Regimen : Oxaliplatin+Modified de Gramont (FOLFOX)

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1 Regimen : Oxaliplatin+Modified de Gramont (FOLFOX) Indication Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumour Treatment of first line or second line palliative therapy for stage IV or relapsed disease Regimen details Administration (For performance status 0 and 1 patients only) Day Drug Route 1 Oxaliplatin 85mg/m 2 IV infusion 1 Calcium Folinate (Folinic acid) 350 mg IV infusion 1 Fluorouracil 400mg/m 2 IV bolus 1-3* Fluorouracil 2400mg/m 2 over 46 hours *i.e. single dose, commenced day 1, finished day 3 IV infusion Order of administration: oxaliplatin and calcium folinate first (together), fluorouracil bolus second, fluorouracil infusion third. Administer calcium folinate and oxaliplatin concomitantly via a 3-way tap/y-site connector over 2 hours. If patients experience laryngopharyngeal dyaesthesia (see below), subsequent infusions should be should be given over 4-6 hours. Infusions must be diluted in Glucose 5% as oxaliplatin is not compatible with Sodium Chloride 0.9%. Lines must not be piggybacked or flushed with Sodium Chloride 0.9% immediately after the Oxaliplatin infusion. The smaller fluorouracil dose is administered by slow intravenous bolus into the side-arm of a fast flowing drip of 0.9% sodium chloride. The larger fluorouracil dose is administered by intravenous infusion (via central venous catheter and ambulatory infusor device or continuous peripheral IV infusion) over 46 hours. (If given via peripheral infusion, the dose is split in two and given in 2x1 litre 0.9% Sodium Chloride). Patients should be observed closely for platinum hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of oxaliplatin. Facilities for the treatment of hypotension and bronchospasm must be available. 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 re-started at a slower infusion rate. Chlorphenamine 10mg IV may be administered. Severe reactions, such as hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of oxaliplatin and appropriate therapy. Cryotherapy (ice cubes) should NOT be used as they may exacerbate oxaliplatin-induced pharyngo-laryngeal dyaesthesias. Similarly, laryngopharyngeal dyaesthesia may be exacerbated by exposure to Controlled document Document Number Version Number Page 1 of 6

2 cold air. If this occurs during infusion, stop infusion immediately and observe patient. Check oxygen saturation: if normal, an anxiolytic agent (e.g.lorazepam 1mg SC/PO/IV) may be given. The infusion can then be restarted at a slower rate (between 4-6 hours) Calcium levofolinate is NOT equivalent to calcium folinate/folinic acid/calcium leucovorin. (Calcium levofolinate is a single isomer of folinic acid and the dose is generally 175mg i.e. half that of calcium folinate). Frequency Every 14 days Maximum 12 cycles Extravasation Oxaliplatin is an exfoliant (Group 4) Fluorouracil is an inflammatant (Group 2) Calcium Folinate (Folinic acid) is neutral (Group 1) Premedication None usually required. 1. Patients who have previously experienced Grade 1 or 2 platinum hypersensitivity should be pre-medicated with as follows: 45 minutes prior to Oxaliplatin: Dexamethasone 20mg IV bolus 30 minutes prior to Oxaliplatin: Chlorphenamine 10mg IV bolus and Ranitidine 50 mg IV bolus diluted in at least 20ml Sodium Chloride 0.9% and given over at least 2 minutes. 2. Patients who develop peripheral neuropathy may be considered for calcium gluconate 1g and magnesium sulphate 1g given together in 250mL 5% Glucose IV over 20 minutes pre- and post-oxaliplatin infusion. Caution is required in giving this treatment to patients with known hypercalcemia or those receiving therapy with digoxin or thiazide diuretics. Emetogenicity Additional recommended supportive medication Pre-treatment evaluations Regular investigations Standard limits for administration to go ahead if blood results not within range, authorisation to administer must be given by prescriber/consultant This regimen has moderate-high emetogenic potential refer to local protocol Mouthwashes as per local policy. Loperamide 4mg po stat then 2mg prn if diarrhoea develops. Pyridoxine 50 mg tds reduces the severity of plantar-palmar erythrodyesthesia (PPE). It should be given for any grade PPE and should be continued until the end of treatment. FBC Baseline results valid for 7 days U+E Baseline results valid for 7 days LFT Baseline results valid for 7 days CEA FBC U+E LFT Ca 2+ CEA (perform monthly) CT scan Baseline results valid for 7 days Results valid for 72 hrs Perform after 6 cycles of treatment Neutrophil count 1.0 x 10 9 /L Platelet count 75 x 10 9 /L Creatinine clearance Bilirubin 50ml/min 26micromol/L Controlled document Document Number Version Number Page 2 of 6

3 modifications Haematological toxicity Renal impairment Hepatic impairment Defer therapy for 1 week if neutrophils <1.0 x 10 9 /L or platelets < 75 x 10 9 /L CrCl (ml/min) Oxaliplatin Fluorouracil % 100% 100% % 100% 100% Omit 100% 100% <10 Omit Consider dose reduction Bilirubin (micromol/l) AST (x ULN) Oxaliplatin Fluorouracil Folinic Acid 100% % 100% 100% % 100% * 100% % 100% ** 100% >85 or >5 Contra-indicated *Consider reducing fluorouracil dose by 33% **Consider reducing fluorouracil dose by 50% (s may be increased back to 100% if there is no toxicity) Note: significant hepatic impairment may indicate disease progression: always discuss deteriorating hepatic function with consultant. NCI Common toxicity criteria Toxicity Definition adjustment Febrile neutropenia Thrombocytopenia Stomatitis/Mucositis Diarrhoea* ANC <0.5 x 10 9 /L plus fever requiring IV antibiotics +/- hospitalisation Platelets x 10 9 /L Platelets< 10 x 10 9 /L Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Folinic Acid Reduce subsequent cycles of fluorouracil by 50% and reduce dose of oxaliplatin to 55mg/m 2. Delay treatment until counts 75 x 10 9 /L. Reduce subsequent doses of oxaliplatin to 65mg/m 2. On second occurrence, reduce dose of oxaliplatin to 55mg/m 2. Delay treatment until counts 75 x 10 9 /L. Reduce subsequent doses of oxaliplatin to 55mg/m 2. On second occurrence, discuss with consultant. 20% 50%. Reduce Oxaliplatin to 65mg/m 2. Discontinue treatment 20% Defer until Grade 1. Add Ciprofloxacin 250mg bd and reduce all subsequent doses of fluorouracil by 50%. Reduce Oxaliplatin to Controlled document Document Number Version Number Page 3 of 6

4 Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/reference texts 65mg/m 2. Grade 4 Discontinue treatment *Patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid (sometimes fatal) deterioration can occur. Palmar-Plantar Erythrodyesthesia (PPE) Grade 2 Grade 3/4 20% 50% Peripheral Grade 2/3 Reduce oxaliplatin to 65mg/m 2. Neuropathy Grade 4 Discontinue oxaliplatin. Rare or serious side effects Palmar-plantar erythema (Hand-Foot Syndrome) Myelosuppression and neutropenic sepsis Cardiac toxicity including tachycardia and angina pectoris Ocular toxicity including excessive lacrimation, blocked tear ducts, visual changes and photophobia. Ototoxicity Interstitial lung disease; pulmonary fibrosis* Deep Vein Thrombosis; pulmonary embolism Laryngopharyngeal dyesthesia** Frequently occurring side effects Mucositis/Stomatitis Diarrhoea Alopecia Nausea & vomiting Peripheral Neuropathy Epistaxis Thrombocytopenia * In the case of unexplained non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude interstitial lung disease. **Needs to be distinguished from platinum hypersensitivity reactions Other Transient cerebellar syndrome, confusion, thrombophlebitis, hypokalaemia Oxaliplatin: Aminoglycosides: increased risk of nephrotoxicity and possibly of ototoxicityavoid concomitant use Diuretics: increased risk of nephrotoxicity and ototoxicity when platinum compounds given with diuretics Fluorouracil: Allopurinol: may potentiate cytotoxic effect-avoid concomitant use Clozapine: increased risk of agranulocytosis, avoid concomitant use Warfarin/coumarin anticoagulants: increased or fluctuating anticoagulant effects. Avoid if possible: in the first instance, consider switching patient to a low molecular weight heparin during treatment or if the patient continues taking an oral anticoagulant monitor the INR at least once a week and adjust dose accordingly. Digoxin tablets: fluorouracil may reduce digoxin absorption (give digoxin in liquid form) Metronidazole and Cimetidine: inhibit metabolism of fluorouracil (increased Controlled document Document Number Version Number Page 4 of 6

5 exposure and risk of toxicity) Phenytoin: reduced absorption of phenytoin. Comments Calcium Folinate: Antiepileptic drugs (phenobarbital, primidone, phenytoin): may increase the frequency of seizures Anti-folates (co-trimoxazole/trimethoprim, pyrimethamine): efficacy may be reduced by concomitant use of leucovorin. Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe toxicity secondary to reduced fluorouracil metabolism avoid use in patients with known DPD deficiency Cardiotoxicity has been associated with fluoropyrimidine therapy, with adverse events being more common in patients with a prior history of coronary artery disease. Caution must be taken in patients with a history of significant cardiac disease, arrhythmias or angina pectoris. Calcium levels should be monitored in patients receiving this regimen and calcium supplementation should be provided if where hypocalcaemia occurs. Cumulative N/A s References Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer (4): de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and Fluorouracil with or without Oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol : Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer. J Clin Oncol 2004; 22 (1):23-30 Louvet C, de Gramont A. Colorectal cancer: integrating Oxaliplatin. Curr Treat Options in Oncol 2003; 4 (5): Maindrault-Goebel F, Louvet C, Andre T, Carola E, Lotz JP, Molitor JL, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer (9): Maindrault-Goebel F, de Gramont A, Louvet C, André T, Carola E, Mabro M, et al. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer (8): Erratum in Eur J Cancer (16):2533. Tournigand C, Louvet C, Quinaux E, Andre T, Lledo G, Flesch M, et al. FOLFIRI followed by FOLFOX versus FOLFOX followed by FOLFIRI in metastatic colorectal cancer (MCRC): Final results of a phase III study. Proc Am Soc Clin Oncol : abstract 494 Gamelin L, Boisdron-Celle M, Delva R, Guérin-Meyer V, Ifrah N, Morel A, Gamelin E, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective Controlled document Document Number Version Number Page 5 of 6

6 study of 161 patients receiving oxaliplatin combined with 5- Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res (12 Pt 1): National Institute for Health and Clinical Excellence. Technology Appraisal 93. Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. [internet] accessed 14/01/2011, available at Daniels S. North London Cancer Network, adjustment for cytotoxics in hepatic impairment [internet]. accessed 12/01/2011 available at Daniels S. North London Cancer Network, adjustment forcytotoxics in renal impairment [internet]. accessed 12/01/2011 available at Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; Accessed online on 06/05/09 available at Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press Summary of Product Characteristics Oxaliplatin Hospira 5mg/ml concentration for solution for infusion (Hospira) [internet]. accessed 14/01/2011 available from Summary of Product Characteristics Fluorouracil 50mg/ml injection (Hospira) [internet]. accessed 12/01/2011 available from Summary of Product Characteristics Calcium Folinate 10mg/mL injection (Hospira) [internet] accessed 14/01/2011 available from Document title Oxaliplatin+Modified de Gramont Document number ASWCS11 GI016 Approval date 19/07/2011 Written by Stephen Falk, Consultant Clinical Oncologist BHOC Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jeremy Braybrooke, Chair ASWCS Drugs and Therapeutics Committee Review date 19/07/2013 Document reviewed by Version number 1.1.a Summary of changes Version Controlled document Document Number Version Number Page 6 of 6