FEC Docetaxel (NEOADJUVANT): Fluorouracil/ Epirubicin/ Cyclophosphamide followed by Docetaxel* in Early Breast Cancer

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1 FEC Docetaxel (NEOADJUVANT): Fluouracil/ Epirubicin/ Cyclophosphamide followed by Docetaxel* in Early Breast Cancer Please, note that Neoadjuvant FEC-Docetaxel has only been approved f use in QEW Trust within SELCN Indication: Alternative Neoadjuvant therapy in Breast Cancer patients FEC Regimen details: Epirubicin 75mg/m 2 IV Fluouracil 600mg/m 2 IV Cyclophosphamide 600mg/m 2 IV Administration: Epirubicin IV Bolus injection via a fast-running Sodium Chlide 0.9% infusion Fluouracil IV Bolus injection via a fast-running Sodium Chlide 0.9% infusion Cyclophosphamide may be administered as IV Bolus injection via a fast-running Sodium Chlide 0.9% infusion as a sht infusion e.g. in 250mls Sodium Chlide 0.9% over 30 minutes Frequency: Every 21 days, f 6 cycles, followed by 4 cycles Docetaxel (see Docetaxel, page 4) Extravasation: Epirubicin: Vesicant Fluouracil and Cyclophophamide: Non-vesicants Anti- emetics: Highly emetogenic. Follow local Anti-emetic policy Supptive medication: Doxycycline/Triamcinolone mouthwash qds f 5 days Regular investigation: FBC LFTs U&Es MUGA scan/echocardiogram see Comments (if necessary) Comments: Maximum cumulative dose Epirubicin= 950mg/m 2 A baseline MUGA scan Echocardiogram should be perfmed where the patient is considered at risk of having impaired cardiac function e.g. significant cardiac histy, hypertension, diabetes, obese, smoker, elderly, previous exposure to anthracyclines, previous thacic radiotherapy. MUGA scan Echocardiogram should be repeated if there is suspicion of cardiac toxicity at any point during treatment, if cumulative anthracycline dose approaches maximum. Page 1 of 6

2 DOSE MODIFICATIONS Haematological Toxicity Day1 WBC < 3.0 x 10 9 /L Neutrophils < 1.5 x 10 9 /L Platelets < 100 x 10 9 /L Delay f 1 week. Repeat FBC - If within nmal parameters, resume treatment with 100% doses In adjuvant treatment, dose reduction and delays can compromise outcome. G-CSF should be considered if me than one delay and/ befe dose reduction. If in doubt, contact the relevant Consultant Subsequent cycles If Neutrophils < 0.5 x 10 9 /L f 1 week, OR Febrile neutropenia is diagnosed, OR Platelets < 50 x 10 9 /L, Seek Consultant advice and consider a longer course of G-CSF a dose reduction to 85% from previous doses in all drugs (do not escalate f subsequent cycles). If the patient continues to experience these side effects at the lower dose, treatment should be discontinued Renal Impairment Epirubicin and Fluouracil: If patients have Creatinine > x ULN higher Creatinine levels OR, GFR < 10ml/min, contact the relevant Consultant and consider dose reduction Full Cyclophosphamide dose is not recommended in patients with a plasma creatinine above the upper limit of the nmal range at the institution. Dose adjustments f Cyclophosphamide should be made using Cockcroft and Gault following the guidelines below. EDTA should be requested so that the dose can be adjusted if necessary, accding to EDTA result, on all subsequent cycles CrCl (ml/min) Cyclophosphamide Dose > 50 Give 100% Give 75% < 10 Give 50% Hepatic Impairment Cyclophosphamide is not recommended in patients with a bilirubin > 17 µmol/l AST/ALT me than 2 3 x upper nmal limit, however, exposure to active metabolites may not be increased, suggesting that dose reduction may not be necessary. Decision should be discussed with the Consultant Epirubicin: The dose should be adjusted as follows Bilirubin (µmol/l) Epirubicin Dose Give 50% Give 25% > 85 Omit Page 2 of 6

3 Fluouracil should be used with caution in patients with reduced liver function jaundice: Bilirubin AST (units) Fluouracil Dose (µmol/l) < 85 <180 Give 100% > 85 >180 Contraindicated DOSE MODIFICATIONS FOR OTHER TOXICITIES AS APPROPRIATE MUCOSITIS / STOMATITIS EPIRUBICIN Mucositis may appear 5-10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, mainly along the side of the tongue and the sublingual mucosa. F grade III Painful erythema ulcers requiring IV rehydration resolving to Grade I less painless ulcers mild seness: give Epirubicin 85% dose and recommend regular mouth care Toxicities: Myelosuppression; cardiotoxicity; mucositis; stomatitis; nausea; vomiting; diarrhoea; fever; fatigue; urine discolation; haemrhagic cystitis; taste disturbances; amenrhoea; early menopause; alopecia Any mild symptoms of dysuria may be treated by encouraging al fluid intake and regular voiding of urine Drug interactions: Fluouracil, Epirubicin and Cyclophosphamide -Clozapine : increased risk of agranulocytosis, avoid concomitant use -Digoxin tablets : reduced absption (resolved by giving the digoxin in liquid) -Phenytoin : reduced absption of the antiepileptic Fluouracil -Allopurinol : avoid concomitant use -Coumarins : enhanced anticoagulant effect -Leucovin : increased cytotoxic and toxic effects of Fluouracil -Metronidazole ; Cimetidine : inhibit metabolism of fluouracil (increased toxicity) -Sivudine : marked and rapidly fatal fluouracil toxicity Epirubicin -Cimetidine and Ciclospin: can increase Epirubicin serum levels -Verapamil : possibly increases Epirubicin bone marrow depressant effects Cyclophosphamide -Allopurinol : can increase the incidence of serious bone marrow depression -Amiodarone : increased risk of pulmonary fibrosis ; avoid combination if possible -Grapefruit juice : decreased delayed activation of Cyclophosphamide Avoid grapefruit juice f 48 hours befe and on day of dose -Indapamide : prolonged leucopenia is possible -Itraconazole : might increase Cyclophosphamide side effects e.g.haemrhagic Cystitis, pigmentation of palms, nails and soles etc.. -Warfarin : the anticoagulant effect is increased Page 3 of 6

4 Followed by Docetaxel *Docetaxel is ONLY given after FEC if the pathological examination of the operative specimen reveals positive axillary lymph nodes Regimen details: Docetaxel 100mg/m 2 IV Administration: Premedication: Docetaxel in 250mls Sodium Chlide 0.9% IV over 1 hour Dexamethasone 8mg po bd f 3 days, starting the mning of the day pri to each Docetaxel administration, to reduce the incidence and severity of fluid retention and hypersensitivity reactions.if the patient has not taken the al pre-med f any reason, Dexamethasone 20mg IV should be administered 1 hour pri chemotherapy Frequency: Every 21 days, f 4 cycles, starting 21 days after the final cycle of FEC Extravasation: Docetaxel: Vesicant Anti- emetics: Low emetogenic. Follow local Anti-emetic policy Supptive medication: Primary Prophylactic Growth Fact suppt should be used starting at least 24 hours post chemotherapy given with each cycle of chemotherapy, following the local Guidelines f the Use of Colony Stimulating Facts to Manage Neutropenia Regular investigation: FBC LFTs U&Es Comments: Hypersensitivity reactions may occur, during the first and second infusions, within a few minutes following the initiation of the infusion Degree of symptoms Hypersensitivity reactions Action Min Flushing Do not require interruption of therapy. Administer Localised cutaneous reaction prophylactic anti-anaphylactic medication befe further cycles of Docetaxel Severe Severe hypotension Require immediate discontinuation of Docetaxel Bronchospasm Administer appropriate aggressive therapy Generalised rash/erythema Page 4 of 6

5 DOSE MODIFICATIONS Haematological Toxicity Day1 WBC < 3.0 x 10 9 /L Neutrophils < 1.5 x 10 9 /L Platelets < 100 x 10 9 / L Delay f 1 week. Repeat FBC - If within nmal parameters, resume Docetaxel at 80% dose and continue G-CSF suppt Subsequent cycles: Neutrophils < 0.5 x 10 9 /L f me than 7 days, OR Febrile neutropenia is diagnosed, OR Platelets < 50 x 10 9 /L, If still these low counts despite Docetaxel dose reduction and G-CSF suppt, seek Consultant advice about further Docetaxel dose reduction Renal Impairment: Docetaxel : No dose adjustment required Hepatic Impairment ALP and AST/ALT and/ Bilirubin Docetaxel dose 2.5 x ULN 1.5 x ULN Full dose x ULN x ULN 75% dose > 6 x ULN > 3.5 x ULN > 22µmol/L Not recommended. Docetaxel should be administered with Consultant approval DOSE MODIFICATIONS FOR OTHER TOXICITIES AS APPROPRIATE CUTANEOUS REACTIONS / PERIPHERAL NEUROPATHY - DOCETAXEL Grade Cutaneous reactions Neuropathy-sensy Docetaxel dose 1 Erythema without associated Paresthesia (including tingling) 100% dose symptoms but not interfering with function 2 Localized erythema of the palms of the hands and soles of the feet with oedema followed by desquamation Paresthesia interfering with function, but not interfering with activities of daily living 3 Severe, generalised eruptions followed by desquamation 4 Generalised exfoliative, ulcerative, bullous dermatitis Paresthesia interfering with activities of daily living Disabling Page 5 of 6 May consider reduce Docetaxel dose to 75mg/m 2 Delay Docetaxel until recovery to grade 2, therafter, reduce Docetaxel dose to 75mg/m 2. If symptoms return, discontinue Docetaxel Discontinue Docetaxel, permanently

6 Toxicities: Drug interactions: References: Myelosuppression; nausea; vomiting; diarrhoea; stomatitis; asthenia; fluid retention; peripheral neuropathy; hypersensitivity reactions; cutaneous reactions (reversible); alopecia; nail disder; ovarian failure; infertility -Concomitant administration of substrates, inducers inhibits of cytochrome P450-3A e.g. ciclospin, terfenadine, ketoconazole, erythromycin etc, may alter the pharmacokinetics of docetaxel, presenting a theetical interaction -Digoxin tablets : reduced absption (resolved by giving the digoxin in liquid) -Phenytoin : reduced absption of the antiepileptic Summary of Product Characteristics. Fluouracil. Medac UK. February 2007 Summary of Product Characteristics. Epirubicin. Hospira UK Ltd. August 2006 Summary of Product Characteristics. Docetaxel. Sanofi Aventis. January 2008 BC Cancer Agency, Cancer Drug Manual. Cyclophosphamide. August 2006 SELCN Breast Tumour Wking Group Clinical Guidelines (Draft). July 200 Van der Hage JA et al. JCO (2001) Vol 19, No 22: pp UCLH- Dosage Adjustment f Cytotoxics in Renal Impairment. November 2003 UCLH- Dosage Adjustment f Cytotoxics in Hepatic Impairment. November 2003 GSTT guidelines f treating nausea and vomiting in adult patients. September 2007 SELCN Cytotoxic Extravasation Guidelines (Draft). July 2008 Stockley s Drug Interactions. Interactions search: Fluouracil, Epirubicin and Cyclophosphamide and Docetaxel. January 2009 CTCAE v3.0.august 2006 Page 6 of 6