OXALIPLATIN & MODIFIED DE GRAMONT Indication: For use in patients following resection of stage III / high risk Stage II CRC (to be discussed with consultant) First-line or subsequent use for metastatic colorectal cancer Drugs/ Dosage: Calcium folinate 350mg IV Oxaliplatin 85mg/m 2 IV 5-Fluorouracil 400mg/m 2 IV 5-Fluorouracil 2400mg/m 2 IVI over 46/24 Administration: Frequency: Main Toxicities: Anti-emetics: Oxaliplatin in 250ml 5% Glucose 5% over 2 hours (not using an aluminium needle) concurrently using a Y-line placed immediately before the site of infusion with: Calcium Folinate in 250ml Glucose 5% over 2 hours Flush central venous catheter with Glucose 5%, then: 5FU bolus injection over 5 minutes 5FU infusion either via central venous catheter and ambulatory infusion device or continuous peripheral IV infusion over 46 hours, given in 2 x 1 litre N/Saline. 2 weekly cycle for 12 cycles, CT scan after 6 weeks. myelosuppression; alopecia (usually mild), mucositis; diarrhoea; neurotoxicity (see Comments); hand-foot syndrome (PPE); allergic reactions (see Comments);cardiotoxicity (uncommon);ovarian failure/infertility Highly emetogenic Supportive medication: Extravasation: Calcium gluconate 1g (10ml of 10% solution) and Magnesium sulphate 1g (2ml of 50% solution) in 100ml Glucose 5% over 15-30minutes before and after oxaliplatin chemotherapy. Care in patients with known hypercalcaemia or already treated with thiazides or digoxin. Monitor Ca 2+ and Mg 2+ levels, and omit if above normal. Loperamide tablets 4mg stat, then 2mg prn for diarrhoea Pyridoxine tablets 50mg tds, if required for palmar-plantar erythema (PPE) Non-vesicant Regular investigations: FBC U&Es Mg 2+ Ca 2+ LFTs CEA 4 weekly CT scan after 6 cycles (for metastatic disease) Page 1 of 5
Toxicities and Dose Modifications Oxaliplatin and Neurotoxicity Acute Cold-related Dysaesthesia (CRD): Many patients experience transient paraesthesia of hands & feet. Onset is during or within hours of infusion, and resolves within minutes to a few days. Symptoms are exacerbated by cold, so patient should be well advised on precautions to be taken. Does not require treatment or dose reduction. Acute laryngopharyngeal dysaesthesia: Some patients experience laryngopharyngeal dysaesthesia (unpleasant sensations in the throat). Onset is during or within hours of infusion, and resolves within minutes to a few days. Symptoms are exacerbated by cold, so patient should be well advised on precautions to be taken. Does not require treatment or dose reduction. Clinical symptoms Laryngo-pharyngeal dysesthesia Platinum hypersensitivity dyspnoea Present Present bronchospasm Absent Present Laryngospasm Absent Present Anxiety Present Present O2 saturation Normal Decreased Difficulty swallowing Present (loss of sensation) Absent Pruritus Absent Present Cold induced symptoms Yes no Blood pressure Normal or increased Normal or decreased treatment Anxiolytics; observation in a Oxygen, steroids, adrenaline, controlled clinical setting until bronchodilators, antihistamine; symptoms abate or at clinician s Fluids and vasopressors if discretion appropriate Subsequent infusions after episode of laryngo-pharyngeal dysesthesia should be given over 6 hours. Cumulative Dose related peripheral sensory neuropathy Usually occurs after a cumulative dose of 800mg/m 2. It can occur after treatment with oxaliplatin is completed, and is usually reversible, taking approx 3 5 months to recovery. Grade 1 of any duration or grade 2 paraesthesias continue with oxaliplatin 85mg/m 2 lasting longer than 7 days Grade 2 paraesthesias persisting until next cycle reduce oxaliplatin dose to 65mg/m 2 Grade 3 paraesthesias lasting longer than 7 days reduce oxaliplatin dose to 65mg/m 2 Grade 3 paraesthesias persisting until next cycle discontinue oxaliplatin permanently or Grade 4 of any duration discontinue oxaliplatin permanently Page 2 of 5
Allergic reactions to oxaliplatin during infusion Immediate intervention is to stop the infusion and call for medical help. Treat with IV corticosteroid and antihistamine. After full recovery, the patient may continue with Folinic Acid and 5FU. At Consultant discretion, the patient may be re-challenged with oxaliplatin on the next cycle, with the following premedication prescribed: Dexamethasone 4mg po 6hrly x 3 doses, starting 24hrs pre-treatment, plus 8mg IV 30 minutes pre dose and Chlorphenamine 10mg IV and Ranitidine 50mg IV 30 minutes pre-dose. Patients who have severe reactions should not be re-challenged, as per SPC. Haematological Toxicity on Neutrophils 1.5 x 10 9 /l and Platelets 75 x 10 9 /l Proceed with treatment, if necessary adjusting doses for any previous haematological toxicity as specified below Neutrophils 1.0 1.4 x 10 9 /l or Platelets 50-74 x 10 9 /l Delay treatment for 1 week. Repeat FBC and, if recovered, no dose adjustment required. This applies whether this is 1 st, 2 nd or 3 rd occurrence. Neutrophils 0.5 0.9 x 10 9 /l or Platelets 10-49 x 10 9 /l Delay treatment for 1 week. Repeat FBC and, if recovered, give 75% of original 5FU dose and oxaliplatin 65mg/m 2. If 2 nd occurrence, maintain 5FU dose but reduce oxaliplatin further to 55mg/m 2. Neutrophils < 0.5 x 10 9 /l or Platelets < 10 x 10 9 /l Delay treatment for 1 week. Repeat FBC and, if recovered, give 50% of original 5FU dose and oxaliplatin 55mg/m 2. If any reoccurrence of Grade 4 haematological toxicity, discontinue treatment. If patient suffers an episode of Grade 3 febrile neutropenia, continue after recovery with oxaliplatin 55mg/m 2 and 5FU at 75% of original dose. For Grade 4 neutropenic sepsis or 2 nd occurrence of grade 3, discuss with Consultant. Renal Impairment Before every course, calculate CrCl using Cockcroft and Gault. If borderline, an EDTA should be requested. Creatinine Clearance (ml/min) 5FU Dose Oxaliplatin Dose > 50 Give 100% dose Give 100% dose 30 50 Give 100% dose Give 100% dose < 30 Give 80% dose Omit Hepatic Impairment Bilirubin > 3 x ULN or ALT/AST > 2.5 ULN Give 50% of 5FU and Oxaliplatin until liver function recovers Page 3 of 5
Non-Haematological Toxicities Note that severe diarrhoea and/or severe mucositis early in the first treatment cycle can be the first presenting toxicity due to DPD enzyme deficiency, in which case potentially fatal neutropenia can quickly follow. Toxicity due to 5FU administration may be managed symptomatically and/or modification of the dose. Once the dose has been reduced, it should not be increased at a later time. Doses of 5FU omitted for toxicity are not replaced or restored. Instead the patient should resume the planned treatment cycle. Fluorouracil non-haematological toxicity dosing table: Diarrhoea, abdo pain,n&v,stomatitis Immediate action Dose next cycle Grade 1 maintain dose 100% Grade 2 1 st appearance Interrupt until resolved to grade 0-1 100% Grade 2 2 nd appearance Interrupt until resolved to grade 0-1 75% Grade 2 3 rd appearance Interrupt until resolved to grade 0-1 50% Grade 2 4 th appearance Discontinue treatment permanently Grade 3 1 st appearance Interrupt until resolved to grade 0-1 75% Grade 3 2 nd appearance Interrupt until resolved to grade 0-1 50% Grade 3 3 rd appearance Discontinue treatment permanently Grade 4 1 st appearance Discontinue or at consultants discretion Interrupt until resolved to grade 0-1 50% Palmar-Plantar Erythema Immediate action Dose next cycle Grade 1 maintain dose 100% Grade 2 1 st appearance Interrupt until resolved to grade 0-1 75% Grade 2 2 nd appearance Interrupt until resolved to grade 0-1 50% Grade 2 3 rd appearance Discontinue treatment permanently Grade 3 1 st appearance Interrupt until resolved to grade 0-1 50% Grade 3 2 nd appearance Discontinue or at consultants discretion Interrupt until resolved to grade 0-1 50% In Grade 3 or 4 stomatitis or diarrhoea reduce Oxaliplatin dose to 65mg/m 2. Other Toxicities Oxaliplatin therapy should be interrupted if symptoms indicative of pulmonary fibrosis develop nonproductive cough, dyspnea, crackles, rales, hypoxia, tachypnea or radiological pulmonary infiltrates. If pulmonary fibrosis is confirmed oxaliplatin should be discontinued. Venous Occlusive Disease is a rare but serious complications that has been reported in patients (0.02%) receiving Oxaliplatin in combination with Fluorouracil. This condition can lead to hepatomegaly, splenomegaly, portal Page 4 of 5
hypertension and/or esophageal varices. Patients should be instructed to report any jaundice, ascites or hematemesis immediately. Oxaliplatin therapy should be interrupted if Hemolytic Uremic Syndrome (HUS) is suspected: hematocrit is <25%, platelets<100,000 and creatinine > 135 umol/l. If HUS is confirmed, Oxaliplatin should be permanently discontinued Cardiotoxicity Coronary artery spasm is a recognised complication of fluoropyrimidines although the evidence base regarding aetiology, management & prognosis is not particularly strong. The incidence is estimated to be between 2% and 18%. Coronary artery spasm is usually reversible on discontinuing the treatment. Should a patient receiving 5FU present with chest pains, stop the treatment. Standard investigation and treatment of angina may be required. If re-challenge is deemed necessary, this can be performed under close supervision, but should symptoms redevelop, 5FU should be withdrawn permanently. Refer to Consultant to discuss. Neurotoxicity Drug interactions: Caution must be exercised in patients with central or peripheral nervous system disease e.g. cerebral metastasis or neuropathy Coumarin anticoagulants-monitor INR Phenytoin- altered plasma levels Aminoglycoside anticiotics- increased risk of ototoxicity with oxaliplatin Metronidazole- increased plasma levels and toxicity Folinic acid- increased toxicity Allopurinol- reduced efficacy Antacids- absorption interference References: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.andre et al., NEJM 2004; 350: 2343-51 Leucovorin and fluorouracil with or without Oxaliplatinas first-line Treatment in Advanced Colorectal Cancer. De Gramont et al, JCO 2000; 18: 2938-2947 Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer.braun et al., BJC 2003; 89 (7): 1155-8 Gamelin et al; Clinical Cancer Research 2004; 10; 4055-4061 GI ASCO, abstract 280. CONCEPT trial. Summerhayes et al. Practical chemotherapy. 2003 Royal Surrey County Hospital chemotherapy protocols www.medicines.org.uk, Summary of Product Characteristics- Fluorouracil, Wockhardt. Revised Sept 2006 Summary of Product Characteristics-Oxaliplatin. Sanofi-Aventis. Revised Aug 2007 Micromedex review, Fluorouracil. Sept2007 BCCA Protocol summary. UGIAJFFOX. Revised July 2007 Page 5 of 5