EC TH s/c Neoadjuvant Breast Cancer

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1 EC TH s/c Neoadjuvant Breast Cancer Background: Neoadjuvant chemotherapy for inoperable locally advanced, inflammatory breast cancer or to downsize tumour prior to surgery. For patients with HER 2 positive non-metastatic breast cancer.. Patient Group: Neoadjuvant treatment for patients with locally advanced breast cancer that are HER 2 positive (T3 N1 or T4; any T + N2 or N3 or + ipsilateral supraclavicular node involvement) and have a satisfactory LVEF. PS 0-1 Pre-treatment Assessment: Confirmed Her-2 positive on histology Blood Pressure Weight, FBC, U&E, LFTs and Creatinine clearance, Appropriate CT Staging Cardiac assessment All patients for treatment with trastuzumab, but especially those with prior anthracycline and cyclophosphamide exposure, should undergo baseline cardiac assessment including history and physical examination and electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan. Trastuzumab is contraindicated in patients with a history of documented congestive heart failure, coronary artery disease with previous Q-wave myocardial infarction or evidence of transmural infarction on ECG, angina pectoris requiring medication, poorly controlled hypertension, clinically significant valvular disease, or high risk of uncontrolled arrhythmias. A left ventricular ejection fraction (LVEF) above the lower limit of normal (> 50%) is required for the treatment to go ahead (measured on ECHO or MUGA). Page1

2 Treatment Threshold WBC 3.0 x 10 9 /L ANC 1.0 x 10 9 /L Platelets 100 x10 9 /L Cr Cl > 20mL/min Bilirubin 21µmol/L Regimen Details: Day 1 (Cycle 1 3) Epirubicin 100mg/m 2 IV bolus over 3-5 minutes Cyclophosphamide 600mg/m 2 IV bolus over 3-5 minutes Day 1 (Cycle 4-6) Trastuzumab 600mg (flat dose) by subcutaneous injection over 2-5 minutes Docetaxel 100mg/m 2 in 500mL sodium chloride 0.9% IV infusion over 60 minutes Surgery followed by: Day 1 (Cycle 7-21) Trastuzumab 600mg (flat dose) by subcutaneous injection over 2-5 minutes Cycles are repeated at intervals of 21 days Administration: Administration of epirubicin should be via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation. Patients should be observed closely for hypersensitivity reactions especially during the first and second docetaxel infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localized cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed Page2

3 severe hypersensitivity reactions should not be re-challenged with docetaxel The 600 mg dose should be administered as a subcutaneous injection only over 2-5 minutes. The injection site should be alternated between the left and right thigh. New injections should be given at least 2.5 cm from the old site and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with trastuzumab subcutaneous formulation other medicinal products for subcutaneous administration should preferably be injected at different sites. Patients should be observed for six hours after the first injection and for two hours after subsequent injections for signs or symptoms of administration-related reactions. The observation time in subsequent doses may be reduced at local clinician s discretion. Although serious administration-related reactions (ARRs), including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, were not reported in the clinical trial with the Herceptin subcutaneous formulation, caution should be exercised as these have been associated with the intravenous formulation. ARRs can be treated with an analgesic/antipyretic such as Paracetamol, or an antihistamine such as chlorphenamine. Serious reactions to intravenous Herceptin have been treated successfully with supportive therapy such as oxygen, betaagonists, and corticosteroids. In rare cases, these reactions were associated with a clinical course culminating in a fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a fatal ARR. Pre-Meds: Cycles 1-3: Dexamethasone 16mg IV/PO and Ondansetron 8mg IV /PO minutes prior to chemotherapy Cycles 4-6: Dexamethasone 8mg PO BD for 3 days starting the day before chemotherapy and Ondansetron 8mg IV /PO minutes prior to chemotherapy. Anti-emetics: Cycles 1-3: Very highly emetic Cycles 4-6: Highly emetic Additional Medication: Cycles 1-6: Filgrastim 30MU or 48 MU S/C daily for 7 days starting day 3. (<70kg Filgrastim 30 MU, >70kg Filgrastim 48MU). Paracetamol PO, Chlorphenamine IV and Hydrocortisone IV for administration related reactions. Page3

4 Monitoring and Assessment: Medical review prior to cycles 1, 3 and 5 with nursing assessment prior to cycles 2, 4 and 6. FBC prior to each cycle during chemotherapy (not required during trastuzumab only) Blood Pressure prior to each trastuzumab dose U&E, LFT creatinine clearance (calculated) prior to each cycle Echocardiogram (LVEF) at 4 and 8 months and as clinically indicated. Dose Modifications: Haematological toxicity Neutrophils < 1.0 x 10 9 /L defer dose Platelets < 100 x 10 9 /L defer dose If febrile neutropenia, neutrophil < 0.5 x 10 9 /L for more than one week, whilst patient is receiving G-CSF support then give EC at 75 % dose or Docetaxel 75mg/m 2 dose. Trastuzumab dose should remain at 100%. Non Haematological Toxicity (Excluding Alopecia) For toxicities of up to grade 2- delay treatment by one or more weeks until recovery to grade 0 or 1. For severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100 to 75mg/m 2.. For other grade 3 or 4 non-haematological toxicities docetaxel should be reduced from 100 to 75mg/m 2 and EC doses reduced by 25%. If the patient continues to experience these reactions the treatment should be discontinued Cardiac toxicity Congestive heart failure (NYHA II-IV) is a common adverse reaction to trastuzumab. It has been associated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab. Cardiac monitoring is carried out at baseline and at 4 months. Beyond this, LVEF should be monitored as clinically indicated (See North Wales Guidelines). If left ventricular ejection fraction (LVEF) drops 10 ejection fraction (EF) points from baseline AND to below 50 %, treatment should be suspended and a repeat LVEF assessment performed within approximately 6 weeks with initiation of e.g. ACE inhibitor ( with monitoring of renal function and blood Page4

5 pressure) to improve cardiac function. If LVEF has not improved, or declined further, or symptomatic congestive heart failure (CHF) has developed, discontinuation of trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks. All such patients should be referred for assessment by a cardiologist and followed up. Pulmonary events Severe pulmonary adverse events have been reported with the use of the intravenous formulation. Fatal events have been reported and may occur as part of an infusion-related reaction or with delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported with the intravenous preparation. Patients experiencing dyspnoea at rest due to advanced malignancy or requiring supplementary oxygen therapy may be at increased risk of a fatal administration-related reaction and should only be treated with trastuzumab with extreme caution. Renal Impairment Creatinine Epirubicin Cyclophosphamide Docetaxel Clearance (ml/min) >20 100% 100% No dose consider dose 75% adjustment required < 10 dose 50% or OMIT Hepatic Impairment AST/ALT Bilirubin Epirubicin or 2-4 X ULN 1-2 x ULN 50% >4 X ULN or 2-4 X ULN 25% >4 X ULN Discontinue Cyclophosphamide Clinical decision (refer to SPC) Docetaxel at 100mg/m 2 as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m 2.For those patients with serum bilirubin > ULN and/or ALT and AST > 3.5 times the ULN associated with alkaline phosphatase > 6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated. Page5

6 Pharmaceutical Care: No loading dose is required for subcutaneous trastuzumab. The final concentration of 0.74mg/mL docetaxel infusion should not be exceeded. Epirubicin - Increased risk of CHF if the cumulative dose exceeds 900mg/m 2 Drug interactions with docetaxel include: ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. Drug interactions with epirubicin have been observed with cimetidine, dexverapamil, dexrazoxane, docetaxel, interferon alfa-2b, paclitaxel and quinine. Most Common Toxicities: Myelosuppression ± infection / bleeding Nausea and vomiting Hypersensitivity (May be severe) Diarrhoea Stomatitis Fatigue Alopecia Sensory neuropathy Skin reaction (May be severe) Oedema Nail disorder Irregular menstruation Myalgia and Arthralgia Hot flushes Motor neuropathy LFTs Anorexia Dizziness Eye disorders/ watery eyes Phlebitis Photosensitivity Cardiotoxicity References: 1. SPC Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion. Actavis UK Ltd. [accessed 20 th May 2014] 2. SPC Epirubicin Hydrochloride 2 mg/ml Injection. Hospira UK Ltd. [accessed 20 th May 2014] Page6

7 3. SPC Herceptin 600mg/5mL solution for injection Roche Products Limited. [accessed 20 th May 2014] 4. Gianni L, Eiermann. W, et al Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort The Lancet, Volume 375, Issue 9712, Pages , 30 January Michel Marty, Francesco Cognetti, Dominique Maraninchi et al Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2 Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group J Clin Oncol 23: North London Cancer Network guidelines for dosage adjustment for cytotoxics in renal and hepatic impairment. NLCN Page7