Modified De Gramont with Oxaliplatin(OxMdg) Metastatic colorectal cancer (GIWOS-002) CONSIDER ENTRY INTO CLINICAL TRIAL IF AVAILABLE/APPROPRIATE

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1 West of Scotland Cancer Network Chemotherapy Protocol Modified De Gramont with Oxaliplatin(OxMdg) Metastatic colorectal cancer (GIWOS-002) Indication Metastatic colorectal cancer Case selection Inclusion CONSIDER ENTRY INTO CLINICAL TRIAL IF AVAILABLE/APPROPRIATE Histological or cytological proof of colorectal cancer PS 0-2 Have life expectancy of at least 3 months No biological major abnormalities: Absolute neutrophil count 1.5 x 10 9 /l, Platelets 75 x 10 9 /l, Creatinine clearance(crcl) 30ml/min, bilirubin 3 times upper limit of normal (ULN) Written informed consent Ideally patients should have measurable disease but this is not a protocol requirement 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 Evidence of CNS metastases Clinically significant cardiac disease uncontrolled CHF, unstable angina or MI within last 6 months 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 Pre-treatment evaluation 1. Informed consent 2. Provision of verbal and written information. 3. Assessment of performance status 4. Height, weight and BSA 5. Copy of histopathology reports 6. Copy of CT or MRI reports 7. Baseline FBC, U&Es, LFTS and CEA 8. Medical history and examination Page 1 of 7

2 Regimen Pre-medication: Dexamethasone 8mg + Granisetron 3mg Intravenously 30 minutes prior to chemotherapy Drug Dose Route Administration Infusion fluid Day to be given Folinic Acid 350mg I.V Over 2 hrs 250ml Glucose 5%* Day 1 Oxaliplatin 85mg/m 2 I.V Over 2 hrs 250ml Glucose 5%* Day 1 5fluorouracil 400mg/m 2 I.V Over 10 min 100ml Sodium Chloride Day 1 0.9% 5fluorouracil 2400mg/m 2 I.V Over 46 hrs 1000ml Sodium Chloride 0.9% or ambulatory infusion device ** Day 1 * folinic acid and oxaliplatin to be given concurrently; line to be flushed with Glucose 5% before administration of 5fluorouracil. ** regimen given as day case treatment if patient has PICC/Hickman line in situ Repeat every 14 days for 12 cycles Emetogenic Risk: Moderate refer to local anti-emetic policy Dose Banding Nomogram: calculate BSA to one decimal place (cap at 2 m 2) and select dose from table below: B.S.A (m 2 ) Standard doses (mg) Oxaliplatin Infusion 85mg/m 2 5FU bolus 400mg/m Adverse effects for both Oxaliplatin and Fluorouracil 5FU infusion 2400mg/m 2 Very Common Haematological: neutropenia, anaemia, thrombocytopenia, infection Application site: injection site reaction, extravasation General: fever, fatigue, allergic reactions including skin rash, conjunctivitis, rhinitis, asthenia, pain, weight increase Central & Peripheral Nervous system: peripheral sensory neuropathy, headache, sensory disturbance Gastrointestinal: diarrhoea, nausea, vomiting, stomatitis/mucositis, abdominal pain, constipation, anorexia Musculoskeletal: back pain Platelets, bleeding and clotting: epistaxis Respiratory system: dysponea, coughing Skin & Appendage: dermatitis, pigmentation, changes in nails, alopecia Special Senses, other: taste perversion Laboratory abnormalities: increase in alkaline phosphatase, bilirubin, transaminases, LDH; glycemia abnormalities, hypokalaemia, natremia abnormalities. Common Haematological: febrile neutropenia Autonomic Nervous system: flushing Cardiovascular: chest pain, palpitations Central & peripheral nervous system: dizziness, neuritis Gastrointestinal: dyspepsia, gastroesophageal reflux, hiccup Metabolism& Nutrition: dehydration Musculoskeletal: arthralgia, skeletal pain Platelets, Bleeding & clotting: haemorrhage nos, haematuria, deep thrombophlebitis, pulmonary embolism Psychiatric: depression, insomnia Respiratory: rhinitis upper respiratory tract infection Skin & Appendage: skin exfoliation (i.e hand foot syndrome), erythematous rash, rash, increased sweating, nail disorder. Urinary System: dysuria, abnormal micturition frequency Vision: conjunctivitis, abnormal vision Page 2 of 7

3 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 of 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 - may be cold induced and usually reversible. Uncommom 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 5fluorouracil 4 Inflammatory Agent In the event of an extravasation occurring refer to local extravasation policy Contraindications A known history of hypersensitivity to any of the drugs In pregnancy and lactation Myelosuppression prior to starting first course, as evidenced by baseline neutrophils < 1.5x10 9 /l and/or platelet count of <100x10 9 /l. Peripheral sensory neuropathy with functional impairment prior to first course. Precautions Chest pain, tachycardia, breathlessness and ECG changes may occur with 5fluorouracil therefore careful monitoring should be performed in those patients with a history of heart disease or those who develop chest pain during treatment. In the case of unexplained respiratory symptoms (not as a result ofpulmonary 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 Drug Interaction Action Coumarin-derivative Increased INR Monitor INR twice weekly anticoagulants Clozapine Increased risk of agranulocytosis Avoid concomitant use Various agents have been reported to biochemically modulate the antitumour efficacy or toxicity of 5FU, common drugs include Methotrexate, Metronidazole, Leucovorin as well as Allopurinol and Cimetidine which canm affect the availability of the active drug obtain advice from pharmacy. Page 3 of 7

4 Investigations prior to subsequent cycles Day 1 - FBC, CEA, LFTs, U&Es - Monitor weight - Delay until neutrophils 1.5 and platelets 75 - Calculated Cr Cl must be > 30 mls/min Dose modifications Specific dose adjustments may apply to Oxaliplatin and Fluorouracil if the toxicity experienced is considered to be due solely to one drug. Haematological as per SPC 11 Treatment should be delayed until Neutrophils 1.5 x 10 9 /l and/or platelets 75 x 10 9 /l Result Value Action Neutrophils (non-febrile neutropenia) x 10 9 /l Delay treatment until 1.5 Platelets Delay treatment until 1.5 and reduce Oxaliplatin < 1 x 10 9 /l dose to 65mg/m 2, 5fluorouracil 300mg/m 2 and 2000mg/m x 10 9 /l Delay treatment until 100 < 50 x 10 9 /l Delay treatment until 100 and reduce Oxaliplatin dose to 65mg/m 2, 5fluorouracil 300mg/m 2 and 2000mg/m 2 Dose Modifications for febrile neutropenia should be made at the discretion of the responsible consultant. Non-haematological Symptoms as per SPC Diarrhoea - grade 3 / 4 reduce oxaliplatin to 65 mg/m 2, bolus fluorouracil to 300mg/m 2 and fluorouracil infusion to 2000 mg/m 2 and treatment should be delayed until these toxicities are CTC (version 3) grade 1 Stomatitis - grade 3 / 4 reduce oxaliplatin to 65 mg/m 2, bolus fluorouracil to 300mg/m 2 and fluorouracil infusion to 2000 mg/m 2 and treatment should be delayed until these toxicities are CTC (version 3) grade1. Palmer planter erythrodysaesthesia ( Hand-Foot syndrome) - grade 3 / 4 reduce fluorouracil bolus to 300 mg/m 2 and infusion to 2000 mg/m 2 ONLY. Page 4 of 7

5 Neurological symptoms (Paraesthesia, dysaethesia) see table below: TOXICITY GRADE 1-7 days 7 days Persistent Acute laryngopharyngeal N/A Not applicable Not applicable dysaesthesia Increase infusion duration to 6 hours Paraesthesia that does not interfere with function 1 No change No change No change Paraesthesia that does interfere with function but not Active Daily Living (ADL) Paraesthesia with pain or functional impairment that does interfere with ADL Persistent paraesthesia that is disabling or life-threatening 4 Discontinue 2 No change No change 65 mg/m 2 3 No change 65mg/m 2 Discontinue Discontinue Discontinue Renal Limited information available If creatinine clearance < 30ml/min discuss with responsible consultant Hepatic Limited information available No studies performed with Oxaliplatin in severe hepatic impairment SPC advises to use fluorouracil with caution in patients with hepatic impairment Evaluation of response to treatment CEA should be assessed with every cycle of chemotherapy Review by consultant following CT scan at least every 6 cycles it may be more frequent in patients with suspected early progression. Only those patients who have formal evidence of stable or responding disease should continue on therapy beyond 6 cycles. Second-line therapy may be offered to those with progressive symptomatic disease Please refer to second-line protocol for further details. Page 5 of 7

6 References 1. Andre, T., et al., Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med, (23): p de Gramont, A. and e. al., Oxaliplatin/5-FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. Proc Am Soc Clin Oncol 2005, : Abstract Andre T et al;multicenter international study of oxaliplatin/5fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. NEng J Med 2004 Jun 3; 350(23): 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 for Oxaliplatin August Summary of product Characteristics for 5Fluorouracil September Prepared By: Sarah Wilson, John Milne and Ashita Waterston Checked and Approved by: BOC colorectal site specific team Approved by: RCAG Prescribing Advisory Subgroup March 2007 Review date: March 2009 Page 6 of 7

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