CONSIDER ENTRY INTO CLINICAL TRIAL IF AVAILABLE/APPROPRIATE

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1 West of Scotland Cancer Network Chemotherapy Protocol Capecitabine Adjuvant Colorectal Cancer (GIWOS-008) Capecitabine is an oral tumour-activated fluropyrimidine which as a result of the X-ACT trial has been shown to be an effective alternative to intravenous 5FU/Folinic acid, for many years the standard adjuvant treatment for stage III colon cancer. The X-ACT trial (first presented ASCO 2004, updated ASCO2005) achieved its primary endpoint of at least equivalence in Disease Free Survival (DFS) 3 years 64.1% for Capecitabine vs. 60.6% for MAYO clinic regimen). Capecitabine improved RFS (65.5% vs. 61.9%) HR 0.86 and was associated with significantly fewer adverse effects compared to 5FU/LV 1. Indication 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 Inclusion: 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 Other intercurrent serious illness which in the opinion of the treating consultant would render patient at risk of severe toxicity History of significant psychiatric disorders Page 1 of 5

2 Pre-treatment evaluation Informed signed consent Assessment of performance status Height, weight and body surface area (BSA) Referral letter from surgeon Copy of histopathology reports Copy of CT or MRI reports Ideally discuss case at MDT and review pathology Baseline FBC, U&Es, LFTs and CEA calculate CrCl using cockcroft-gault equation. Medical history and examination Written and verbal information given to patient and carer/family member where appropriate. Regimen Capecitabine 1250mg/m 2 TWICE daily for 14 days of a 21 day cycle. Total of 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: LOW Dose Banding Nomogram calculate BSA (cap at 2.2 m 2 ) and select dose from table below Dose per administration B.S.A. (m 2 ) 100% 1250mg/m 2 950mg/m 2 625mg/m 2 </= >/= mg 1650mg 1800mg 2000mg 2150mg 2300mg 2500mg 2650mg 2800mg 1150mg 1450mg 1500mg 1650mg 1800mg 1950mg 2000mg 2150mg 800mg 800mg 950mg 1000mg 1000mg 1150mg 1450mg Adverse effects Very Common Skin & Subcutaneous: palmerplantar erythrodysesthesia Gastrointestinal: diarrhoea, nausea, stomatitis, vomiting, abdominal pain General disorders & administration site: fatigue, asthenia Metabolism & Nutrition: anorexia 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, paresthesia, 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 Page 2 of 5

3 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 Uncommon: Refer to medicines compendium for comprehensive list of undesirable effects Contraindications History of severe and unexpected reactions to fluoropyrimidine therapy, Hypersensitivity to capecitabine or to any of the excipients or fluorouracil, Known dihydropyrimidine dehydrogenase (DPD) deficiency, During pregnancy and lactation, In patients with severe leucopenia, neutropenia or thrombocytopenia. In patients with severe renal impairment (creatinine clearance below 30 ml/min Cockcroft and Gault), 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. Drug Interactions 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 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 early relapse at each cycle visit. Monitor patients weight Page 3 of 5

4 Dose modifications The following dose modifications are provided as guidance from the Summary of product characteristics for capecitabine 10 however they are subject to change at the discretion of the responsible consultant. Haematological & Non-Haematological Toxicity Treatment should be interrupted until neutrophil count 1.5 and platelets 75 x 10 9 /L Common Toxicity Criteria (CTCAE Version 3) During a course of treatment Dose adjustments (%age of starting dose) GRADE 1 Maintain dose level 100% GRADE 2 1 st appearance 100% 2 nd 3 rd 4 th GRADE 3 1 st appearance 2 nd 3rd GRADE 4 1 ST appearance Discontinue permanently Discontinue permanently Discontinue permanently or Interrupt until 0 or 1 at clinicians discretion Renal function Drug GFR % of full dose Capecitabine > 50ml/min Full dose 30 50ml/min of dose < 30ml/min discontinue Hepatic function 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 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. Page 4 of 5

5 References 1. Twelves, C., et al., Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med, (26): p Gray, R., QUASAR: a randomized study adjuvant chemotherapy (CT) vs observation including 3238 colorectal patients. Proc Am Soc Clin Oncol 2004, : Abstr Compton, C., et al., Prognostic factors in colorectal cancer. College of American Pathologist Consensus Statement Archives Pathology Laboratory Medicine, : p Mamounas, E., et al., Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol, (5): p Berger, A.C., et al., Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol, (34): p 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, Scottish medicines consortium: Adjuvant treatment of patients following surgery for stage 3 Duke s C stage colon cancer; July National Institute for Clinical Execellence: Improving outcomes in colorectal cancers manual update; May Available from Summary of Product Characteristics: Capecitabine; June 2006 Prepared By: Sarah Wilson, John Milne and Aisling Hennessey Checked and Approved by: BOC colorectal site specific team Approved by: RCAG Prescribing Advisory Subgroup March 2007 Review date: March 2009 Page 5 of 5