Regimen : EOX (Epirubicin, Oxaliplatin and Capecitabine (Xeloda )) Indication Regimen details Administration First line palliative treatment for locally advanced, inoperable oesophago-gastric cancer for patients unsuitable for radical therapy. Day Drug Dose Route 1 Epirubicin 50mg/m 2 IV bolus 1 Oxaliplatin 130mg/m 2 IV infusion 1-21 Capecitabine 625mg/m 2 Twice Daily PO Order of administration: epirubicin first, oxaliplatin second. Epirubicin is administered by slow intravenous bolus in to the side arm of a fast flowing drip of 0.9% sodium chloride. Oxaliplatin is administered in 250-500ml Glucose 5% over 2 hours. If patients experience laryngo-pharyngeal dyaesthesia (see below), subsequent infusions should be should be given over 4-6 hours. Infusions must be diluted in Glucose 5% as oxaliplatin is not compatible with Sodium Chloride 0.9%. Lines must not be piggybacked or flushed with Sodium Chloride 0.9% immediately after the Oxaliplatin infusion. Patients should be observed closely for platinum hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of oxaliplatin. Facilities for the treatment of hypotension and bronchospasm must be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require discontinuation of therapy: the infusion may be temporarily interrupted and when symptoms improve re-started at a slower infusion rate. Chlorphenamine 10mg IV may be administered. Severe reactions, such as hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of oxaliplatin and appropriate therapy. Cryotherapy (ice cubes) should NOT be used as they may exacerbate oxaliplatin-induced pharyngo-laryngeal dyaesthesias. Similarly, laryngopharyngeal dyaesthesia may be exacerbated by exposure to cold air. If this occurs during infusion, stop infusion immediately and observe patient. Check oxygen saturation: if normal, an anxiolytic agent (e.g.lorazepam 1mg SC/PO/IV) may be given. The infusion can then be restarted at a slower rate (between 4-6 hours) Capecitabine tablets should be swallowed whole with water within 30 minutes of eating a meal. Available as 500mg and 150mg tablets. Doses should be banded in accordance with the table below: Controlled document Document Number Version Number Page 1 of 6
Body Surface Area (m 2 ) Dose level 625mg/m 2 bd Dose (mg) to be given twice daily 1.25 1.36 800 1.37 1.52 1000 morning, 800 evening 1.53 1.66 1000 1.67 1.78 1150 morning, 1000 evening 1.79 1.90 1150 1.91 2.04 1500 morning, 1000 evening 2.05 2.16 1300 2.17 2.32 1500 morning, 1300 evening 2.33 1500 Frequency Every 21 days Maximum 8 cycles Extravasation Epirubicin is a vesicant (Group 5) Oxaliplatin is an exfoliant (Group 4) Capecitabine is an oral agent. Premedication None usually required. 1. Patients who have previously experienced Grade 1 or 2 platinum hypersensitivity should be pre-medicated with as follows: 45 minutes prior to Oxaliplatin: Dexamethasone 20mg IV bolus 30 minutes prior to Oxaliplatin: Chlorphenamine 10mg IV bolus and Ranitidine 50 mg IV bolus diluted in at least 20ml Sodium Chloride 0.9% and given over at least 2 minutes. 2. Patients who develop peripheral neuropathy may be considered for calcium gluconate 1g and magnesium sulphate 1g given together in 250mL 5% Glucose IV over 20 minutes pre- and post-oxaliplatin infusion. Caution is required in giving this treatment to patients with known hypercalcemia or those receiving therapy with digoxin or thiazide diuretics. Emetogenicity This regimen has high emetogenic potential refer to local protocol Additional recommended supportive medication Pre-treatment evaluation Regular investigations Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant Mouthwashes as per local policy. Loperamide 4mg po stat then 2mg prn if diarrhoea develops. Pyridoxine 50 mg tds reduces the severity of plantar-palmar erythrodyesthesia (PPE). It should be given for any grade PPE and should be continued until the end of treatment. FBC Baseline results valid for 14 days U+E Baseline results valid for 14 days LFT Baseline results valid for 14 days FBC Results valid for 72 hrs U+E Results valid for 7 days LFT Results valid for 7 days Ca 2+ and Mg 2+ Results valid for 7 days CT scan Perform after 4 cycles of treatment Neutrophil count 1.0 x10 9 /L Platelet count 75 x10 9 /L Creatinine clearance Bilirubin 50 ml/min <1.5 x ULN Controlled document Document Number Version Number Page 2 of 6
Dose modifications Haematological toxicity Neutrophil count Platelet count Action 1.0 75 Go ahead Full dose 0.5-0.9 50-74 Stop capecitabine and delay next cycle until count Dose modification once count recovery Restart capecitabine at full dose, epirubicin at 75% dose and oxaliplatin at 100mg/m 2 Renal impairment Hepatic impairment NCI Common toxicity criteria CrCl (ml/min) Capecitabine Oxaliplatin Epirubicin >50 100% 100% 100% 30-49 75% 75% 100% <30 Contra-indicated Omit Omit Bilirubin Epirubicin <1.5 x ULN 100% 1.5-3 x ULN 50% 3-5 x ULN 25% >5 x ULN Omit Capecitabine: Lack of information available. In patients with mild to moderate hepatic dysfunction due to liver metastases (<3 x ULN bilirubin; <5 x ULN AST/ALT). Probably no dose reduction necessary: clinical decision Oxaliplatin: Little information available. Probably no dose reduction necessary: clinical decision Toxicity Definition Dose adjustment Neurotoxicity (Oxaliplatin) Grade 1 paraesthesia Grade 2 paraesthesia persisting until next cycle 100% Reduce dose to 100mg/m 2 Controlled document Document Number Version Number Page 3 of 6
Grade 3 paraesthesia >7 days but resolved before next cycle Reduce dose to 100mg/m 2 Grade 3 Discontinue oxaliplatin paraesthesia persisting until next cycle or Grade 4 of any duration 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 advised to avoid cold. 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 advised to avoid cold drinks. Does not require treatment or dose reduction. Palmar-Plantar Erythrodyesthesia (Capecitabine) Diarrhoea/Mucositis and Stomatitis * (Capecitabine) Grade 1:Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain Grade 2: Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL Grade 3: Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self care ADL 100% resume at 100% 3 rd appearance: delay until 3 rd appearance: discontinue Grade 1 100% Grade 2 resume at 100% 3 rd appearance: delay until Grade 3 Controlled document Document Number Version Number Page 4 of 6
Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/reference texts Comments 3 rd appearance: discontinue Grade 4 Discontinue * 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. This can lead to potentially fatal neutropenia. Serious side effects Myelosuppression (common) Cardiomyopathy / toxicity Frequently occurring side effects Peripheral Neuropathy Diarrhoea Secondary malignancy Palmar-plantar erythrodyesthesia Ovarian failure/infertility Alopecia (complete) Nephrotoxicity Stomatitis/ Mucositis Nausea and vomiting Pink urine for 24 hours post epirubicin Fatigue Other dysgeusia, headache, dizziness Warfarin/courmarin anticoagulants Avoid use switch patients to low molecular weight heparin during treatment elevations in INR Oxaliplatin: Aminoglycosides: increased risk of nephrotoxicity and possibly of ototoxicityavoid concomitant use Diuretics: increased risk of nephrotoxicity and ototoxicity when platinum compounds given with diuretics Capecitabine: Phenytoin and fosphenytoin toxicity has occurred during concomitant capecitabine therapy monitor levels regularly. Sorivudine and its analogues co-administration causes increased fluoropyrimidine toxicity which may be fatal Allopurinol A decrease in capecitabine activity as been shown when taken in combination of allopurinol. Avoid if possible. Folinates Avoid concomitant use of folinic and folic acid enhanced toxicity of capecitabine Antacids the use of antacids with capecitabine can decrease absorption avoid. Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe toxicity secondary to reduced fluorouracil metabolism avoid use of capecitabine in patients with known DPD deficiency Cardiotoxicity has been associated with fluoropyrimidine therapy, with adverse events being more common in patients with a prior history of coronary artery disease. Caution must be taken in patients with a history of significant cardiac disease, arrhythmias or angina pectoris. Cumulative Doses Epirubicin has a life time maximum cumulative dose of 900mg/m 2 References Cunningham D, Rao S, Starling N, Iveson T, Nicolson M, Coxon F, et al. Randomised multicentre phase III study comparing capecitabine Controlled document Document Number Version Number Page 5 of 6
with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophago-gastric (OG) cancer: The REAL 2 trial. J Clin Oncol 2006. 24;18S (June 20 supplement abstract):4017. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, et al. Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer N Engl J Med 2008; 358: 36-46. Daniels S. North London Cancer Network, Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 12/01/2011 available at http://www.bopawebsite.org/tikidownload_file.php?fileid=621 Daniels S. North London Cancer Network, Dose adjustment forcytotoxics in renal impairment [internet]. accessed 12/01/2011 available at http://www.bopawebsite.org/tikidownload_file.php?fileid=620 Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; 2009. Accessed online on 06/05/09 available at https://www.medicinescomplete.com/mc/ Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press. 2002. Summary of Product Characteristics Epirubicin Hydrochloride 2mg/ml Injection (Hospira) [internet]. accessed 23/02/2011 available from http://www.medicines.org.uk/emc/medicine/18609/spc Summary of Product Characteristics Oxaliplatin Hospira 5mg/ml concentration for solution for infusion (Hospira) [internet]. accessed 14/01/2011 available from http://www.medicines.org.uk/emc/medicine/20911/spc Summary of Product Characteristics Xeloda (Capecitabine) 500mg and 150mg Tablets (Roche) [internet], accessed 23/02/2011 available from http://www.medicines.org.uk/emc/medicine/4619/spc/xeloda/ Document title EOX (Epirubicin, Oxaliplatin and Capecitabine (Xeloda )) Document number ASWCS11 GI001 Approval date 19/07/2011 Written by Stephen Falk, Consultant Clinical Oncologist BHOC Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jeremy Braybrooke, Chair ASWCS Drugs and Therapeutics Committee Review date 19/07/2013 Document reviewed by Version number 1.1.a Summary of changes Version 1.1.a Controlled document Document Number Version Number Page 6 of 6