/m2 Fludarabine Ibrutinib Idelalisib Imatinib Lapatinib Lenalidomide Osimertinib Nilotinib Pazopanib Ponatinib Regorafenib Sonidegib Sunitinib uracil Thalidomide Trametinib Vandetanib Vorinostat

Table 2. Recommended Daily Doses of 5-HT3 Receptor Antagonists to be administered one hour prior to chemotherapy 2,3,4. Preferable to administer orally where possible.  Dolasetron 100mg od orally  Granisetron 2mg od orally or 1mg intravenously  Ondansetron 8mg b.d. orally or intravenously  Palonosetron 0.25mg intravenously or 0.5mg orally  Tropisetron 5mg od orally or intravenously

Table 3: Oral Antiemetic regimens to PREVENT chemotherapy induced nausea and vomiting (oral and iv are

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equally efficacious. Iv immediately before chemotherapy can be substituted for oral administration)

Emetogenic Potential Pre-chemotherapy Schedule ( for each day of Post Chemotherapy ( day after chemotherapy) chemotherapy finished) High Risk (start antiemetics 1 hour pre- chemotherapy) Aprepitant 80mg po for 2/7 Risk of emesis > 90% Single day treatment: Patients on an Aprepitant 125mg po/ Fosaprepitant 150mg Dexamethasone 8mg OM for and cyclophosphamide or iv 20-30 minutes on day 1 only 2-3 days after chemotherapy cisplatin ≥ 70mg/m2 or if Dexamethasone 6mg BD po/iv aprepitant indicated Ondansetron 8mg bd po/iv or locally (check local trust for funding approved 5HT-3 receptor antagonist as Table Metoclopramide 10mg-20mg for aprepitant/fosaprepitant) 2 above po qds or domperidone 10mg po tds for 3/7 Multiple Day Treatment: Day 1: Aprepitant 125mg po/ Fosaprepitant 150mg iv 20-30 minutes on day 1 only Dexamethasone 6mg BD po/iv Ondansetron 8mg bd po/iv or locally approved 5HT-3 receptor antagonist Subsequent days: Aprepitant 80mg po 2/7 Dexamethasone 6mg bd on days of highly emetogenic chemotherapy Ondansetron 8mg bd po/iv or locally approved 5HT-3 receptor antagonist until 24 hours after highly emetogenic chemotherapy

Metoclopramide 10mg-20mg qds po or domperidone 10mg po tds High Risk (start antiemetics 1 hour pre- chemotherapy) Dexamethasone 8mg OM for Risk of emesis > 90% Dexamethasone 6mg BD po/iv on days of 2-3 days after chemotherapy ( without aprepitant) highly emetogenic chemotherapy Metoclopramide 10mg-20mg Ondansetron 8mg bd po/iv or locally po qds or domperidone 10mg approved 5HT-3 receptor antagonist po tds for 3/7 On days of highly emetogenic chemotherapy

Metoclopramide 10mg-20mg po qds or domperidone 10mg po tds for Moderate Risk (start antiemetics 1 hour pre- chemotherapy) Dexamethasone 8mg OM for Risk of emesis 30-90% Dexamethasone 8mg OD po/iv 2-3 days after chemotherapy (discuss use of Ondansetron 8mg bd po/iv or locally dexamethasone in approved 5HT-3 receptor antagonist haematology regimens with On days of moderately emetogenic Metoclopramide 10mg-20mg local haematology team) chemotherapy po qds or domperidone 10mg po tds for 3/7 Metoclopramide 10mg-20mg po qds or domperidone 10mg po tds Low Risk (start antiemetics 1 hour pre- chemotherapy) Metoclopramide 10mg-20mg Risk of emesis 10-30% Metoclopramide 10mg-20mg po qds or po qds or domperidone 10mg Dexamethasone 6mg bd for days of low tds PRN for 3/7 emetic risk chemotherapy Minimal Risk Risk of emesis< No routine prophylaxis 10% Anticipatory nausea and If nausea and vomiting is well controlled vomiting during and after chemotherapy, anticipatory nausea is unlikely to occur

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Table 4: Breakthrough treatment for chemotherapy induced nausea and vomiting Drug and Schedule Comments 1st Line Metoclopramide 10mg-20mg Do NOT use domperidone and metoclopramide together For patients not po/iv QDS taking regular (Patients should be informed to contact triage if they start antiemetics Or vomiting at home. Delayed nausea and vomiting may cause acute renal failure due to dehydration exacerbating Domperidone 10mg po TDS the nephrotoxicity of chemotherapy) 2nd Line Prochloperazine po 5-10mg tds Prochlorperazine, levomepromazine/ cyclizine replaces (1st line for po or 3-6mg BD bucally metoclopramide or domperidone as post chemotherapy anti- patients already Or emetic on antiemetics) Levomepromazine 6.25mg- 12.5mg po od-tds po/sc (Patients should be informed to contact triage if they start Or vomiting at home. Delayed nausea and vomiting may Cyclizine 50mg po/iv tds cause acute renal failure due to dehydration exacerbating the nephrotoxicity of chemotherapy) 3rd Line Lorazepam 0.5-2mg Dexamethasone most useful agent for delayed nausea and (2nd line for po/iv/sublingual every 4-6 hours vomiting. Consider gradual reducing course of dexamethasone patients already Or for prolonged nausea and vomiting. It can be prescribed as on antiemetics) Haloperidol 1-2mg every 4-6 Dexamethasone 4mg bd for 1 day, then 4mg od for day then hours 2mg od for 2 days Or Nabilone 1-2mg po bd Consider adding antacids/ proton pump inhibitors for patients Or that are sensitive to dexamethasone. Dexamethasone if not previously given (Patients should be informed to contact triage if they start Or vomiting at home. Delayed nausea and vomiting may Aprepitant 125mg OD for 1day cause acute renal failure due to dehydration exacerbating then 80mg OD for 2 days with the nephrotoxicity of chemotherapy) next course of chemotherapy

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Did your patient have any nausea or vomiting last cycle? Continue current management NO Yes

Anxiety or signs of Yes Add in lorazepam 0.5-2mg po/SL every 12 anticipatory nausea and hours starting the night before chemotherapy. vomiting?

NO ACUTE Yes Yes Is the patient on the highest pre- Vomited within 24hours of chemotherapy antiemetic chemotherapy? regimen?

NO NO

Vomited >24 hours of Increase to a higher risk pre- chemotherapy? chemo regimen

Yes

Treat next course for the duration of emesis plus 1 Increase to a higher risk pre-chemo regimen or add in NK-1 day i.e. patient suffered receptor antagonist or change the 5HT3 antagonist nausea for 8 days – treat for 9 days.

May add one or more of - Cyclizine 50mg tds - Levomepromazine 6mg (unlicensed) 2-4 x daily and - Hyoscine patch every 72 hours - Prochlorperazine 5-10mg qds Yes - Nabilone 1mg bd Is the patient on the highest - Haloperidol 1.5mg od-bd post chemotherapy - Continue dexamethasone for longer if delayed regimen? nausea and vomiting - Olanzapine 5mg bd (unlicensed) if within formulary and at consultant’s discretion

NO

Increase to a higher risk Not regimen post-chemotherapy Controlled Consider nabilone 1mg tds

Controlled Not Controlled

Continue current Consider modification to chemotherapy management

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Section 2 Radiotherapy induced nausea & vomiting The majority of patients having radiotherapy do not experience sickness: a significant minority do. It is the Clinicians responsibility to prescribe appropriate anti-emetics and for the radiographer to verify the anti-emetics have been prescribed where appropriate and to liaise with clinicians when necessary. Patients who are on radiotherapy and antineoplastic agents should receive antiemetic therapy appropriate for the emetic risk level of the antineoplastic agent unless the risk level of radiation is higher. During periods when prophylactic antineoplatic treatment has ended and ongoing radiation would be managed with its own prophylactic therapy, patients should use antiemetic that is appropriate for the emetic risk of the radiation therapy until the next period of antineoplastic therapy, rather than receiving rescue therapy as needed.

The incidence, severity and duration depend on Site: most likely when upper abdomen included in treatment volume Field Size: Large volumes increase the likelihood Dose: Large single fractions more emetogenic than fractionated treatment

Pattern of emesis from a large single treatment: Sudden and unexpected vomiting Latency 2 hours Acute phase 2-6 hours

Table 5:Risk of emesis with radiotherapy and prophylaxis3

Level of risk Procedure/site of Pre- Radiotherapy Anti-emetic breakthrough irradiation Medication High risk (>90%) TBI 5HT3 antagonist starting Metoclopramide 10mg- Cranial Stereotactic 1 hour before each 20mg QDS PRN for 3/7 radiosurgery fraction and dexamethasone Prior to each fraction of RT and the day after each fraction if RT is not planned for the day Moderate Risk (30-90%) Hemibody (upper or 5HT3 antagonist daily Metoclopramide 10mg- lower) approx 30 mins before 20mg QDS PRN for 3/7 Whole abdomino-pelvic each fraction field Consider Craniospinal Dexamethasone 4mg od Upper abdominal fields days 1-5 or days of including PA nodes radiotherapy with PPI.

(if ondansetron, increase up to 8 mg twice daily as needed) Low risk (10-30%) Brain, head and neck, No routine prophylaxis Brain – consider thorax, pelvis Dexamethasone Head and neck, thorax or pelvis- consider Metoclopramide 10mg- 20mg QDS PRN for 3/7 Minimal risk (<10%) Extremities, breast No routine prophylaxis Metoclopramide 10mg- 20mg QDS PRN for 3/7

NB for failure of anti-emesis where there is prolonged, distressing nausea or 2 or more episodes of vomiting in 24 hours treat as higher risk category

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References: 1. Chambers, P. and Daniels, S. Antiemetic Guidelines for Adult Patients Receiving Chemotherapy and Radiotherapy. London Cancer New Drugs Group. November 2013 version 2. 2. Gralla, R.J., Roila, F., Tonato, M., Herstedt, J. (2013) MASCC Antiemetic Guidelines. Available at http://www.mascc.org/antiemetic-guidelines [15 July 2014]. 3. Paul J. Hesketh, Mark G. Kris, Ethan Basch, Kari Bohlke, Sally Y. Barbour, Rebecca Anne Clark-Snow, Michael A. Danso, Kristopher Dennis, L. Lee Dupuis, Stacie B. Dusetzina, Cathy Eng, Petra C. Feyer, Karin Jordan, Kimberly Noonan, Dee Sparacio, Mark R. Somerfield, and Gary H. Lyman Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update (http://ascopubs.org/doi/10.1200/JCO.2017.74.4789 accessed on 6/2/2019) 4. National Comprehensice Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Antiemesis Version 2.2014. Available from http://NCCN.org [15 July 2014]. 5. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 4.0. Bethesda, Md: National Cancer Institute, Division of Cancer Treatment and Diagnosis, 2009. Available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf [15 July 2014] 6. MHRA press release (25 April 2014) New advice for domperidone. Available at http://www.mhra.gov.uk/home/groups/comms-po/documents/news/con409260.pdf [15 July 2014] 7. MHRA Drug Safety Update August 2013 vol 7, issue1:S2. Metoclopramide. Available at http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con300408.pdf [15 July 2014] 8. MHRA Drug Safety Update August 2012 Volume 6, Issue 1. Ondansetron: risk of QTc prolongation – important new intravenous dose restriction. 9. MHRA Drug Safety Update July 2013 Volume 6, Issue 12. Ondansetron. Available at ww.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON296402 [15 July 2014] 10. ERRATA (2014). JCO, July 1, 2014. 32(19):21117. Available at http://jco.ascopubs.org/content/32/19/2117.1.full [15 July 2014]. 11. Gralla R.J. et al. (1999) Recommendations for the Use of Anti-emetics: Evidence-Based, Clinical Practice Guidelines. Journal of Clinical Oncology 17(9), 2971-2994. 12. Feyer P.C. et al. (1998) Aetiology and prevention of emesis induced by radiotherapy. Supportive Care in Cancer 6, 253-260. 13. Herrstedt J. (2000) European Society for Medical Oncology (ESMO) Recommendations for Prophylaxis of Chemotherapy-Induced Nausea and Vomiting (NV). www.esmo.org/reference/anti_emetics.htm. 14. Roila F. et al. (1997) 5-HT3 Receptor Antagonists: Differences and Similarities. European Journal of Cancer 33(9), 1364-1370. 15. Tramer M.R. et al. (1998) Efficacy of 5-HT3 Receptor Antagonists in Radiotherapy-induced Nausea and Vomiting: A Quantitative Systematic Review. European Journal of Cancer 34(12), 1836-1844. 16. Loannidis et al. (2000) Contribution of Dexamethasone to Control of Chemotherapy-Induced Nausea and Vomiting: A Meta-Analysis of Randomized Evidence. Journal of Clinical Oncology 18, 3409-3422. 17. Kirkbridge P. et al. (2000) Dexamethasone for the prophylaxis of radiation-induced emesis: a National Cancer Institute of Canada Clinical Trials Group phase III study. Journal of Clinical Oncology 18(9), 1960-6. 18. Fauser A.A. et al. (1999) Guidelines for anti-emetic therapy: acute emesis. European Journal of Cancer 35(3), 361-370. 19. Du Bois, A. (2003) Emerging Trends in the Treatment and Management of Chemotherapy-Induced Nausea and Vomiting. MASCC/ISOO 15th International Symposium Supportive Care in , Berlin, June 18-21. 20. Roila, F(2003) Optimal Dose of Dexamethasone in Preventing Acute Emesis Induced by Highly-Moderately Emetogenic Chemotherapy MASCC/ISOO 15th International Symposium Supportive Care in Cancer Berlin June 18-21 21. Martin, M.(1996) The Severity and Pattern of Emesis following Different Cytotoxic Agents. Oncology 53 (suppl 1):26-31. 22. The antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). (2006) Preventiion of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Annals of Oncology 17:20-28. 23. Kris, M.G. et al. (2006) American Society of Clinical Oncology (ASCO) Guideline for Antiemetics in Oncology: Update 2006. J. Clin. Onc. 24(18):2932-2947. (www.asco.org) 24. National Comprehensive Cancer Network (NCCN) (2008). NCCN Clinical Practice Guidelines in Oncology Antiemesis v.3.2008. www.nccn.org 25. Roila, F. et al. (2010) Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Annals of Oncology 21 (Supplement 5):232-243. 26. Priestman et al Nausea and vomiting following high dose upper abdominal irradiation .Clin Oncology 1999;2:71-75 27. Twycross, R, Wilcock, A., Howard, P. (2014) Palliative Care Formulary. Fifth Edition. www.palliativedrugs.com Ltd. 28. Hesketh, P.J. et al. (2015). Antiemetics: American Society of Clinical Oncology Focused Guideline Update. Available at: http://jco.ascopubs.org/content/early/2015/10/26/JCO.2015.64.3635.full.pdf+html [2nd February 20

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Appendix 1: Emetic risk of haematology regimens Lymphoma High emetogenic risk Moderate emetogenic risk Low emetogenic risk Minimal emetogenic risk ABVD Bendamustine / R-Bendamustine / O-bendamustine Alemtuzumab Chlorambucil BEACOPDac-14 / BEACOP-DAc- Escalated DRC Brentuximab vedotin Cladribine ChIVPP Fludarabine/Cyclophosphamide + Rituximab (FCR) Ibrutinib Methotrexate ORAL Weekly CHOEP High-dose Cytarabine (>1000mg/m2) Nivolumab DA-EPOCH-R High-dose Methotrexate >1000mg/m2 Etoposide/Dexamethasone - HLH Pixantrone E-SHAP/R-E-SHAP R-BAC Obinutuzumab and Chlorambucil Rituximab High dose METHOTREXATE and high dose CYTARABINE MeAD Ofatumumab and Chlorambucil Obinutuzumab MATRix R-CP Venetoclax Ofatumumab MaxiCHOP R-CVP/O-CVP Bexarotene R-VP Mini-BEAM R-GemOx R-CODOX-M / R-IVAC R-GCVP R-CHOP/CHOP / Mini-CHOP Temozolomide R-GDP R-Hyper-CVAD / R-MA SMILE

Myeloid High emetogenic risk Moderate emetogenic risk Low emetogenic risk Minimal emetogenic risk FLA-IDA/ FLAG-IDA ADE ALL maintenance Blinatumumab HD Ara-C + ALL Phase 1 Induction ATRA + Arsenic Trioxide Busulfan MACE ALL Phase 2 Induction Dasatinib Chlorambucil ALL intensification/CNS prophylaxis (HDMXT) Etoposide Oral Cladribine Azacitidine Gemtuzumab Ozogomicin Hydroxycarbamide Bosutinib Imatinib Ruxolitinib DA Lenalidomide EZ Nelarabine FLA/FLAG Nilotinib High-dose ARA-C (>1g/m2) Ponatinib LD-ARA-C and MidAC Nelarabine/Cyclophosphamide/Etoposide (Nel-Cyc-Etop)

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Myeloma High emetogenic risk Moderate emetogenic risk Low emetogenic risk Minimal emetogenic risk CarLenDex/CarDex DTPACE Cyclophosphamide +/- Prednisolone (Carfilzomib/Lenalidomide/Dexamethasone) Bortezomib/Dexamethasone Dara/Len/Dex VTDPACE BTD (Bendamustine/Thalidomide/Dex) (Daratumumab/Lenalidomide/Dexamethadone) Carfilzomib/Dexamethasone Dara/Bor/Dex BVD (Bendamustine/Bortezomib/Dex) (Daratumumab/Bortezomib/Dexamethasone) Daratumumab Monotherapy Melphalan (PO) +/- Cyclophosphamide +/- Prednisolone Lenalidomide +/- Dexamethasone Prednisolone Z-DEX (Idarubicin PO + Dex) MelBorPred (Melphalan/Bortezomib/prednisolone) Sultuximab CTD/CTDa (Cyclophsphamide/Thalidomide/Dexamethasone)- on weekly cyclophosphamide days MPT (Melphalan PO /Prednisolone/Thalidomide) CyBorDex (Cyclophsphamide/Bortezomib/Dexamethasone)- on weekly cyclophosphamide days Pomalidomide + Dexamethasone CyCarDex (Cyclophosphamide/Carfilzomib/Dexamethasone)- on weekly cyclophosphamide days Thalidomide + Dexamethasone Cy/Len.Dex (Cyclophosphamide/Lenalidomide/Dexamethasone)- on weekly cyclophosphamide days VRD (Bortezomib/Lenalidomide/Dexamethasone) IRD (Ixazomib/Lenalidomide/Dexamethasone)- on weekly Ixazomib days VTD (Bortezomib/Thalidomide/Dexamethasone) PanBorDex (Panobinostat/Bortezomib/Dexamethasone)- on panobinostat days RCD (Lenalidomide/Cyclophsphamide/Dexamethasone)- on weekly cyclophosphamide days

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Bone Marrow Transplant (Allograft & Autograft) High emetogenic risk Moderate emetogenic risk Low emetogenic risk Minimal emetogenic risk Fludarabine/Cyclophosphamide/ATG +/- TBI BCNU Thiotepa (high dose) (high risk if having TBI) Fludarabine/Cyclophosphamide/Alemtuzumab BEAM +/- TBI (high risk if having TBI) BEAM Campath Fludarabine/Melphalan Busulfan/Cyclophosphamide Fludarabine/ Melphalan /Alemtuzumab Busulfan/Fludarabine/ATG Treosulfan/Melphalan for Autograft Cyclophosphamide Priming Cyclophosphamide/ATG (allograft) Cyclophosphamide /ATG Conditioning Autograft (CROHN’S AUTOLOGOUS TRANSPLANTATION) Cyclophosphamide/Fludarabine/ TBI Cyclophosphamide/TBI Cyclophosphamide/TBI/Alemtuzumab FLAMSA-BU High Dose Melphalan for Autograft LEAM Thiotepa/Busulfan/Fludarabine/ATG Total Lymphoid Irradiation (TLI)/Rabbit Anti- Thymocyte Globulin (rbATG) for Non- myeloablative Allograft TopCat (Topotecan / Carboplatin / Thiotepa)

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Appendix 2: Emetogenic risk of oncology regimens

Breast Cancer Name of Protocol Emetic Risk AC (60/600) Highly CMF IV (21 day) Moderate CMF IV Classical (Cyclo IV day 1&8 q28d) Moderate D1,8 CMF PO Classical (Cyclo PO days 1 to 14 (q28d) Moderate D1,8 EC Highly Trastuzumab Adjuvant 8/6 (21 day) Minimal FEC 60 Highly FEC 75/600 Highly FEC 75/500 Moderate FEC 100 Highly FEC 100 Highly FEC 75 Docetaxel Highly Docetaxel 100 Adjuvant (21 day) Low Capecitabine 1000 monotherapy Low Capecitabine 2000mg (7 days on 7 days off) Low Cyclophosphamide +/- Methotrexate Mild Docetaxel 75 Capecitabine 1250 Low Docetaxel 100 Capecitabine 1000 Low Doxorubicin 75 Moderate Doxorubicin 20 (7 day) Moderate Epirubicin 60 Moderate Epirubicin 20 (7 day) Moderate Eribulin Moderate Lapatinib + capecitabine Low MMM Low Docetaxel 100 metastatic (3 weekly) Low Docetaxel 40 weekly (day 1,8,15 q28d) Low Gemcitabine and Carboplatin Moderate Paclitaxel 175 (q21d) Low Paclitaxel 90mg (weekly) Low Paclitaxel 80mg (day 1,8,15 q28d) Low Paclitaxel albumin bound Low Paclitaxel Carboplatin Moderate Pacltiaxel/Gemcitabine (q21d) Low Trastuzumab 4/2 (weekly) Minimal Trastuzumab 8/6 (3 weekly) Minimal Vinorelbine 30 (3 weekly) Minimal Vinorelbine 25 (4 weekly) Minimal Vinorelbine oral (4weekly) Moderate D1,8,15 TCH Moderate Trastuzumab Emtansine Moderate

Central Nervous System Tumours Name of Protocol Emetic Risk PCV Moderate risk Temozolomide 150/200 Moderate risk 5 days Temozolomide and radiotherapy High risk Carboplatin Moderate risk Vincristine + VCP Vincristine single agent: minimal risk (Medulloblastoma) VCP – High risk day 1 Bevacizumab 2 weekly Minimal

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Colorectal cancer Name of Protocol Emetic Risk 5FU + FA with RT (weekly) Low risk 5FU + FA (weekly) Low risk 5FU (96 hour) with RT infusion Low risk 5FU (96 hour) with RT infusor Low risk Modified de Gramont infusor Low risk Capecitabine metastatic 1250 Low risk Capecitabine (5 day) with RT Low risk Capecitabine adjuvant 1250 Low risk Irinotecan 350 21 day Moderate Irinotecan + Modified de Gramont Moderate Irinotecan + Modified de Gramont + Cetuximab Moderate Irinotecan + capecitabine 21 day Moderate Oxaliplatin + Modified de Gramont Moderate Oxaliplatin + Modified de Gramont + cetuximab Moderate Mitomycin + Modified de Gramont Low risk Mitomycin + capecitabine 42 days Low risk Oxaplatin + capecitabine 21 day Moderate Panitumumab Minimal Raltitrexed Moderate Raltitrexed + oxaliplatin Moderate Cisplatin capecitabine Highly Mitomycin + capecitabine + RT Low – Moderate day 1 Mitomycin + fluorouracil (MF) continuous infusion Low risk Mitomycin + fluorouracil (MF) during RT continuous infusion Low risk Mitomycin + 5FU (MF) with RT <70 years infusion (inpt) Low risk Mitomycin + 5FU (MF) with RT <70 years infusion (daypt) Low risk Mitomycin + 5FU (MF) with RT >70 years infusion (inpt) Low risk Mitomycin + 5FU (MF) with RT >70 years infusion (daypt) Low risk Cisplatin + 5FU infusional (daypt) High risk Cisplatin + 5FU infusor (daypt) High risk Tegafur with Uracil (Uftoral) Low risk Trifluridine-Tipiracil Low risk

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Gynaecological Cancer Name of Protocol Emetic Risk BIP inpatient High risk Cisplatin 40 weekly with RT High risk Cisplatin 70 pre radiotherapy High risk Cisplatin 50 High risk Topotecan Cisplatin High risk BEP 3 day metastatic High risk D1,2, Low risk D3, Minimal D8,15 BEP 5 day metastatic Moderate risk D1-5 Lowrisk D8,15 BEP 3 day adjuvant High risk D1,2 Low risk D3 Minimal D8, 15 EMA/CO High risk Carboplatin AUC7 Moderate risk may need HR 5HT Methotrexate 50 Mildly Methotrexate weekly Mildly CAP High risk Paclitaxel carboplatin (21 day) Moderate risk may need HR 5HT Paclitaxel cisplatin High risk Carboplatin 21 day Moderate risk may need HR 5HT Carboplatin 28 days Moderate risk may need HR 5HT Cisplatin / oral etoposide High risk D1,8,15 Cisplatin weekly High risk Trabectadin and Liposomal Doxorubicin Low risk Cisplatin 21 day High risk Etoposide IV Low risk Etoposide oral Low risk Liposomal doxorubicin Low risk Paclitaxel 3 weekly (q21d) Low risk Paclitaxel weekly (q7d) Low risk Topotecan weekly Low risk Topotecan Low risk Gemcitabine carboplatin Moderate risk (met and dex) but may need 5HT Paclitaxel 7 day and carboplatin Moderate risk day 1 (met and dex but may need 5HT, D8,15 low risk Paclitaxel 7 days and carboplatin 7 days Moderate risk D1,8,15,22,29 Liposomal doxorubicin and carboplatin Moderate risk Doxorubicin Moderate risk Cisplatin 100 adjuvant High risk Doxorubicin + cisplatin High risk Doxorubicin + ifosfamide High risk D1,2,3 Doxorubicin (30) + ifosfamide (3g) High risk D1,2,3

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Head and Neck Cancer Name of Protocol Emetic Risk Cisplatin/Fluorouracil (CF) infusion CF 100 Aprepitant High risk D1 Low risk D2,3,4 Cisplatin/Fluorouracil (CF) infusor CF 100 Aprepitant High risk D1 Low risk D2,3,4 Cisplatin Docetaxel Fluorouracil (TPF) High risk D1 Low risk D 2,3,4 Cetuximab with Radiotherapy Minimal Cetuximab Minimal Cetuximab 2 weekly Minimal Cisplatin/Fluorouracil (CF 80) infusor day patient Aprepitant High risk D1 Low risk D2,3,4 Carboplatin/Fluorouracil infusor daypatient Moderate risk D1 Low risk D2,3,4 Cisplatin with Radiotherapy (100) Aprepitant High risk D1 Cisplatin with Radiotherapy (80) Aprepitant High risk D1 Cisplatin weekly with radiotherapy (40) Moderate risk D1 Docetaxel 75 Low risk Paclitaxel weekly Low risk Methotrexate weekly Minimal

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Lung Cancer Name of Protocol Emetic Risk ACE High risk D1 Low risk D2,3 CAV High risk Carboplatin Etoposide Moderate risk D1 Low risk D2,3 Cisplatin (75) Etoposide (100) High risk D1 Low risk D2,3 Cisplatin (60) Etoposide (120) High risk D1 Low risk D2,3 Topotecan oral Low risk Afatinib Minimal Ceritinib Minimal Cisplatin (50) Etoposide (50) with concurrent RT High risk D1,8,29,36 Cisplatin Vinorelbine with concurrent RT High risk D1-4 and 22-25 Minimal risk D8,19 and 26 Gemcitabine Cisplatin High risk D1 Low risk D8 Cisplatin 40 RT Moderate risk Crizotinib Minimal Docetaxel 75 Low risk Docetaxel (75) cisplatin (75) High risk Docetaxel (75) carboplatin Moderate/High risk Erlotinib Minimal Gefitinib Minimal Gemcitabine (1200) carboplatin Moderate risk D1 Minimal risk D8 Gemcitabine Low risk Nintedanib Docetaxel Low risk Osimertinib Minimal Paclitaxel 80mg (7 day) Low risk Pembrolizumab Low risk Vinorelbine (25) Carboplatin Moderate risk D1 Minimal risk D8 Vinorelbine (25) Cisplatin (80) High risk D1 Minimal risk D8 Vinorelbine Minimal Vinorelbine (oral) Moderate risk D1,8,15 Vinorelbine elderly (oral) Moderate risk D1,8 Vinorelbine (oral) Cisplatin High risk D1 Moderate risk D8 Vinorelbine (oral) carboplatin High risk D1 Moderate risk D8 Carboplatin Pemetrexed High risk Cisplatin/Pemetrexed High risk Maintenance Pemetrexed Low risk

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Rare Tumours Name of Protocol Emetic Risk Low risk Everolimus Minimal risk Steptozocin + Modified De Gramont High risk D1+8 Low risk D2+3 Streptozocin + capecitabine High risk Steptozocin/cisplatin/5FU(FCiST) inpatient High risk Sunitinib Minimal risk Temzolomide & capecitabine Low risk D1-9 Moderate risk D10-14 Capecitabine Low risk Cisplatin & etoposide inpatient High risk D1 Low risk D2,3 Doxorubicin/cisplatin/vincristine/cyclophosphamide High risk D1 (ACOC) inpatient Moderate risk D4 Cyclophosphamide, vincristine and dacarbazine (CVD) High risk D1,2 Cabozantinib Minimal risk Doxorubicin Thyroid Moderate risk Sorafenib Minimal risk Vandetanib Minimal risk 5FU/Cyclophosphamide/Dacarbazine High risk Doxorubicin/cisplatin/etoposide (EDP) inpatient Moderate risk D1,2 High risk D3,4 Cisplatin, methotrexate and bleomycin (PMB) High risk D1 Low risk D8

Skin Cancer Name of Protocol Emetic Risk Dacarbazine High risk Dabrafenib Low risk Dabrafenib Trametinib Low risk Ipilimumab Low risk Ipilimumab Nivolumab Low risk Vemurafenib Low risk Pembrolizumab Low risk Imiquimod None Cisplatin and fluouracil (CF) infusor day patient High risk D1 Low risk D2,3,4 Cisplatin and fluouracil (CF PS>2) infusor day patient Moderate risk D1 Low risk D2,3,4 Vismodegib Low risk Carbolatin etoposide Moderate risk D1 Low risk D2,3 Liposomal doxorubicin (Caelyx) Low risk Liposomal daunorubicin (Daunoxome) Moderate risk

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Upper Gastrointesinal Cancer Name of Protocol Emetic Risk Cisplatin + 5FU (CF 80 pre-op) infusor day patient High risk D1 Low risk D2,3,4 ECF High risk D1 Low risk D2-21 EC capecitabine (ECX) High risk D1 Low risk D2-21 Epirubicin, oxaliplatin and capecitabine (EOX) High risk D1 Paclitaxel carboplatin 21 day Moderate risk D1 Trastuzumab, capecitabine and cisplatin Cycles 1-6 High risk D1 Low risk D2-13

Cycles 7-18 Minimal risk Cisplatin + 5FU (CF 75 RT) + RT infusor day patient High risk D1 Low risk D2,3,4 Cisplatin + capecitabine + RT High risk D1 Low risk D2-21 Cisplatin + capecitabine High risk D1 Low risk D2-21 Docetaxel 75 Low risk Mitomycin + Fluorouracil (MF) Low risk Paclitaxel 7 day Carboplatin 7 day + RT Moderate risk Capecitabine (5 day) + RT Low risk Gemcitabine Low risk Gemcitabine + RT Low risk Gemcitabine and capecitabine Low risk Fluouracil continuous + RT Low risk Folfirinox High risk D1 Low risk D2 Oxaliplatin + capecitabine Moderate risk D1 Low risk D2-21 Gemcitabine + Paclitaxel albumin bound Moderate risk D1 Cisplatin + Modified De Gramont infusor daypatient High risk D1 Low risk D2,15,16 Gemcitabine (1000) + Cisplatin (25) day patient High risk D1 and 8 Sorafenib None required

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Urological Cancer Name of Protocol Emetic Risk Abiraterone Minimal risk Low risk Enzalutamide Minimal risk Mitoxantrone Low risk Docetaxel Low risk Docetaxel weekly Low risk CMV High risk D1 Minimal risk D8 Gemcitabine/cisplatin High risk D1 Minimal risk D8 Gemcitabine/carboplatin Moderate risk D1 Low risk D8 Gemcitabine + RT Mild risk Mitomycin fluorouracil + RT Low risk MVAC accelerated inpatient High risk D1 Paclitaxel carboplatin Moderate risk BEP 3 day (adjuvant) High risk D1,2 Low risk D3 Minimal risk D9,16 BEP 3 day (metastatic) High risk D1,2 Low risk D3 Minimal risk D9,16 BEP 5 day (metastatic) High risk D1-5 Minimal risk D9,16 Carboplatin AUC7 Moderate risk IPO High risk D1 Low risk D8,15 Paclitaxel/ifosfamide/cisplatin (TIP) High risk D1-5 POMB/ACE POMB: Moderate risk D1 Minimal risk D2 High risk D3 ACE: Moderate risk D1-3 PEC Moderate risk D1 High risk D15 EP (seminoma) High risk D1,2 Low risk D3 BEP (3 day) High risk D1,2 Low risk D3 Axitinib None required Everolimus Minimal risk Interferon (roferon) Non emetogenic Nivolumab None required Pazopanib Minimal risk Sunitinib Minimal risk Temsirolimus Minimal risk bladder installation weekly Non emetogenic Mitomycin c bladder installation 14 day Non emetogenic Mitomycin C bladder installation post op Non emetogenic BCG bladder installation Non emetogenic

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