Oxaliplatin plus Capecitabine (XELOX) Adjuvant Colorectal Cancer (GIWOS-007)

West of Scotland Cancer Network Chemotherapy Protocol Indication Oxaliplatin plus Capecitabine (XELOX) Adjuvant Colorectal Cancer (GIWOS-007) 1. Duke s C colon cancer patients 2. Duke s C rectal cancer patients 3. Poor prognosis Duke s B patients: T4, perforated, obstructed, extramural vascular invasion, poorly differentiated, <12 nodes examined. No direct evidence from RCT for the routine treatment of Duke s B. Case selection CONSIDER ENTRY INTO CLINICAL TRIAL IF AVAILABLE/APPROPRIATE Patients to be treated within this protocol should fulfil all of the following criteria:- Histologically proven stage Dukes «B» (certain patients as above) and «C» (stage III: any T N 1-2 M0) colon or rectal carcinoma. Patients must have undergone complete resection of the primary tumour without gross or microscopic evidence of residual disease Patients should ideally start treatment within 8 weeks after surgery PS 0-2 (Karnofsky 60%) No biological major abnormalities: Absolute neutrophil count 1.5 x 10 9 /l, Platelets 75 x 10 9 /l, Creatinine clearance 30ml/min, bilirubin 3 times upper limit of normal (ULN). CEA falling with the appropriate half life. Men and women who are fertile must use a medically acceptable contraceptive throughout the treatment period and for 6 months following cessation of treatment. Written informed consent Exclusion: Pregnant or lactating females / women of child bearing potential not using a contraceptive method Clinically significant cardiac disease uncontrolled coronary heart disease, unstable angina or myocardial infarction within last 6 months Malabsorption syndrome or inability to comply with oral medication Known or suspected DPD deficiency Known hypersensitivity to platinum based therapeutics Interstitial pneumonia or extensive symptomatic lung fibrosis Peripheral neuropathy of CTC (Version 3) grade 1 Other intercurrent serious illness which in the opinion of the treating consultant would render patient at risk of severe toxicity History of significant psychiatric disorder Page 1 of 9

Alternative therapy In some patients who may be considered for chemotherapy for advanced colorectal cancer the use of this protocol may be considered inappropriate. This may include patients with neuropathy not related to their cancer, patients with poor social circumstances or lack of support at home or those with extensive co-morbidity. Such patients may be treated with single agent capecitabine or alternative IV schedules of 5Fluorouracil (5FU). These are detailed in other protocols. Pre-treatment evaluation 1. Informed consent 2. Provision of verbal and written information. 3. Assessment of performance status 4. Height, weight and BSA 5. Referral letter from surgeon 6. Copy of pathology reports 7. Copy of CT or MRI reports 8. Baseline FBC, U&Es, LFTs and CEA calculate creatinine clearance using Cockcroft-Gault equation 9. Medical history and examination Regimen Pre-medication: Dexamethasone 8mg + Granisetron 3mg Intravenously 30 minutes prior to chemotherapy Drug Dose Route Administration Infusion fluid Oxaliplatin 130mg/m 2 I.V Over 2 hours 250ml Glucose 5%* Day to be given Day 1 Capecitabine 1000mg/m 2 Oral Twice daily N/A First dose to be taken on the evening of Day 1 following end of Oxaliplatin infusion for 14 days (last dose to be taken on morning of Day 15. 3 weekly for 8 cycles Capecitabine should be taken with plenty of water within 30 minutes after a meal Loperamide and Domperidone (or anti-emetic as per local policy) should be supplied to all patients with advice to be taken in the event of diarrhoea or nausea/vomiting occurring. Emetogenic Risk: MODERATE Page 2 of 9

Is GCSF indicated? Primary prophylaxis - Not recommended Secondary prophylaxis. Not routinely recommended. Consider dose reduction instead. Dose Banding Nomogram s calculate BSA to one decimal place (cap at 2.2 m 2 ) and select dose from table below Oxaliplatin BSA (m2) Oxaliplatin 130mg/m 2 Dose Banded dose (mg) 1.4 180 1.5 200 1.6 200 1.7 230 1.8 230 1.9 260 2.0 260 2.1 280 2.2 280 Capecitabine Capecitabine 1000mg/m2 BSA (m 2 ) Dose Banded dose (mg) 1.22 1150 1.23 1.4 1300 1.41 1.57 1500 1.58 1.72 1650 1.73 1.90 1800 1.91 2.07 2000 2.08 2.2 2150 Capecitabine 750mg/m2 BSA (m 2 ) Dose Banded dose (mg) 1.22 800 1.23 1.4 1000 1.41 1.57 1150 1.58 1.90 1300 1.91 2.07 1500 2.08 1650 Capecitabine 500mg/m2 BSA (m 2 ) Dose Banded dose (mg) 1.22 500 1.23 1.4 650 1.41 1.90 800 1.91 2.07 1000 2.08 1150 Page 3 of 9

Adverse effects Oxaliplatin Very Common Infection Haematological: anaemia, neutropenia,thrombocytopenia, leucopenia, lymphopenia Immune system: Allergic reaction Metabolism: anorexia, glycaemia abnormalities, hypokalaemia, natraemia abnormalities Nervous system: peripheral sensory neuropathy, sensory disturbance, headache Vascular: epistaxis Respiratory: dyspnoea, cough Gastrointestinal: nausea & vomiting, diarrhoea, stomatitis/mucositis, abdominal pain, constipation Skin: skin disorder, alopecia Musculoskeletal: back pain General: fatigue, fever,asthenia, pain, injection site reaction Investigations: increase in liver enzymes, AlkPhos, Bil Common Infection: rhinitis, febrile neutropenia Metabolism: dehydration Psychiatric disorders: depression, insomnia Nervous system: dizziness, motor neuritis Eye disorders: conjunctivitis, visual disturbances Vascular: flushing, haematuria, deep vein thrombosis, pulmonary embolism Respiratory: hiccups, chest pain Gastrointestinal: dyspepsia, gastrointestinal reflux Skin: skin exfoliation, rash, nail disorder Musculoskeletal: arthralgia, bone pain Renal: dysuria, abnormal micturition Oxaliplatin is associated with two types of neuropathy (see Dose modification table): 1. Laryngopharyngeal dysaesthesia - generally cold induced, short duration and self-limiting with no evidence bronchospasm although may cause shortness of breath. - reassure patient, avoid cold drinks and prolong oxaliplatin infusion time to 6 hours. 2. Mixed Sensory and Motor Neuropathy - transient at first between cycles becoming permanent with cumulative dosing Capecitabine Very Common Skin & Subcutaneous: palmer-plantar erythrodysesthesia Gastrointestinal: diarrhoea, nausea, stomatitis, vomiting, abdominal pain General disorders & administration site: fatigue, asthenia - may be cold induced and usually reversible. Common Haematological: neutropenia, anaemia Skin & Subcutaneous: rash, alopecia, erythema, dry skin, pruritis, skin hyperpigmentation; skin desquamation, dermatitis, nail disorder Gastrointestinal: constipation, dyspepsia, flatulence, dry mouth General disorders & administration site: lethargy, peripheral oedema, malaise Metabolism & Nutrition: dehydration, decreased appetite Nervous System: dizziness, headache, paraesthesia, lethargy Eye: increased lacrimation, conjunctivitis, eye irritation Hepatobiliary: hyperbilirubinemia Respiratory: dyspnoea, epistaxis, cough, rhinorrhea Musculoskeletal & Connective tissue: pain in extremeties, back pain, arthralgia Investigations: weight decreased Psychiatric: insomnia, depression Infection: nasopharyngitis Metabolism & Nutrition: anorexia Palmar-plantar erythrodysaesthesia should initially be managed by appropriate dose reduction see dose modifications. Pyridoxine 50 mg three times daily may have additional benefit for symptomatic relief. Page 4 of 9

Uncommon For more detailed information regarding Oxaliplatin and 5fluorouracil please refer to the full current summary of product characteristics (SPC). Extravasation risk category: Drug Group Category Oxaliplatin 2 Exfoliant Capecitabine N/A N/A Contraindications A known history of hypersensitivity to Oxaliplatin or Capecitabine or of severe and unexpected reactions to fluoropyrimidine therapy In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, In pregnancy and lactation Have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x10 9 /l and/or platelet count of <100x10 9 /l. Have a peripheral sensitive neuropathy with functional impairment prior to first course. Have a severely impaired renal function (CrCl < than 30 ml/min). Treatment with SORIVUDINE or its chemically related analogues, such as BRIVUDINE. Precautions Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiac shock, sudden death and ECG changes caution should be exercised in those patients with significant cardiac disease. There is a lack of safety and efficacy data in patients with hepatic impairment therefore use of Capecitabine should be carefully monitored regardless of the presence or absence of liver metastasis. In the case of unexplained respiratory symptoms (not as a result of pulmonary metastases) such as non-productive cough, dyspnoea, hypoxia or radiological infiltrates Oxaliplatin should be interrupted pending investigations. If interstitial pulmonary fibrosis is confirmed, discontinue Oxaliplatin. Drug Interactions Oxaliplatin Drug Interaction Action CLOZAPINE INCREASED RISK OF AGRANULOCYTOSIS AVOID CONCOMITANT USE Coumarin-derivative anticoagulants Increase in INR can occur up to one month after stopping Oxaliplatin therapy Monitor INR twice weekly consider switching to low molecular weight heparin Page 5 of 9

Capecitabine Drug Interaction Action SOROVUDINE AND ANALOGUES INHIBITION OF DIHYDROPYRIMIDINE DEHYDROGENASE AVOID CONCOMITANT USE POTENTIALLY FATAL Phenytoin Folinic Acid Coumarin-derivative anticoagulants Antacids Allopurinol Increase in plasma phenytoin concentration Potential for increased capecitabine toxicity Increase in INR can occur up to one month after stopping capecitabine therapy Increase capecitabine concentration Decreased efficacy of Capecitabine - theoretical Regular monitoring of plasma phenytoin levels Avoid concomitant use where possible Monitor INR twice weekly consider switching to low molecular weight heparin Not to be taken at same time of day Review risk of recurrence of Gout avoid concomitant use where possible. Investigations prior to subsequent cycles Medical review (or review by nurse/pharmacist in appropriate clinic) at each cycle with repeat FBC, U&Es, LFTs and toxicity assessment documented by CTCAE Version 3. Monitor CEA and LFTS for disease progression at each cycle visit. Monitor patients weight Dose modifications Haematological Treatment should be delayed until Neutrophils 1.5 x 10 9 /l and/or platelets 75 x 10 9 /l s are required for anaemia which should be treated by supportive transfusion if required. NEUTROPENIA GRADE 2 GRADE 3 GRADE 4 1.0 ANC<1.5 x 10 9 /L 0.5 ANC<1.0 x 10 9 /L ANC<0.5 x 10 9 /L 1 st occurrence 2 nd occurrence 3 rd occurrence Capecitabine 75% of original dose + Oxaliplatin 100mg/m 2 Capecitabine 75% of original dose + Oxaliplatin 85mg/m 2 Stop treatment (unless it is in the best interest of the patient to continue with capecitabine monotherapy at 75% of original dose Always discuss with responsible consultant Capecitabine 50% of original dose + Oxaliplatin 85mg/m 2 - Always discuss with responsible consultant Stop treatment Not applicable Page 6 of 9

Dose Modifications for febrile neutropenia should be made at the discretion of the responsible consultant GRADE 2 50 Plts <75 x10 9 /L THROMBOCYTOPENIA GRADE 3 10 Plts <50 x10 9 /L GRADE 4 Plts <10 x10 9 /L 1 st occurrence 2 nd occurrence Capecitabine 75% of original dose + Oxaliplatin 100mg/m 2 Capecitabine 75% of original dose + Oxaliplatin 85mg/m 2 3 rd occurrence Capecitabine 50% of original dose + Oxaliplatin 85mg/m 2 Capecitabine 50% of original dose + Oxaliplatin 85mg/m 2 - Always discuss with responsible consultant Stop treatment (unless it is in the best interest of the patient to continue with capecitabine monotherapy at 50% of original dose Always discuss with responsible consultant Stop treatment Non Haematological Specific dose adjustments may apply to Oxaliplatin and Capecitabine if the toxicity experienced is considered to be due solely to one drug e.g neuropathy with Oxaliplatin Treatment must be interrupted for toxicities grade 2 and cannot continue until toxicities resolve to grade 1. Any grade 4 toxicity MUST be discussed with the responsible consultant for a decision on the patient s future management. The non-haematological side-effects of this regimen are usually attributable to Capecitabine. and include: hand-foot syndrome, mucositis / stomatitis, nausea and vomiting and diarrhoea CAPECITABINE GRADE 2 GRADE 3 GRADE 4 Toxicity 1 st time Interrupt treatment until then continue at same dose with prophylaxis Interrupt treatment until then restart at 75% dose with prophylaxis Discontinue unless consultant feels it is in best interests to continue at 50% dose once recovered 2 nd time Interrupt treatment until then restart at 75% dose with prophylaxis Interrupt treatment until then restart at 50% dose Discontinue 3 rd time Interrupt treatment until then restart at 50% dose 4 th time Discontinue Discontinue For grade 3 nausea and vomiting or diarrhoea the dose of Oxaliplatin should be reduced to 100 mg/m 2 in addition to above. Page 7 of 9

Neuropathy In the case of oxaliplatin neurotoxicity, when oxaliplatin requires to be discontinued, it is permissible to continue therapy with single agent capecitabine. OXALIPLATIN GRADE 1-7 days 7 days Persistent Toxicity Paraesthesia that does not interfere with function 1 No change No change No change Paraesthesia that does not interfere with function but 2 No change No change 100 mg/m 2 not ADL Paraesthesia with pain or functional impairment that does interfere with ADL Persistent paraesthesia that is disabling or lifethreatening ACUTE laryngopharyngeal dysaesthesia Cardiac toxicity 3 No change 100 mg/m 2 Discontinue 4 Discontinue Discontinue Increase infusion Not duration to 6 hours applicable Discontinue Not applicable For grade 2 cardiac toxicity which is attributable to capecitabine this should be discontinued. Allergic Reactions For grade 1 or 2 hypersensitivity no dose modification of oxaliplatin is required if it is the patients best interests to continue discuss with responsible consultant. Pre-medication with dexamethasone, anti-histamines and H2 blockers given intravenously 30 minutes before drug administration should be used. For acute grade 3 or 4 hypersensitivity OXALIPLATIN SHOULD BE DISCONTINUED. Renal function Drug GFR % of full dose Capecitabine > 50ml/min Full dose 30 50ml/min 75% of dose < 30ml/min discontinue Limited information available for Oxaliplatin & renal impairment Hepatic If creatinine clearance < 30ml/min discuss with responsible consultant Limited information available No studies performed with Oxaliplatin in severe hepatic impairment Transient increases in bilirubin and/or AST/ALT are common with Capecitabine Drug Bilirubin AST/ALT % of full dose Comments Capecitabine > 3 ULN > 2.5 ULN discontinue Treatment may be restarted at full dose when Bilirubin < 3 ULN or AST/ALT <2.5 ULN Page 8 of 9

Evaluation of response to treatment CEA to be assessed with every cycle of chemotherapy Review by consultant within 1 month of treatment cessation to ensure follow-up policy is adhered to. For more detailed information regarding oxaliplatin or capecitabine please refer to the full current Summary of product Characteristics References 1. Summary of product Characteristics for Oxaliplatin August 2006 http://emc.medicines.org.uk/ 2. Summary of product Characteristics for Capecitabine June 2006 http://emc.medicines.org.uk/ 3. Cockcroft & Gault, Nephron 16: 31-41,1976 4. Cancer Therapy Evaluation Program, Common Terminolgy Criteria for Adverse Events, Version 3.0, DCTD, NCI,NIH, DHHS March 31, 2003 (http://ctep.cancer.gov), Publish date: December 12, 2003 5. Clinical trial protocol number N016966: A 2x2 factorial randomized Phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin ( XELOX ) with/without bevacizumab versus bolus and continuous infusion Fluorouracil / Intravenous Leucovorin with intravenous Oxaliplatin ( FOLFOX 4 ) with / without intravenous bevacizumab as first line treatment for patients with metastatic colorectal cancer. Roche August 4, 2003 Prepared By: Sarah Wilson, John Milne and Aisling Hennessey/Jim Cassidy Checked and Approved by: BOC colorectal site specific team Approved by: RCAG Prescribing Advisory Subgroup March 2007 Review date: March 2008 Page 9 of 9