Regimen : Bevacizumab for metastatic colorectal cancer ICD10 codes pre-fixed with: C18, C19, C20

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1 Regimen : Bevacizumab for metastatic colorectal cancer ICD10 codes pre-fixed with: C18, C19, C20 Indications First or second line treatment of advanced colorectal cancer, in combination with irinotecan and fluoropyrimidine First or second line treatment of advanced colorectal cancer, in combination with oxaliplatin-based chemotherapy Note: Patients with liver-only unresectable metastases should receive cetuximab if k-ras wild type. Bevacizumab may be prescribed if k-ras mutant. This drug is only available through application to the NHS South West Cancer Drugs Fund. Exclusion Criteria Regimen details Administration Contraindicated in patients who have a history of hypersensitivity reaction to bevacizumab or other recombinant human or humanized antibodies Caution in patients with: Untreated central nervous system metastases Uncontrolled hypertension History or risk factors for thromboembolic events Significant cardiac risk factors for development of congestive heart failure Day Drug Dose Route 1 Bevacziumab (if given two weekly)* OR 1 Bevacizumab (if given three weekly)* 5mg/kg 7.5mg/kg *The two weekly schedule is used with fluorouracil-based regimens (FOLFOX, FOLFIRI); the three weekly schedule is used with the capecitabine-based regimens (XELOX, XELIRI) Bevacizumab is administered as an intravenous infusion, ensuring the concentration of the diluted infusion solution is within the range 1.4 to 16.5mg/ml. Doses up to 1650mg are administered in 100ml sodium chloride 0.9%, doses greater than 1650mg are administered in 250ml sodium chloride 0.9%. IV IV The first infusion must be given over 90 minutes. If tolerated, the next infusion can be given over 60 minutes; if this is also tolerated, subsequent infusions can be given over 30 minutes. Units administering bevacizumab must have facilities available for resuscitation and the treatment of anaphylaxis. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require discontinuation of therapy; the infusion may be temporarily interrupted and when symptoms improve Controlled document Document Number Version Number Page 1 of 6

2 Frequency Extravasation Neutral (Group 1) Premedication Emetogenicity Additional recommended supportive medication Pre-treatment evaluation re-started at a slower infusion rate. Chlorphenamine 10mg IV may be administered. Severe reactions, such as hypotension, dyspnoea, angioedema or generalised urticaria require immediate discontinuation of bevacizumab and appropriate therapy. Paracetamol can be used to treat reactions. Bevacizumab therapy should not be initiated for at least 35 days following major surgery or until the surgical wound is fully healed. If elective surgery is planned, bevacizumab should be withheld for at least 35 days. For minor surgery, including port placement, it is recommended that bevacizumab is withheld for 7 days after surgery. Every 14 or 21 days depending on chemotherapy regimen used (see Regimen details above) None routinely. If a patient experiences a mild infusion related reaction, then future doses can be given with Paracetamol 1gram PO and Chlorphenamine 10mg IV. This regimen has low emetogenic potential refer to local protocol None usually required. Antihypertensives may be required to manage the hypertension commonly observed with bevacizumab therapy. FBC U+E LFT Cardiac assessment including history and physical exam. ECHO is required in patients who have had chest wall radiation or prior treatment with an anthracycline. Proteinuria (dipstick analysis) Blood Pressure. Must be < 150/100mmHg. Baseline results valid for 72 hours Regular investigations Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant Blood Pressure Proteinuria (dipstick analysis) Perform prior to infusion on first day of cycle 1. Monitor every 2-3 weeks or more frequently in patients with hypertension Before each dose; if 3+ on dipstick, perform 24-hour urinalysis and delay treatment until urine protein < 2g/24hrs. None, unless specified by clinician in individual cases. Dose Controlled document Document Number Version Number Page 2 of 6

3 modifications Haematological toxicity Renal impairment Hepatic impairment NCI Common toxicity criteria No dose reduction required. There are no data for bevacizumab in patients with renal impairment but dose adjustments should not be required since the kidneys are not a major route of bevacizumab metabolism or excretion. However, deteriorating organ function should be discussed with the consultant as this may be a sign of disease progression. There are no data for bevacizumab in patients with hepatic impairment but dose adjustments should not be required since the liver is not a major route of bevacizumab metabolism or excretion. However, deteriorating organ function should be discussed with the consultant as this may be a sign of disease progression. Toxicity Definition Dose adjustment Infusion-related reactions Hypertension Grade 2 Grade >2 Grade 1 90-minute infusion: continue with dose as normal but give premedications (e.g. paracetamol 1g PO and chlorpheniramine 10mg IV) with the next dose and give this over 90 minutes. If the next dose is well tolerated, subsequent infusions may be reduced by 30 minutes as long as premedication is used. 60-minute infusion: all subsequent doses should be given over 90 minutes (with pre-medication). 30-minute infusion: all subsequent doses should be given over 60 minutes (with premedication). Permanently discontinue Asymptomatic transient (< 24 hrs) increase by > 20 mmhg (diastolic) or to > 140/90 mmhg if previously within normal limits. Re-check BP 1 hour later: (a) If BP <140/90mmHg: administer as normal; no further action needed Grade 2 (b) If BP 140/90mmHg 150/100mmHg, administer bevacizumab but re-check BP 48 hours later. (c) If BP >150/100mmHg omit bevacizumab and recheck BP 48 hours later. For (b) and (c), commence antihypertensive therapy if BP remains >140/90mmHg Recurrent or persistent (> 24 hr) increase by 20 mmhg (diastolic) or to > 140/90 mmhg if previously within normal limits. Controlled document Document Number Version Number Page 3 of 6

4 Proteinuria (on dipstick) Anti-hypertensive therapy should be commenced. Once controlled to <140/90 mmhg, continue bevacizumab therapy. Grade 3 Requiring more than one antihypertensive or more intensive therapy than previously. Withhold bevacizumab for persistent hypertension >140/90 mmhg. If hypertension cannot be controlled, permanently discontinue bevacizumab. Grade 4 Life threatening (e.g. hypertensive crisis). This is a medical emergency. Permanently discontinue bevacizumab. < 2 Continue with bevacizumab as normal 2+ See algorithm below Nephrotic syndrome Permanently discontinue bevacizumab Adverse effects the contents of the table indicate the adverse Rare but serious side effects Arterial/venous thromboembolism GI perforation, fistulas, wound dehiscence Frequently occurring side effects Infusion-associated symptoms / acute hypersensitivity reactions Controlled document Document Number Version Number Page 4 of 6

5 effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/reference texts Comments Cumulative Doses References Haemorrhage Pulmonary haemorrhage/haemoptysis Pneumonitis Osteonecrosis of the jaw Reversible posterior leukoencephalopathy syndrome Congestive heart failure Other No significant interactions. None N/A Hypertension Proteinuria Headache Fatigue Diarrhoea Nausea and vomiting Abdominal pain Hurwitz HI, Fehrenbacjer L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for firstline metastatic colorectal cancer. J Clin Oncol 2005; 23(15): Saltz LB, Clarke S, Diaz-Rubio E, Scheihauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 2008; 26 (12): Tyagi P and Grothey A. Commentary on a phase III trial of bevacizumab plus XELOX or FOLFOX4 for first-line treatment of metastatic colorectal cancer: the NO16966 trial. Clin Colorectal Cancer 2006; 6(4): Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23(16): Giantonio BJ, Catalano PJ, Meropol NJ, O Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007; 25(12): Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009; 20 (11): Daniels S. North London Cancer Network, Dose adjustment for cytotoxics in hepatic impairment [internet]. accessed 02/03/2012 available at %20Dosage%20adjustment%20for%20cytotoxics.doc Daniels S. North London Cancer Network, Dose adjustment for cytotoxics in renal impairment [internet]. accessed 02/03/2012 available at 20-%20Dosage%20adjustment%20for%20cytotoxics.doc Summary of Product Characteristics Avastin 25mg/ml concentrate for solution for infusion (Roche) [internet]. accessed 27/02/2012 available from North of England Cancer Network. Bevacizumab (Avastin) for Colorectal Cancer Protocol [internet]. Accessed 27/02/2012 available from rectal South East London Cancer Network. Bevacizumab protocol [internet]. Accessed 27/02/2012 available from Controlled document Document Number Version Number Page 5 of 6

6 Surrey, West Sussex and Hampshire Cancer Network. Bevacizumab (Avastin) [internet]. Accessed 27/02/2012 available from Document title Bevacizumab for colorectal cancer Document number ASWCS12 GI028 Approval date 07/01/2013 Written by Steve Falk, Consultant Clinical Oncologist, BHOC Checked by Georgina Holmes, Pharmacist, UHBristol NHSFT Authorised by Jeremy Braybrooke, Chair ASWCS Network Chemotherapy Group Review date 07/01/2015 Document reviewed by Version number Summary of changes Version 0.3.a Controlled document Document Number Version Number Page 6 of 6