Docetaxel, Doxorubicin & Cyclophosphamide (TAC) for. Early Breast Cancer

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1 Regimen: Docetaxel, Doxubicin & Cyclophosphamide (TAC) f Early Breast Cancer Indication Adjuvant chemotherapy f node-positive early breast cancer (NICE CG 80) Adjuvant chemotherapy f high risk node-negative breast cancer Regimen detail Day(s) Drug Dose Route 1 Doxubicin 50mg/m 2 IV 1 Cyclophosphamide 500mg/m 2 IV 1 Docetaxel (Taxotere ) 75mg/m 2 IV G-CSF: give one of the following agents (accding to local policy) Primary prophylaxis with GCSF is recommended 2-6 Filgrastim 60kg = 300μg od SC >60kg = 480μg od SC 2-6 Lenograstim 1.75m 2 = 263μg od SC >1.75 m 2 = 150μg/m 2 od 2 Pegfilgrastim (Neulasta ) 6mg stat SC At least 5 days of G-CSF (either filgrastim lenograstim) should be given, although me may be required in patients at high risk of neutropenia Pegfilgrastim (Neulasta ) should be given as a single dose on day 2 Administration Doxubicin and cyclophosphamide are given by slow intravenous bolus into the side-arm of a fast-flowing drip of 0.9% sodium chlide. Cyclophosphamide may also be given in ml 0.9% sodium chlide over 30 minutes Docetaxel is administered in a 250ml PVC-free sodium chlide 0.9% bag over 60 minutes. Doses >190mg should be diluted in 500ml (maximum concentration 0.74mg/ml). F the first cycle, docetaxel should be administered 1-hour after giving doxubicin and cyclophosphamide (AC). If well-tolerated, then docetaxel can be given immediately after the AC component f subsequent cycles. Frequency Patients should be observed closely f hypersensitivity reactions, particularly during the first and second infusions. If hypersensitivity reactions occur, min symptoms such as flushing localised cutaneous reactions do not require discontinuation of therapy. The infusion may be temparily interrupted and when symptoms improve re-started at a slower infusion rate. Severe reactions, such as hypotension, bronchospasm generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel. Every 21 days Maximum 6 cycles Extravasation Doxubicin is a vesicant (Group 5) Docetaxel is an exfoliant (Group 4) Cyclophosphamide is a neutral agent (Group 1) Page 1 of 5

2 Premedication Emetogenicity Additional recommended supptive medication Pre- treatment evaluation Regular investigation Standard limits f administration to go ahead if blood results not within range, authisation to administer must be given by prescriber/consultant Dose modifications Haematological toxicity Renal impairment Dexamethasone 8mg bd PO f 3 days, starting the day befe each cycle of chemotherapy. Patient should receive 3 doses pri to treatment. In the case where 3 doses have not been taken, dexamethasone 20mg IV should be administered minutes pri to chemotherapy and the remaining 3 al doses should be administered as per standard. This regimen has moderate-high emetogenic potential - refer to local protocol Mouthwashes as per local policy H 2 antagonist Proton Pump Inhibit if required Ciprofloxacin 500mg bd from days 5-14 (i.e. f 10 days) should be considered as prophylactic treatment following an episode of febrile neutropenia FBC Baseline - results valid f 4 weeks LFT Baseline - results valid f 4 weeks U&E (inc. SrCr) Baseline - results valid f 4 weeks ECHO MUGA Baseline if significant cardiac histy previous anthracycline therapy, repeated if suspicion of cardiac toxicity as necessary FBC Pre D1 results valid f 72 hours, LFT Pre D1 results valid f 7 days U&E (inc. SrCr) Pre D1 results valid f 7 days Clinical Assessment Clinically assess patient pri to each cycle, particularly focusing on whether the patient has experienced infection, neurological, gastrointestinal, hypersensitivity, cutaneous oedematous symptoms. Consider risk of cardiotoxicity. Neutrophil count 1.0 x 10 9 /l Platelet count 100 x 10 9 /l Creatinine Clearance > 50ml/min Bilirubin < 1.5 x ALT +/- Alk Phos < 2.5 x Consider changing G-CSF treatment duration if neutrophil count >10x10 9 /L if the patient complains of intolerable bone pain Delay 1 week if neutrophils <1.0 x 10 9 /l and/ platelets <100 x 10 9 /l. Dose reduction should be considered if myelosuppression results in delay of subsequent courses despite GCSF. CrCl Cyclophosphamide Doxubicin dose (ml/min) dose Docetaxel dose >20 100% 100% 100% % 75% 100% <10 50% reduction reduction reduction of doxubicin and docetaxel in severe renal impairment (CrCl <10ml/min) discuss with consultant Page 2 of 5

3 Hepatic impairment Bilirub AST +/- ALT Alk Phos Doxubicin Cyclophosphamide Docetaxel x and 3-5 x >5 x >1.5 x >3.5x >2.5 x 5-10 x >10 x 50% 100%* 75% 25% 100%* Omit. Consider alternative regimen reduction / use alternative regimen Not recommended. Clinical decision Contra-indicated. Consider alternative regimen * Cyclophosphamide is not recommended in patients if bilirubin > 1.5 x AST/ALT >2 3x, but exposure to active metabolites may not be increased and therefe a dose reduction may not be necessary. Consultant decision. NCI Common Toxicity Criteria Toxicity Definition Dose adjustment Febrile neutropenia Stomatitis & Mucositis Other toxicities ANC <0.5 x 10 9 /l plus fever requiring IV antibiotics +/- hospitalisation f Grade III painful erythema ulcers requiring rehydration resolving to Grade I less by day 21 Grade III/IV toxicity (except alopecia) Consider a longer prophylactic course of conventional G-CSF f subsequent cycles and give a 20% reduction of doxubicin, cyclophosphamide and docetaxel. Also consider the prophylactic use of ciprofloxacin 500mg bd from days 5-14 (i.e. f 10 days). 20% reduction of doxubicin and docetaxel Continue with 20% dose reduction of suspected causative agent(s) provided toxicity has resolved to Grade I less If further toxicity occurs, an additional reduction may be made after discussion with consultant. Defer treatment f any grade III/IV non-haematological toxicity (excluding alopecia) If a delay of me than 3 weeks is required f recovery, me than 2 dose reductions are necessary, the patient should discontinue treatment Adverse effects the contents of the table indicate the adverse effects that should be included in consent to treatment fms Rare Serious Side Effects Grade 3/4 febrile neutropenia Myelosuppression Risk of second malignancy Cardiac toxicity Teratogenicity Long term risk of early menopause, reduced fertility Peripheral neuropathy Frequently occurring Side Effects Nausea and vomiting Fatigue Stomatitis and mucositis Taste disturbance Diarrhoea Alopecia Se veins (phlebitis) Other side effects include: loss of appetite, taste disturbance, myalgia, neuralgia, Page 3 of 5

4 fluid retention, skin sensitivity, nail changes, bladder irritation (i.e. haemrhagic cystitis), allergic reactions and altered liver and kidney function. Significant drug interactions F full details consult product literature/ reference texts Comments Enzyme inducers/inhibits - in vitro studies suggest that CYP3A inhibits (such as ketoconazole and erythromycin) will raise docetaxel levels, whereas CYP3A inducers (such as rifampicin and barbiturates) will reduce docetaxel levels. Cardiotoxicity has been associated with anthracyclines, with adverse events being me common in patients with a pri histy of conary artery disease. Caution must be taken in patients with a histy of significant cardiac disease, arrhythmias angina pectis. Cumulative Doses Life time cumulative dose doxubicin 450mg/m 2 References National Institute f Health and Clinical Excellence. Clinical Guideline 80 Early and locally advanced breast cancer. Diagnosis and treatment, February 2009 [internet]. Accessed 06/04/2011 available at Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, et al. Adjuvant Docetaxel f High-Risk, Node-Negative Breast Cancer. N Engl J Med 2010; 363: Perez E A, TAC - A New Standard in Adjuvant Therapy f Breast Cancer? N Engl J Med 2005; 352; 22: Martin M, Lluch A, Segui MA, Ruiz A, Ramos M, Ardrover E, et al. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxubicin, cyclophosphamide (TAC) 5-fluouracil, doxubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocytecolony stimulating fact to the TAC regimen. Ann Oncol 2006; 17: Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla J-P, Weaver C,et al. Adjuvant Docetaxel f Node-Positive Breast Cancer. N Engl J Med 2005; 352: Daniels S. Nth London Cancer Netwk, Dose adjustment f cytotoxics in hepatic impairment [internet]. accessed 16/04/2009 available at Daniels S. Nth London Cancer Netwk,. Dose adjustment f cytotoxics in renal impairment [internet]. accessed 16/04/2009 available at Baxter K, edit. Stockley s Drug Interactions. Pharmaceutical Press; Accessed on line on 06/05/09 available at Summary of Product Characteristics Doxubicin solution f injection (Pfizer) [internet]. accessed 01/09/2010 available from Summary of Product Characteristics Taxotere (Docetaxel) 20mg and 80mg concentrate and solvent f infusion (Sanofi Aventis) [internet]. accessed 21/05/2009 available from Summary of Product Characteristics TAXOTERE (Docetaxel) 20 mg/1ml and 80mg/4ml and 160 mg/8ml concentrate f solution f infusion (Sanofi Aventis) [internet]. Accessed 01/09/2010 available from Summary of Product Characteristics Cyclophosphamide 500mg injection (Baxter) [internet]. accessed 11/11/2009 available from Page 4 of 5

5 Allwood M, Stanley A, Wright P, edits. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press Trissel LA. Handbook of Injectable Drugs. 15th ed. American Society f Health- Systems Pharmacists Accessed on line on 06/05/09 available at Document title TAC f Breast Cancer Document number Approval date 15/10/2010 Written by Jeremy Braybrooke, Consultant Medical Oncologist, BHOC, and Chair, ASWCS Drugs and Therapeutics Committee Checked by Becky Bagnall, Consultant Pharmacist, NBT Authised by Jeremy Braybrooke, Chair ASWCS Drugs and Therapeutics Committee Review date 15/10/2011 Document reviewed by Version number 1.2.a Summary of changes Version 1.2.a New indication added Page 5 of 5