EOX Page 1 of 6 As an alternative to ECX: For locally advanced (inoperable) or metastatic oesophageal or gastric cancer For patients able to take oral medications Drugs/Dosage: Epirubicin 50mg/m 2 IV D1 Oxaliplatin 130mg/m 2 IV D1 Capecitabine 625mg/m 2 PO BD daily throughout treatment (Refer to the dose banding table for prescribing Capecitabine dose, appendix 1.) Administration: Frequency: Main Toxicities: Epirubicin via fast running infusion of 0.9% Sodium Chloride Oxaliplatin in 250ml-500ml 0.5% Glucose IV over 2 hours Capecitabine tablets (available as 500mg and 150mg) should be swallowed whole with water within 30 minutes after a meal. 3 weekly cycle Advanced / metastatic use: 8 cycles (CT scan after cycles 4 and 8) myelosuppression, diarrhoea, mucositis, nephrotoxicity, nausea/vomiting, alopecia, palmar-plantar erythema (PPE), peripheral neuropathy, cardiotoxicity (see Comments),ovarian failure/infertility Anti-emetics: Day 1: highly emetogenic Days 2 21: mildly emetogenic Extravasation: Epirubicin is a vesicant Supportive medication: Loperamide tablets 4mg stat, then 2mg prn for diarrhoea Pyridoxine tablets 50mg tds, if required for palmar-plantar erythema (PPE) Regular FBC D1 Investigations: LFTs & U&Es D1 Mg 2+ and Ca 2+ D1 MUGA scan see Comments ECG if previous history of heart disease Comments: Maximum cumulative dose Epirubicin = 950mg/m 2 Page 1 of 6
Toxicities and Dose Modifications Page 2 of 6 Haematological toxicity: Day 1 haematological toxicity (EOX). Neutrophils/ platelets (x 10 9 /l) Immediate action Dosing after recovery & for subsequent cycles Neutrophils 1.0 and/ or platelets 75 Continue treatment if otherwise well tolerated 100% doses (EOX) Neutrophils 0.5-0.9 and/ or Capecitabine 100% dose Delay until recovered and within platelets 50-74 Epirubicin 75% dose normal parameters, then Neutrophils < 0.5 and/ or platelets 25-49 platelets < 25 Discuss with consultant. Delay until recovered and within normal parameters, then Oxaliplatin 100mg/m² (from 130mg/m²) Capecitabine 100% dose Epirubicin 50% dose Oxaliplatin 100mg/m² (from 130mg/m²) Capecitabine 100% dose Omit Epirubicin Oxaliplatin 100mg/m² (from 130mg/m²) Renal Impairment Before every course, calculate CrCl using Cockcroft and Gault. If borderline, an EDTA should be requested. Creatinine Clearance (ml/min) Capecitabine Dose Oxaliplatin Dose > 50 Give 100% dose Give 100% dose 30 50 (discuss with consultant) Give 75% dose Give 100% dose < 30 Omit Omit Hepatic Impairment Hepatic Impairment: Bilirubin (µmol/l) Epirubicin Dose 24-51 Give 50% dose 52-85 Give 25% dose > 85 Omit If bilirubin > 3 x ULN or ALT/AST > 2.5 ULN, omit capecitabine until liver function recovers. Non-Haematological Reduce Epirubicin dose to 75% of previous dose in Grade 3-4 stomatitis. In Grade 3 or 4 diarrhoea or stomatitis reduce Oxaliplatin dose to 100mg/m 2. Page 2 of 6
Oxaliplatin and Neurotoxicity Page 3 of 6 Acute Cold-related Dysaesthesia (CRD): Many patients experience transient paraesthesia of hands & feet. Onset is during or within hours of infusion, and resolves within minutes to a few days. Symptoms are exacerbated by cold, so patient should be well advised on precautions to be taken. Does not require treatment or dose reduction. Acute laryngopharyngeal dysaesthesia: Some patients experience laryngopharyngeal dysaesthesia (unpleasant sensations in the throat). Onset is during or within hours of infusion, and resolves within minutes to a few days. Symptoms are exacerbated by cold, so patient should be well advised on precautions to be taken. Does not require dose reduction. Clinical symptoms Laryngo-pharyngeal dysesthesia Platinum hypersensitivity dyspnoea Present Present bronchospasm Absent Present Laryngospasm Absent Present Anxiety Present Present O2 saturation Normal Decreased Difficulty swallowing Present (loss of sensation) Absent Pruritus Absent Present Cold induced symptoms Yes no Blood pressure Normal or increased Normal or decreased treatment Anxiolytics; observation in a Oxygen, steroids, adrenaline, controlled clinical setting until bronchodilators, antihistamine; symptoms abate or at clinician s Fluids and vasopressors if discretion appropriate Subsequent infusions following laryngo-pharyngeal dysesthesia should be given over 6 hours. Cumulative Dose related peripheral sensory neuropathy Usually occurs after a cumulative dose of 800mg/m 2. Localized moderate paresthesias or paresthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation. Grade 1 of any duration or grade 2 paraesthesias continue with oxaliplatin 130mg/m 2 lasting longer than 7 days Grade 2 paraesthesias persisting until next cycle reduce oxaliplatin dose to 100mg/m 2 Grade 3 paraesthesias lasting longer than 7 days reduce oxaliplatin dose to 100mg/m 2 Grade 3 paraesthesias persisting until next cycle discontinue oxaliplatin permanently or Grade 4 of any duration discontinue oxaliplatin permanently Page 3 of 6
Capecitabine and neurotoxicity Toxicities: Note that severe diarrhoea and/or severe mucositis early in the first treatment cycle can be the first presenting toxicity due to DPD enzyme deficiency, in which case potentially fatal neutropenia can quickly follow. Page 4 of 6 Neurotoxicity Capecitabine toxicities may be managed symptomatically, with modification of the dose (treatment interruption or dose reduction) according to the information below. Once the dose has been reduced, it should not be increased at a later time. Capecitabine doses omitted for toxicity are not replaced or restored. Capecitabine Dose Adjustment Guidelines for Non-Haematological Toxicities Dose adjustment for next Common Toxicity Criteria During Course of Therapy cycle (% of start dose) Grade 1 Maintain dose level Maintain dose level Grade 2: 1 st Appearance Interrupt until resolved to Give 100% dose, except if PPE give 85% dose* Grade 2: 2 nd Appearance Interrupt until resolved to Give 75% dose Grade 2: 3 rd Appearance Interrupt until resolved to Give 50% dose Grade 2: 4 th Appearance Discontinue treatment permanently Grade 3: 1 st appearance Interrupt until resolved to Give 75% dose, except if PPE give 70% dose* Grade 3: 2 nd appearance Interrupt until resolved to Give 50% dose Grade 3: 3 rd appearance Discontinue treatment permanently Grade 4: 1 st appearance Discontinue permanently or, with Consultant approval, interrupt until resolved to Give 50% dose * If PPE Grade 2 3 occurs after 10 weeks, stop capecitabine. On resolution of toxicity, NO dose reduction is necessary. Allergic reactions to oxaliplatin during infusion Immediate intervention is to stop the infusion and call for medical help. Treat with IV corticosteroid and antihistamine. At Consultant discretion, the patient may be re-challenged with oxaliplatin on the next cycle, with the following premedication prescribed: Dexamethasone 4mg po 6hrly x 3 doses, starting 24hrs pre-treatment, plus 8mg IV 30 minutes pre dose and Chlorphenamine 10mg IV and Ranitidine 50mg IV 30 minutes pre-dose. Page 4 of 6
Page 5 of 6 Other Toxicities Oxaliplatin therapy should be interrupted if symptoms indicative of pulmonary fibrosis develop nonproductive cough, dyspnea, crackles, rales, hypoxia, tachypnea or radiological pulmonary infiltrates. If pulmonary fibrosis is confirmed oxaliplatin should be discontinued. Oxaliplatin therapy should be interrupted if Hemolytic Uremic Syndrome (HUS) is suspected: hematocrit is <25%, platelets<100,000 and creatinine > 135 umol/l. If HUS is confirmed, Oxaliplatin should be permanently discontinued Cardiotoxicity Any patient who develops cardiac failure while on treatment should permanently discontinue epirubicin. Coronary artery spasm is a recognised complication of capecitabine although the evidence base regarding aetiology, management & prognosis is not particularly strong. The incidence is estimated to be between 2% and 18%. Coronary artery spasm is usually reversible on discontinuing the treatment. Should a patient receiving capecitabine present with chest pains, stop the treatment. Standard investigation and treatment of angina may be required. If re-challenge is deemed necessary, this can be performed under close supervision, but should symptoms redevelop, capecitabine should be withdrawn permanently. Refer to Consultant to discuss. Drug interactions: Phenytoin, Carbamazepine (Cisplatin, Capecitabine) Coumarin anticoagulants-monitor INR (Capecitabine) Folinic acid- increased toxicity (Capecitabine) Allopurinol- reduced efficacy (Capecitabine) Antacids- absorption interference (Capecitabine) Ciclosporin, Verapamil, Cimetidine- increased serum levels (Epirubicin) References: Cunningham D. et al. NEJM 2008; 358(1):36-46 Okines A.F.C. et al. Ann Oncol. 2009; 20:1529-1534 REAL 3 study protocol, version 5, July 2010 www.medicines.org.uk www.micromedex.com Page 5 of 6
Appendix 1. Page 6 of 6 Capecitabine Dose Calculation according to BSA Dose Level 625 mg/m 2 Number of tablets administered Number of tablets administered in the morning in the evening BSA (m 2 ) Dose per 150mg 500mg 150mg 500mg administration (mg) 1.26 750 5-5 - 1.27 1.38 800 2 1 2 1 1.39 1.52 950 3 1 3 1 1.53 1.66 1000-2 - 2 1.67 1.78 1100 4 1 4 1 1.79 1.92 1150 1 2 1 2 1.93 2.06 1300 2 2 2 2 2.07 2.18 1300 2 2 2 2 2.19 1450 3 2 3 2 Page 6 of 6