Regimen: Docetaxel, Carboplatin and Trastuzumab (TCH i.e. Taxotere Carboplatin, Herceptin ) for Early Breast Cancer Indication Approved for the treatment of early and locally advanced breast cancer in patients with lymph node positive, HER2 positive breast cancer where an anthracycline is contra-indicated. Regimen details Day Drug Dose Route 1 Docetaxel 75mg/m 2 IV 1 Carboplatin AUC6 IV 1 Trastuzumab* 8mg/kg IV loading then 6mg/kg *See protocol ASWCS10 BR018 (adjuvant trastuzumab) for monitoring guidelines. Administration Order of administration: trastuzumab first, docetaxel second, carboplatin third. Docetaxel is administered in a 250ml PVC-free sodium chloride 0.9% bag over 60 minutes. Doses >190mg should be diluted in 500ml (maximum concentration 0.74mg/ml). Carboplatin is administered in 500ml 5% dextrose (or 0.9% sodium chloride) over 60 minutes. Avoid any device containing aluminium that may come into contact with Carboplatin. Frequency Patients should be observed closely for hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, carboplatin or trastuzumab. 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 docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel. Every 21 days 6 cycles chemotherapy 18 cycles of Trastuzumab Page 1 of 5
Extravasation Docetaxel is an exfoliant (Group 4) Carboplatin is an irritant (Group 3) Trastuzumab is neutral (Group 1) Premedication Dexamethasone 8mg bd PO for 3 days, starting the day before each cycle of chemotherapy. Patient should receive 3 doses prior to treatment. In the case where 3 doses have not been taken, dexamethasone 16-20mg IV should be administered 30-60 minutes prior to chemotherapy and the remaining 3 oral doses should be administered as per standard. Emetogenicity This regimen has moderate-high emetic potential refer to local protocol Additional recommended supportive medication Mouthwashes as per local policy H 2 antagonist or Proton Pump Inhibitor if required Consider GCSF if patients develop febrile neutropenia Give diclofenac 50mg tds from Days 1-5 if the patient develops myalgia/arthralgia. Prednisolone 5-10mg od from Days 2-6 and/or gabapentin 300mg stat Day 0, 300mg bd Day 1 & 300mg tds Days 2-7 are alternative agents to use if myalgia/arthralgia persists Pre- treatment evaluation ECHO* Pre-treatment and subsequent monitoring of cardiac function is required. It is recommended that this follows UK guidelines with an echocardiogram pre chemotherapy and at 4 and 8 months. Further assessment after completion of trastuzumab is recommended for patients requiring cardiovascular intervention. FBC Baseline - results valid for 28days LFT Baseline - results valid for 28 days U&E (inc. SrCr) Baseline - results valid for 28 days *or MUGA scan may be used according to local practice Regular investigation ECHO At 4 months and 8 months (more frequently only if clinically indicated) FBC Pre D1 results valid for 72 hours LFT Pre D1 results valid for 7 days U&E (inc. SrCr) Pre D1 results valid for 7 days Clinical Assessment Clinically assess patient prior to each cycle, particularly focusing on whether the patient has developed marked fatigue, neurological, gastrointestinal, hypersensitivity, cutaneous or oedematous symptoms. Standard limits for Neutrophil count 1.0 x 10 9 /l administration to go Platelet count 100 x 10 9 /l ahead if blood results not Bilirubin 1.5 x ULN within range, authorisation to administer must be given by ALT +/- Alk Phos 1.5 x ULN prescriber/consultant Dose modifications Cardiac Toxicity See protocol ASWCS10 BR018 (adjuvant trastuzumab) for monitoring guidelines. Haematological toxicity Day 1: If neutrophils <1.0 x 10 9 /l and/or platelets <100 x 10 9 /l delay 1 week or until recovery. Page 2 of 5
Renal impairment Trastuzumab: no modifications required. Docetaxel : no modifications required. Discuss with consultant if severe renal impairment (CrCl < 10ml/min) Carboplatin: GFR ml/min Carboplatin dose >30 Use AUC as per protocol 30 calculated EDTA then use AUC as per protocol 30 EDTA Discuss with consultant Hepatic impairment AST +/or ALT Alk Phos Docetaxel Dose < 1.5 x ULN and < 2.5 x ULN 100% 1.5 3.5 x ULN 2.5-6 x 75% NCI Common Toxicity Criteria and ULN > 3.5 x ULN and 6 10 x ULN Not recommended. Discuss with consultant Unless due to bone metastases only If Bilirubin > 1.5 x ULN, docetaxel should usually be withheld. Consultant decision to treat. Carboplatin and Trastuzumab do not normally require dose reductions in hepatic impairment. Toxicity Definition Dose adjustment Febrile neutropenia Peripheral neuropathy ANC <0.5 x 10 9 /l plus fever requiring IV antibiotics +/- hospitalisation 1 st episode reduce docetaxel to 75% dose and carboplatin to AUC5. Consider prophylactic GCSF for subsequent cycles. 2 nd episode reduce docetaxel to 60% dose and carboplatin to AUC4 Grade 2 Reduce docetaxel to 75% dose Diarrhoea or stomatitis Other toxicities grade 3 grade 3 grade 3 toxicity (except alopecia) Discuss with consultant 1 st episode reduce docetaxel to 75% 2 nd episode reduce docetaxel to 60% Defer therapy for 1 week until resolved to grade 1. Discuss with consultant if >1 week delay Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Rare or Serious Side Effects Febrile neutropenia Myelosuppression Risk of second malignancy e.g. leukaemia Infusion related reaction Teratogenicity Long term risk of early menopause, reduced fertility Frequently occurring Side Effects Nausea and vomiting Alopecia Stomatitis and mucositis Diarrhoea Fatigue Sore veins (phlebitis) Page 3 of 5
Cardiac Toxicity Other side effects include: myalgia, fluid retention, skin sensitivity/changes, nail ridges and nail loss, altered liver function. Significant drug interactions For full details consult product literature/ reference texts Comments Cumulative Doses References Docetaxel: concomitant administration of substrates, inducers or inhibitors of CYP-3A e.g. ciclosporin, terfenadine, ketoconazole, erythromycin, rifampicin, barbiturates etc, may alter the pharmacokinetics of docetaxel Carboplatin: Aminoglycoside antibiotics : increased risk of nephrotoxicity and ototoxicity Clozapine : increased risk of agranulocytosis, avoid concomitant use Diuretics : increased risk of nephrotoxicity and ototoxicity Nephrotoxic drugs : increased nephrotoxicity ; not recommended Phenytoin : reduced absorption of the antiepileptic Warfarin : increased anticoagulant effect of warfarin Offer scalp cooling (cold capping) to appropriate patients None Slamon D, Eiermann,W, Robert N, Pienkowski T,Martin M, Rolski J et al. on behalf of BCIRG006 Investigators. Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study. San Antonio Breast Cancer Symposium, 2009; Abstract 62 AL Jones, M Barlow, PJ Barrett-Lee, et al (2009) Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. British Journal of Cancer 2009, 100. 684-692 Summary of Product Characteristics Taxotere (Docetaxel) 20mg and 80mg concentrate and solvent for infusion (Sanofi Aventis) [internet] accessed 25/08/2010 available from http://emc.medicines.org.uk/document.aspx?documentid=4594 Summary of Product Characteristics Taxotere (Docetaxel) 20 mg/1ml and 80mg/4ml and 160 mg/8ml concentrate for solution for infusion (Sanofi Aventis) [internet] accessed 25/08/2010 available from http://www.medicines.org.uk/emc/medicine/23210 Summary of Product Characteristics Carboplatin 10mg/ml Intravenous Infusion (Hospira) [internet] accessed 11/11/2010, available at http://www.medicines.org.uk/emc/medicine/622/spc Summary of Product Characteristics Herceptin (Trastuzumab) 150mg powder for concentrate for solution for infusion (Roche) [internet] accessed 28/10/2010, available from Page 4 of 5
http://www.medicines.org.uk/emc/medicine/3567/spc Daniels S. North London Cancer Network. Dose adjustment for cytotoxics in renal impairment [internet]. accessed 21/05/2009 available at http://www.bopawebsite.org/tikidownload_file.php?fileid=620 Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; 2009. Accessed online on 21/05/09 available at https://www.medicinescomplete.com/mc/ Trissel LA. Handbook of Injectable Drugs, 15 th ed. American Society for Health-Systems Pharmacists 2009. Accessed online on 21/05/09 available at http://www.medicinescomplete.com/mc/hid/current/ Allwood M, Stanley A, Wright P, eds. The cytotoxic handbook, 4 th ed, Radcliffe Medical Press, 2002. Document title TCH for Breast Cancer Document number Approval date 18/01/2011 Written by Jeremy Braybrooke, Consultant Oncologist, BHOC Checked by Becky Bagnall, Consultant Pharmacist, NBT Authorised by Jeremy Braybrooke, Chair, ASWCS Drugs and Therapeutics Committee Review date 18/01/2012 Document reviewed by Version number Summary of changes Version Page 5 of 5