Epirubicin, Cisplatin and Capecitabine (ECX) - Metastatic Gastric cancer (GIWOS-101/1)

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1 West of Scotland Cancer Network Chemotherapy Protocol Indication Epirubicin, Cisplatin and Capecitabine (ECX) - Metastatic Gastric cancer (GIWOS-101/1) Patients with inoperable gastric or oesophago-gastric junction cancer that is either locally advanced or with metastatic disease. Case Selection Inclusion Histologically or cytological proven documented adenocarcinoma of stomach Metastatic or locally advanced disease Performance status ECOG 0-2 Life expectancy of > 8 weeks No major biochemical abnormalities: Absolute neutrophil count 1.5, platelets > 100, Creatinine clearance (CrCl) >60ml/min, Bilirubin 2 x upper limit of normal (ULN), hepatic transaminases (AST/ALT) 3 ULN Men and women who are fertile must use a medically acceptable contraceptive throughout the treatment period and for 6 months following cessation of treatment. Exclusion Pregnant or lactating females / woman of child bearing potential not using a contraceptive method Current or previously significant cardiac disease LVEF < 50%, uncontrolled congestive heart disease, unstable angina or myocardial infarction within the last 6 months Other intercurrent serious illness which in the opinion of the treating consultant would render patient at risk of severe toxicity History of significant neurologic or psychiatric disorders Any patient with complete dysphagia CNS metastases Pre-treatment evaluation Informed signed consent Assessment of performance status Height, weight and body surface area (BSA) Baseline FBC, U&Es, & LFTs - calculate CrCl using cockcroft-gault equation. (If calculated CrCl < 60ml/min ensure EDTA arranged prior to first cycle of chemotherapy. Baseline ECG, ECHO where appropriate (at clinicians discretion) Ideally discuss case at MDT and review pathology Copy of CT or MRI reports Medical history and examination Written and verbal information given to patient and carer/family member where appropriate.

2 Regimen Fluid hydration as per local policy must be administered pre and post cisplatin Drug Dose Route Admin Infusion Fluid Schedule * Epirubicin 50mg/m 2 I.V Slow bolus Via fast flowing Saline drip 3 weekly Cisplatin 60mg/m 2 I.V Over 4 hours 1000ml Sodium Chloride 0.9% 3 weekly Capecitabine 625mg/m 2 Oral Twice daily N/A CONTINUOUSLY * Epirubicin may be administered over 15 minutes in 100ml Sodium Chloride 0.9% if patient has a central intravenous line in situ (i.e Hickman line or PICC line) 6 cycles to a maximum of 8 in total. Capecitabine should be taken with plenty of water within 30 minutes of eating Loperamide should be supplied to all patients with advice to be taken in the event of diarrhoea occurring. Emetogenic Risk: HIGH refer to local anti-emetic policy Extravasation risk category: Drug Epirubicin Cisplatin Capecitabine Category Vesicant Exfoliant N/A Adverse effects Cardiotoxicity, Myelosuppression, Nausea & Vomiting, Diarrhoea, Stomatitis, Nephrotoxicity, Ocular toxicity, Neuropathy, Ototoxicity, Serum electrolyte disturbances, Palmer plantar erythema, Alopecia, fatigue Uncommon: Refer to medicines compendium for comprehensive list of undesirable effects Contraindications Hypersensitivity to capecitabine, fluorouracil, epirubicin, cisplatin or to any of the excipients of these drugs Known dihydropyrimidine dehydrogenase (DPD) deficiency Patients previously treated with maximum cumulative doses epirubicin or any other anthracycline Patients with current or previously significant cardiac disease (please refer to exclusion criteria) During pregnancy and lactation Patients with severe leucopenia, neutropenia or thrombocytopenia Patients with severe renal impairment (CrCl < 40 ml/min cockcroft-gault equation) Patients with hearing impairment Treatment with SOROVUDINE or its chemically related analogues, such as brivudine. Precautions Cardiac monitoring is essential: Epirubicin is cardiotoxic, maximum cumulative dose of 900mg/m2 should never be exceeded. Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrrhythmias, cardiac shock, sudden death and ECG changes caution should be exercised in those patients with significant cardiac disease (see SPC for full details).

3 Liver function monitoring is essential: Epirubicin is mainly excreted via the hepatobiliary system therefore caution should be exercised in hepatic impairment (see dose modifications) Cisplatin produces cumulative nephrotoxicity which may be potentiated by aminoglycoside antibiotics. Monitor blood biochemistry before each chemotherapy cycle Cisplatin induced neurotoxicity and ototoxicity is cumulative. Monitor carefully throughout treatment Epirubicin may impart a red colour to the urine for one or two days after administration Drug Interactions Epirubicin - cimetidine may increase plasma levels - avoid concomitant use. Dexrazoxane, quinine, dexverapamil, taxanes, interferon may also interact - obtain advice from pharmacy Cisplatin - nephrotoxicity and ototoxicity may be exacerbated by treatment with other nephrotoxic/ototoxic drugs e.g aminoglycoside antibiotics, loop diuretics. May reduce phenytoin serum levels note below. Capecitabine Drug Interaction Action SOROVUDINE AND ANALOGUES INHIBITION OF DIHYDROPYRIMIDINE DEHYDROGENASE AVOID CONCOMITANT USE POTENTIALLY FATAL Phenytoin Increase in plasma phenytoin concentration nb cisplatin may reduce plasma levels Regular monitoring of plasma phenytoin levels Folinic Acid Potential for increased capecitabine toxicity Avoid concomitant use where possible Coumarin-derivative Increase in INR can occur up to one month Monitor INR twice weekly anticoagulants after stopping capecitabine therapy Antacids Increase capecitabine concentration Not to be taken at same time of day Allopurinol Decreased efficacy of Capecitabine - theoretical Review risk of recurrence of Gout avoid concomitant use where possible. Investigations prior to subsequent cycles FBC, U&Es & LFTs weight & performance status assessment of toxicity, documented by CTCAE version 3.0 Dose modifications GCSF not recommended. consider dose reduction instead. Haematological Result Value Action Neutrophils (x 10 9 /l) > 1.0 Full dose Delay until > 1.0. Reduce Epirubicin next cycle by 25% < 0.5 Delay until > 1.0. Reduce Epirubicin next cycle by 50%. Always discuss with responsible consultant NB Reduce Epirubicin by 25% if greater than 2 week delay due to neutropenia FEBRILE NEUTROPENIA (GRADE 3 OR 4) AT ANY TIME DURING CYCLE MUST BE DISCUSSED WITH THE RESPONSIBLE CONSULTANT FOR APPROPRIATE DOSE MODIFICATIONS.

4 Result Value Action Platelets (x 10 9 /l) > 75 Full dose Delay until > 75. Reduce Epirubicin next cycle by 25% Delay until > 75. Reduce Epirubicin next cycle by 50%. Always discuss with responsible consultant < 25 Delay until > 75. Omit Epirubicin from subsequent cycles. Always discuss with responsible consultant Renal Drug GFR (ml/min) % of full dose Comments Epirubicin No dose reduction necessary Cisplatin > Dose = GFR EDTA MUST be performed. Discuss with responsible consultant < 40 Omit Discuss with responsible consultant. Consider Carboplatin Capecitabine > <30 omit Hepatic Drug Bil AST/ALT Alk Ph % of full dose Comments (ULN) Epirubicin > 1.5 Omit Until returns to <1.5 d/w pharmacy for further dose adjustment. Cisplatin No modification Capecitabine > 3 > 2.5 NA Omit May be transient increase, may be restarted when normal levels resumed Other Toxicity Grade Action Non-haematological toxicities 3 or 4 Delay treatment until resolution to grade 0 to 1. Discuss with consultant for future dose modifications Cardiac Any unexplained should be evaluated with MUGA and omit Epirubicin if cardiac function compromised Neurotoxicity > 2 Omit Cisplatin - Discuss with responsible consultant. Consider Carboplatin Ototoxicity New functional deterioration in hearing, tinnitus or significant high frequency hearing loss on audiogram Omit Cisplatin Palmer Plantar Erythema 2 Delay capecitabine until resolved to grade 0-1 then restart capecitabine at 15% dose reduction. Consider Pyridoxine 3 Delay capecitabine until resolved to grade 0-1 then restart capecitabine at 30% dose reduction. Consider Pyridoxine

5 See below for capecitabine dose modifications for non-haematological toxicities: Grade 2 Grade 3 Grade 4 1 st appearance Delay until resolved to grade 0-1 then same dose Delay until resolved to grade 0-1 then continue 2 nd appearance of same toxicity Delay until resolved to grade 0-1 then continue at 75% dose 3 rd appearance Delay until resolved to grade 0- of same toxicity 1 then continue at 50% dose 4 th appearance Discontinue at 75% dose Delay until resolved to grade 0-1 then continue at 50% dose Discontinue Delay until resolved to grade 0-1 then discuss with responsible consultant. Evaluation of response to treatment Formal disease assessment by CT scan should be performed at 3 rd cycle of therapy it may be more frequent in patients with suspected early progression. Only those patients with disease stabilisation or response should go on to 6 cycles of treatment. Second line therapy - if patients are fit they should be considered for Phase I clinical trials References 1. Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O'Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol Jan;15(1): D. Cunningham Md, S. Rao, N. Starling, T. Iveson, M. Nicolson, F. Coxon, G. Middleton, F. Daniel, J. Oates, A. R. Norman, NCRI Upper GI Study Group Randomised multicentre phase III study comparing capecitabine with 5FU and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: The REAL 2 trial Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: LBA Summary of Product Characteristics see 4. Cockcroft & Gault, Nephron 16: 31-41, Cancer Therapy Evaluation Program, Common Terminolgy Criteria for Adverse Events, Version 3.0, DCTD, NCI,NIH, DHHS March 31, 2003 ( Publish date: December 12, 2003 Written by: Sarah Wilson, John Milne Approved by: A Hennessey on behalf of BWOSCC Upper GI site specific team RCAG Prescribing Advisory Subgroup Dec 2007 Date prepared: January 2008 Review Date: January 2010

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