Cetuximab in Combination with Irinotecan based Chemotherapy for the 1 st, 2 nd and 3 rd treatment Metastatic of Colorectal Cancer DRUG ADMINISTRATION SCHEDULE Day Drug Daily Dose Route Diluent and rate Day 1 Cetuximab 500mg/m 2 Intravenous Day 1 Irinotecan 180 mg/m 2 IV Infusion Day 1 Chlorpheniramine 10mg IV Bolus Day 1 Paracetamol 1000mg ORAL Day 1 Ranitidine 150mg ORAL 500ml Sodium Chloride 0.9% over 2 hours 250mls N/Saline over 90 minutes **If patient reacts during first administration consider adding steroid pre-medication on subsequent cycles (e.g. hydrocortisone 100mg IV or dexamethasone 20mg IV) NUMBER OF DAYS PER CYCLE 14 days until disease progression PREMEDICATION Patients MUST receive pre-medication with a paracetamol, ranitidine and antihistamine prior to the first cycle of Cetuximab, administration of paracetamol, ranitidine and antihistamine is recommended on all other cycles. Some patients may require pre-medication with a cortico-steroid. *If acute cholinergic syndrome appears atropine sulphate should be administered unless clinically contraindicated. The manufacturer recommends the use of prophylactic atropine sulphate with subsequent doses of Irinotecan. RECOMMENDED TAKE HOME MEDICATION Ondansetron 8mg twice daily for 2-3 days Dexamethasone 4mg twice daily for 1-3 days Metoclopramide 10-20mg three to four times daily as required Loperamide as required (4mg after first loose stool and 2mg every 2 hours, to a maximum of 16 (2mg) tablets in 24 hours) Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 1 of 6
APPROVED INDICATIONS 2 Weekly Cetuximab with Irinotecan 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. Metastatic colorectal cancer 3. a) 1st line indication (given as a 2 weekly regimen at a dose of 500mg/m2) OR b) 3 rd line indication OR c) 3 rd line indication 4. Patients with wild type RAS 5. Given in combination with irinotecan based combination chemotherapy 6. Performance status of 0 or 1 Additional Criteria 1 st line 7. Not eligible for NICE TA176 approved indications OR 7. Eligible for treatment under TA176 and no progression after receiving the approved 16 weeks treatment with Cetuximab but unsuitable for surgery and meet criteria 1-6 2 nd /3 rd line 8. No previous treatment with Cetuximab or Panitimumab OR 8. Response to previous Cetuximab in the context of NICE TA176 and discontinuation at 16 weeks for consideration of surgery (and therefore not treated to disease progression) Note: Cetuximab is not approved for use as 1 st line treatment with any oxaliplatin based combination other than FOLFOX4, or FOLFOX6 or OxMdG or with upfront single agent fluouropyrimidine chemotherapy. Note: Cetuximab is not approved for use as 2 nd or 3rd line treatment with any oxaliplatin based combination or with upfront single agent fluouropyrimidine chemotherapy. Note: If excessive toxicity with irinotecan, cetuximab can be continued with a fluoroppyrimidine alone until disease progression only No treatment breaks of more than 4 weeks are allowed. Should treatment breaks be required, then an Individual Funding Request must be submitted as per CDF processes. INVESTIGATIONS / MONITORING REQUIRED FBC, U&Es, LFT s. Magnesium and tumour markers as appropriate prior to each course of chemotherapy. There should not be a need to repeat all tests on day 15. Where CEA is elevated this should be measured before each cycle (no need to await result before proceeding with treatment). Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 2 of 6
ASSESMENT OF RESPONSE 2 Weekly Cetuximab with Irinotecan Tumour size and patient symptomatic response to be assessed at appropriate intervals. All patients must have radiological assessment of disease no later than 8 weeks after starting Cetuximab and treatment must be discontinued if there is evidence of disease progression. ELIGIABILITY CRITERIA As stated above REVIEW BY CLINICIAN Before each cycle as appropriate NURSE / PHARMACIST LED REVIEW On cycles where not seen by clinician ADMINISTRATION NOTES Cetuximab 500mg/m 2 can be administered faster than 2 hours provided the infusion rate does not exceed 10mg/min. Cetuximab 2 weekly schedule is unlicensed therefore used with prescriber accepting responsibility for any drug reactions. Sodium Chloride 0.9% must be used for line flushing with Cetuximab Cetuximab (as with all monoclonal antibodies) can cause infusion reactions. Administration must only take place in facilities with resuscitation facilities. Management of Cetuximab infusion reactions is outlined in the table below: CTC Grade Allergic / Infusion Related Reaction Grade 1 mild (Transient rash during infusion, drug fever < 38 C) Grade 2 moderate (Rash during infusion, flushing, urticaria, dyspnoea, drug fever 38 C) Grade 3 or 4 severe or life threatening (Symptomatic bronchospasm, with or without urticaria, parenteral medication indicated, allergyrelated oedema, angio- oedema, hypotension, anaphylaxis) Action required Reduce Cetuximab infusion rate by 50% and monitor for worsening of symptoms. Ensure infusion rate does not exceed 4hours. Use lower rate on all subsequent infusions. Stop Cetuximab infusion. Resume at 50% of rate once symptoms have resolved or reduced to Grade 1. Continue to monitor closely for worsening of symptoms. Use lower rate on all subsequent infusions. Stop infusion immediately. Do not re-treat with Cetuximab. Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 3 of 6
Patients should be warned that on rare occasions they may experience an infusion reaction several hours after cetuximab Pulse, Respiration, Blood Pressure and Temperature must be measured during and I hour following infusion. Patients must be made aware of the risk of delayed diarrhoea occurring 24 hours after the administration of Irinotecan and at any time before the next cycle. This means supplying information sheets to the patient and if appropriate to their GP. Early onset diarrhoea (within the first 24 hours) can be a result of acute cholinergic syndrome and may occur in 9% of patients. Symptoms are short lasting and respond within minutes of administration of atropine (0.25-1mg subcutaneously). Delayed diarrhoea must be treated immediately with high dose loperamide (4mg after the first stool and 2mgs every 2 hours, to a maximum of 16 (2mg) tablets in 24 hours. Hospitalise if condition not resolved in 48 hours. For diarrhoea lasting greater than 24 hours add ciprofloxacin 250mg BD. Note many units give patient a supply of loperamide and ciprofloxacin at the start of the treatment. Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with irinotecan should be cautious in this population. Refer to oncologist for age > 70 and performance status 2. No treatment breaks of more than 4 weeks from the start of the previous cycle are allowed. Should treatment breaks be required, then an Individual Funding Request must be submitted as per CDF processes. EXTRAVASATION See local Guidelines TOXICITIES Allergic reaction Cardio-pulmonary arrest Rash/skin reaction to Cetuximab Hypomagnesia Pulmonary toxicity Acute cholinergic syndrome (defined as early diarrhoea and various other symptoms such as sweating, abdominal cramping, lacrimation, myosis and salivation) Diarrhoea Risk of severe delayed diarrhoea can be life threatening Myelosuppression Alopecia Dizziness during treatment Anaphylaxis DOSE MODIFICATION Haematological Toxicity: Cetuximab does not normally cause myelosuppression, but is associated with anaemia in up to 10% of patients Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 4 of 6
Irinotecan Delay treatment until ANC >1.5, platelets >100 If delay > 2 weeks, dose reduce Irinotecan by 20% and continue at this dose unless further toxicity occurs. If ANC < 0.5 or febrile neutropenia or neutropenic infection occurs during course of treatment, dose reduce Irinotecan by 20% Non-haematological toxicity: Irinotecan Diarrhoea grade 2 during course of treatment delay until recovered and give full dose Diarrhoea grade 3/ 4 during a course of treatment, delay until recovered and resume treatment at 20% reduced dose of Irinotecan Hepatic, bilirubin rising consider 50% irnotecan dose reduction. Omit if bilirubin 3 x ULN Renal rising creatinine and GFR < 30mls/min, consider 50% dose reduction Renal function Cetuximab is not renally excreted Skin Reactions Grade 1 Grade 2 Grade 3 CTC (v2) definition Macular or popular eruption/erythema without symptoms Delay Cetuximab (continue other chemotherapy) Treatment Macular or popular eruption/erythema with pruritis or other symptoms; localised desquamation or other lesions covering <50% of body Symptomatic generalised erythroderma or macular, popular or vesicular eruption or desquamation covering >50% of body No No Yes see below Topical anti-acne cream (eg benzoyl peroxide) for face. Salicylic acid in alcoholic lotion for chest/back As grade 1 plus menthol in aqueous cream. Oral antihistamine and oral tetracycline (for 3 months) As grade 2 plus saline compresses if required. Systemic or topical steroids for treatment of rash are not generally advised. Patients on tetracyclines should be advised to avoid prolonged exposure to the sun. Topical treatments can have a drying effect on the skin. Care should be taken to avoid aggravating xerosis, especially when acne-like rash is fading or becoming scaly. Switch to moisturising creams instead of alcoholic lotion or gel if this occurs. Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 5 of 6
Occurrence of Grade 3 Toxicity Dose once resolved to grade 2 or better First 250mg/m 2 Second 200mg/m 2 Third 150mg/m 2 Fourth Discontinue treatment If skin toxicity has not resolved at Grade 2 or better within 3 weeks, discontinue Cetuximab TREATMENT LOCATION Cancer Centre or Cancer Unit where there is an Oncologist with a specialisation in Colorectal patients as appropriate. Document Title: Document No: Author: Approved by: Due for Review: Summary of Changes Cetuximab (2 Weekly) in combination with Irinotecan for the treatment of Metastatic Colorectal Cancer NCDF Current Version: 1.0 Mandy Nagra Approval NHS England CNTW Area Signature* Steve Williamson Date Area Team Cancer Pharmacist Approved: 31 March 2014 31 March 2016 Cetuximab 2 weekly with irinotecan colorectal CR14 029 v1.1 Page 6 of 6