Thames Valley. Thames Valley Chemotherapy Regimens Breast Cancer

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1 Chemotherapy Regimens Breast Cancer

2 Notes from the editor These regimens are available on the Network website Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Acknowledgements These regimens have been compiled by the Network Pharmacy Group in collaboration with the Breast PODG with key contribution from Dr Bernadette Lavery, Consultant Oncologist, OUH Dr Nicola Stoner, Consultant Pharmacist, OUH Alison Ashman, formerly Lead Pharmacist Cancer Network Pharmacist Nicky Levitt, Consultant Oncologist, OUH Anne Kendall, Consultant Oncologist, GWH Maria Karina, Consultant Oncologist, MK Joss Adams, Consultant Oncologist, RBFT Sileida Oliveros, Consultant Oncologist, OUH Catherine Chaytor, Pharmacist, OUH Cancer SCN. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner. Chemotherapy Regimens Breast Cancer 2 of 86

3 Chemotherapy Regimens Breast Cancer Network Chemotherapy Regimens used in the management of Breast cancer. Date published: November 2018 Date of review: November 2020 Chemotherapy Regimens Name of regimen Indication Page List of amendments to this version 5 AC (60/600) Adjuvant breast 6 CMF IV 28 day High risk adjuvant breast 8 CMF oral 28 day High risk adjuvant breast 10 Docetaxel Cyclophosphamide Adjuvant breast 12 EC Metastatic breast 14 Trastuzumab adjuvant 8/6 (21 day) Adjuvant breast 16 Docetaxel Carboplatin Trastuzumab TCH Adjuvant breast 18 Docetaxel Carboplatin Pertuzumab Trastuzumab Neoadjuvant breast FEC 75/500 Neoadjuvant / adjuvant breast 21 FEC 100 Neoadjuvant / adjuvant breast 23 FEC 100 Docetaxel 100 Neoadjuvant / adjuvant breast 25 FEC 100 Docetaxel Pertuzumab Trastuzumab Neoadjuvant breast Docetaxel 100 adjuvant (21 day) Neoadjuvant / adjuvant breast 27 Pertuzumab Neoadjuvant breast 29 Capecitabine 1000 monotherapy Metastatic breast 32 Cyclophosphamide +/- Methotrexate (oral) Metastatic breast 34 Capecitabine (1250) Docetaxel (75) Metastatic breast 35 Carboplatin Metastatic breast 38 Doxorubicin 75 Metastatic breast 40 Doxorubicin 20 (weekly) Metastatic breast 41 Epirubicin 60 Metastatic breast 42 Epirubicin 20 (weekly) Metastatic breast 43 Eribulin Metastatic breast 44 Everolimus Metastatic breast 46 Fulvestrant (Funding depends on Trust agreement) Metastatic breast 48 MMM Metastatic breast 49 Docetaxel 100 metastatic (21 day) Metastatic breast 51 Chemotherapy Regimens Breast Cancer 3 of 86

4 Name of regimen Indication Pag38e Docetaxel 40 (7 day) Metastatic breast 53 Gemcitabine Carboplatin Metastatic breast 55 Paclitaxel 175 (21 day) Metastatic breast 57 Paclitaxel 90mg (7 day) Metastatic breast Adjuvant 59 Paclitaxel 80mg (days 1, 8 and 15) Metastatic breast 61 Paclitaxel albumin bound Metastatic breast 63 Paclitaxel Carboplatin Metastatic breast 64 Pertuzumab Trastuzumab Docetaxel Metastatic breast Trastuzumab 4/2 (7 day) Metastatic breast 66 Trastuzumab 8/6 (21 day) Metastatic breast 68 Trastuzumab sub-cutaneous Neoadjuvant, adjuvant and metastatic 70 breast Trastuzumab emtansine (Kadcyla) Metastatic breast 72 Vinorelbine 30 (21 day) Metastatic breast 75 Vinorelbine oral Metastatic breast 77 Chemotherapy Regimens Breast Cancer 4 of 86

5 List of amendments in this version Regimen type: Breast Tumours Date due for review: November 2020 Previous Version number: 4.1 This version number: 4.2 Table 1 Amendments Page Action Type Amendment Made/ asked by Table 2 New regimens to be approved and checked by PODG included in this version Name of regimen Indication Reason / Proposer For anti-emetic guidelines: For dose banded chemotherapy standardized product specifications: Chemotherapy Regimens Breast Cancer 5 of 86

6 AC (60/600) Indication: Adjuvant or metastatic DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 600mg/m 2 IV bolus DOXORUBICIN 60mg/m 2 IV bolus Cycle Frequency: Every 21 days for 4 cycles DOSE MODIFICATIONS Doxorubicin Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit If ALT/AST is 2-3 x ULN give 75% dose If ALT/AST is >3 x ULN give 50% dose Maximum lifetime cumulative dose = mg/m 2 (in normal cardiac function) = 400mg/m 2 (in patients with cardiac dysfunction or exposed to medi astinal irradiation) Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression 3) ECG (possible ECHO) required if patient has preexisting cardiac disease (Doxorubicin) AC Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 6 of 86

7 CONCURRENT MEDICATION ANTIEMETIC POLICY Highly emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cyclophosphamide may irritate bladder, drink copious volumes of water. AC Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 7 of 86

8 CMF IV (28 day) Indication: High risk adjuvant breast DRUG REGIMEN Day 1 *CYCLOPHOSPHAMIDE 600mg/m 2 IV bolus METHOTREXATE 40mg/m 2 IV bolus FLUOROURACIL 600mg/m 2 IV bolus Day 8 CYCLOPHOSPHAMIDE* 600mg/m 2 IV bolus METHOTREXATE 40mg/m 2 IV bolus FLUOROURACIL 600mg/m 2 IV bolus *N.B. an alternative exists using oral Cyclophosphamide (see separate regimen) Cycle Frequency: Every 28 days for 6 cycles DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant. Methotrexate GFR ml/min give 65% dose GFR ml/min give 50% dose GFR <30mL/min omit dose Bilirubin 51-85micromol/L or ALT/AST >180 give 75% dose Bilirubin >85 micromol/l omit Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Palmar plantar (handfoot syndrome) treat with pyridoxine and if symptoms fail to improve then consider reducing the dose of 5FU Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose Classical CMF (IV) Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 8 of 86

9 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Calcium folinate (calcium leucovorin) 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate if:. Pleural effusions/ascites. Previous mucositis. Serum creatinine > 120micromols/L ANTIEMETIC POLICY Moderately emetogenic days 1, 8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (handfoot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Cyclophosphamide may irritate bladder, drink copious volumes of water. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. Classical CMF (IV) Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 9 of 86

10 CMF oral (28 day) Indication: High risk adjuvant breast DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE* 100mg/m 2 PO for 14 days METHOTREXATE 40mg/m 2 IV bolus FLUOROURACIL 600mg/m 2 IV bolus Day 8 METHOTREXATE 40mg/m 2 IV bolus FLUOROURACIL 600mg/m 2 IV bolus *N.B. an alternative exists using IV cyclophosphamide day 1 and 8 (see separate regimen) Cycle Frequency: Every 28 days for 6 cycles DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant. Methotrexate GFR 45-60mL/min give 65% dose GFR 30-45mL/min give 50% dose GFR <30mL/min omit dose Bilirubin 51-85micromol/L or ALT/AST >180 give 75% dose Bilirubin >85 micromol/l omit Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Palmar plantar (handfoot syndrome) treat with pyridoxine and if symptoms fail to improve then consider reducing the dose of 5FU Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose Classical CMF (PO) Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 10 of 86

11 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Calcium folinate (calcium leucovorin) 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate if:. Pleural effusions/ascites. Previous mucositis. Serum creatinine > 120micromols/L ANTIEMETIC POLICY Moderately emetogenic days 1, 8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (handfoot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Cyclophosphamide may irritate bladder, drink copious volumes of water. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. Classical CMF (PO) Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 11 of 86

12 DOCETAXEL CYCLOPHOSPHAMIDE Indication: Adjuvant breast cancer when anthracycline sparing required DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy (or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour CYCLOPHOSPHAMIDE 600mg/m2 IV bolus Cycle Frequency: Every 21 days usually no more than 4 (subject to tolerance and response) DOSE MODIFICATIONS Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) >1.5xULN and ALP > 2.5 x ULN: recommended SPC dose is 75mg/m 2. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests. Tests relating to disease response/progression Docetaxel Cyclophosphamide Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 12 of 86

13 CONCURRENT MEDICATION Ensure premedication given This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) ANTIEMETIC POLICY Moderate emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course REFERENCE Jones et al, JCO, volume 27, number 27, March Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735 Docetaxel Cyclophosphamide Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 13 of 86

14 EC Indication: Metastatic DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus EPIRUBICIN 75mg/m 2 IV bolus Cycle Frequency: Every 21 days for 4 cycles DOSE MODIFICATIONS Epirubicin Bilirubin 24-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment (ie GFR <30ml/min) Maximum lifetime dose = 1000mg/m 2 (with normal cardiac function) = 650mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression 3) ECG (possible ECHO) required if patient has preexisting cardiac disease (Epirubicin) EC Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 14 of 86

15 CONCURRENT MEDICATION ANTIEMETIC POLICY Highly emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Epirubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cyclophosphamide may irritate bladder, drink copious volumes of water. EC Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 15 of 86

16 TRASTUZUMAB Adjuvant 8/6 (21 day) Indication: Adjuvant treatment of early breast cancer. May be given with concurrent RT. NICE guidance - Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer: Trastuzumab, given at 3-week intervals for 1 year or until disease recurrence (whichever is the shorter period) is recommended as a treatment option for early stage HER2 positive breast cancer following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). In keeping with NICE guidance, patients must have received (neo)adjuvant chemotherapy and have adequate cardiac function (LVEF >50). DRUG REGIMEN Cycle 1 only Day 1 Loading dose (to be given day 1 cycle 1 only) TRASTUZUMAB 8mg/kg in 250ml sodium chloride 0.9% infusion over 90 minutes Cycles 2 to 18 Day 1 Maintenance dose TRASTUZUMAB 6mg/kg in 250ml sodium chloride 0.9% infusion over 30** to 90 minutes NB. ** If loading dose is tolerated cycle 2 may be given over 60 minutes and cycle 3 onwards over 30 minutes. SPC states patients need to be monitored for 6 hours after the start of the first dose and 2 hours after the start of subsequent doses. Monitor for 3.5 hours post start of infusion (2 hours after completion) of the first dose, if the patient tolerates the previous cycles then cycles 2 and 3 may be monitored for 30 minutes post infusion and cycle 4 onwards does not require monitoring however this is unlicensed and the patient needs to be informed and consented Cycle Frequency: Loading dose once only followed by 17 maintenance doses 3 weekly (unless reloading required following a break in treatment) (18 cycles in total) DOSE MODIFICATIONS No dose reduction or cessation of Trastuzumab is required if patient has acute reversible Neutropenia. Refer to TVCN adjuvant Trastuzumab guidelines If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg. Continuation and discontinuation of trastuzumab based on interval LVEF assessment If LVEF <44 hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline then stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF > 50 or LVEF and <10 EF points from baseline continue trastuzumab. New LVEF assessment results should be available by the day of the next scheduled trastuzumab administration and a decision to give or hold the dose must be made based on this algorithm. Trastuzumab adjuvant 21 day Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 16 of 86

17 INVESTIGATIONS Routine Blood test 1) Blood results required 3 monthly Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 U&Es & LFTs Baseline weight and 3 monthly weight. Monitor cardiac function (ECG/ECHO/MUGA) of all patients baseline and at 3, 6, 9, 12 months during treatment and at 6, 12 and 24 months following cessation after treatment. 2) Tests relating to disease response/progression CONCURRENT MEDICATION Trastuzumab infusion related chills and/or fevers treat with paracetamol and chlorphenamine. ANTIEMETIC POLICY Minimal emetogenic risk. ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Trastuzumab infusion related chills and/or fevers are commonly observed during the first infusion (but infrequently with subsequent infusions). Other symptoms may include nausea, hypertension, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. Some adverse reactions to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. If symptoms of back ache, nausea or vomiting, do a set of obs. Give hydrocortisone 100mg IV, chlorphenamine 10mg IV. REFERENCE 1 Piccart-Gebhart MJ et al. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. New England Journal of Medicine 2005; 353: Trastuzumab adjuvant 21 day Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 17 of 86

18 DOCETAXEL CARBOPLATIN TRASTUZUMAB (TCH) Indication: Her2 positive breast cancer, unsuitable for an anthracycline DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy (or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour CARBOPLATIN AUC 6 IV in 500ml glucose 5% over 1 hour TRASTUZUMAB 8mg/kg IV in 250ml sodium chloride 0.9% infusion cycle 1 TRASTUZUMAB 6mg/kg IV in 250ml sodium chloride 0.9% infusion cycles 2 to 18 NB.SPC states patients need to be monitored for 6 hours after the start of the first dose and 2 hours after the start of subsequent doses. Monitor for 3.5 hours post start of infusion (2 hours after completion) of the first dose, if the patient tolerates the previous cycles then cycles 2 and 3 may be monitored for 30 minutes post infusion and cycle 4 onwards does not require monitoring however this is unlicensed and the patient needs to be informed and consented Cycle Frequency: Every 21 days for 6 cycles (Trastuzumab to continue up to 18 cycles) DOSE MODIFICATIONS Trastuzumab No dose reduction or cessation of Trastuzumab is required if patient has acute reversible neutropenia. Refer to TVCN adjuvant Herceptin guidelines as per HERA schedule. If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg. Continuation and discontinuation of trastuzumab based on interval LVEF assessment If LVEF <44 hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline then stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF > 50 or LVEF and <10 EF points from baseline continue trastuzumab. New LVEF assessment results should be available by the day of the next scheduled trastuzumab administration and a decision to give or hold the dose must be made based on this algorithm. Docetaxel Carboplatin Trastuzumab Page 1 of 3 Published: November 2018 Chemotherapy Regimens Breast Cancer 18 of 86

19 Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: recommended SPC dose is 75mg/m 2. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. Carboplatin If GFR/ calculated CrCl = or < 20ml/min discuss with consultant. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests. Tests relating to disease response/progression - U&Es & LFTs - Baseline weight and 3 monthly weight. - Monitor cardiac function (ECG/ECHO/MUGA) of all patients at baseline and at 3, 6, 9, 12 months during treatment, and at 6, 12 and 24 months following cessation after treatment. CONCURRENT MEDICATION Ensure premedication given This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) Carboplatin - Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours. GCSF to be added if delays / neutropaenic sepsis. ANTIEMETIC POLICY Moderate emetogenic risk cycles 1 to 6 Minimal emetic risk cycle 7 onwards Docetaxel Carboplatin Trastuzumab Page 2 of 3 Published: November 2018 Chemotherapy Regimens Breast Cancer 19 of 86

20 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Cardiotoxicity - monitor cardiac function. Trastuzumab infusion related chills and/or fevers are commonly observed during the first infusion (but infrequently with subsequent infusions). Other symptoms may include nausea, hypertension, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. Some adverse reactions to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. If symptoms of back ache, nausea or vomiting, do a set of obs. Give hydrocortisone 100mg IV, chlorpheniramine 10mg IV. Ototoxicity - monitor Neurotoxicity - monitor Docetaxel Carboplatin Trastuzumab Page 3 of 3 Published: November 2018 Chemotherapy Regimens Breast Cancer 20 of 86

21 DOCETAXEL CARBOPLATIN PERTUZUMAB TRASTUZUMAB Indication: The neoadjuvant treatment of locally advanced, inflammatory or early breast cancer at high risk of recurrence where all the following criteria are met (NICE TA424): Treatment being given with neoadjuvant intent, Newly diagnosed locally advanced, inflammatory or early breast cancer at high risk of recurrence (i.e must have stage T2-T4b and M0 disease) HER2 3+ by IHC or FISH/CISH positive disease, Baseline LVEF greater than or equal to 55% No prior treatment with chemotherapy or HER2 therapy for this breast cancer Given in combination with docetaxel-containing chemotherapy plus intravenous trastuzumab*. *Trastuzumab should be given IV when given in combination with Pertuzumab but trastuzumab may be given IV or SC when given as a single agent in the adjuvant phase. DRUG REGIMEN Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy (or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered) DOCETAXEL 75mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour cycles 2 to 6 CARBOPLATIN AUC 6 IV in 500ml glucose 5% over 1 hour cycles 2 to 6 TRASTUZUMAB 8mg/kg IV in 250ml sodium chloride 0.9% infusion cycle 1 only TRASTUZUMAB 6mg/kg IV in 250ml sodium chloride 0.9% infusion cycles 2 to 18 PERTUZUMAB 420mg in 250ml sodium chloride 0.9% IV infusion cycles 2 to 6 Day 2 DOCETAXEL 75mg/m 2 in 250ml sodium chloride 0.9% infusion over 1 hour cycle 1 only CARBOPLATIN AUC 6 IV in 500ml glucose 5% over 1 hour cycle 1 only PERTUZUMAB 840mg in 250ml sodium chloride 0.9% IV infusion cycle 1 only NB. SPC states patients need to be monitored for 6 hours after the start of the first dose and 2 hours after the start of subsequent doses. Monitor for 3.5 hours post start of infusion (2 hours after completion) of the first dose, if the patient tolerates the previous cycles then cycles 2 and 3 may be monitored for 30 minutes post infusion and cycle 4 onwards does not require monitoring however this is unlicensed and the patient needs to be informed and consented Cycle Frequency: Every 21 days for 6 cycles (Trastuzumab to continue up to 18 cycles) DOSE MODIFICATIONS Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: recommended SPC dose is 75mg/m 2. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. Docetaxel Carboplatin Pertuzumab Trastuzumab Page 1 of 4 Published: November 2018 Chemotherapy Regimens Breast Cancer 21 of 86

22 Carboplatin If GFR/ calculated CrCl = or < 20ml/min discuss with consultant. Trastuzumab No dose reduction or cessation of Trastuzumab is required if patient has acute reversible neutropenia. Refer to TVCN adjuvant Herceptin guidelines as per HERA schedule. If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg. Continuation and discontinuation of trastuzumab based on interval LVEF assessment If LVEF <44 hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline then stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF > 50 or LVEF and <10 EF points from baseline continue trastuzumab. New LVEF assessment results should be available by the day of the next scheduled trastuzumab administration and a decision to give or hold the dose must be made based on this algorithm. Pertuzumab Dose reductions are not recommended for Pertuzumab. Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time If trastuzumab treatment is discontinued, treatment with Pertuzumab should be discontinued. If docetaxel is discontinued, treatment with Pertuzumab and trastuzumab may continue until disease progression or unmanageable toxicity. Left ventricular dysfunction Pertuzumab and trastuzumab should be withheld for at least 3 weeks for any of the following: - signs and symptoms suggestive of congestive heart failure (Pertuzumab should be discontinued if symptomatic heart failure is confirmed) - a drop in left ventricular ejection fraction (LVEF) to less than 40% - a LVEF of 40%-45% associated with a fall of = 10% points below pre-treatment values. Pertuzumab and trastuzumab may be resumed if the LVEF has recovered to > 45% or 40-45% associated with < 10% points below pretreatment value. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, discontinuation of Pertuzumab and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks Infusion reactions Docetaxel Carboplatin Pertuzumab Trastuzumab Page 2 of 4 Published: November 2018 Chemotherapy Regimens Breast Cancer 22 of 86

23 The infusion rate may be slowed or interrupted if the patient develops an infusion reaction (see section 4.8 of SmPC). The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists, antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms. The infusion should be discontinued immediately if the patient experiences a NCI- CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome Patients with renal impairment Dose adjustments of Pertuzumab are not needed in patients with mild or moderate renal impairment. No dose recommendations can be made for patients with severe renal impairment because of the limited pharmacokinetic data available. Patients with hepatic impairment The safety and efficacy of Pertuzumab have not been studied in patients with hepatic impairment. No specific dose recommendations can be made INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests. Tests relating to disease response/progression - U&Es & LFTs - Baseline weight and 3 monthly weight. - Monitor cardiac function (ECG/ECHO/MUGA) of all patients at baseline and at 3, 6, 9, 12 months during treatment, and at 6, 12 and 24 months following cessation after treatment. Restage with CT staging every 3 cycles CONCURRENT MEDICATION Ensure premedication given This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) Carboplatin - Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. DEXAMETHASONE 20mg IV bolus CHLORPHENAMINE 10mg IV bolus RANITIDINE 50mg IV bolus Carboplatin should be given at a slower rate e.g. 2-4 hours. GCSF to be added if delays / neutropaenic sepsis. Docetaxel Carboplatin Pertuzumab Trastuzumab Page 3 of 4 Published: November 2018 Chemotherapy Regimens Breast Cancer 23 of 86

24 ANTIEMETIC POLICY Moderate emetogenic risk cycles 1 to 6 Minimal emetic risk cycle 7 onwards ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Cardiotoxicity - monitor cardiac function. Trastuzumab infusion related chills and/or fevers are commonly observed during the first infusion (but infrequently with subsequent infusions). Other symptoms may include nausea, hypertension, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. Some adverse reactions to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. If symptoms of back ache, nausea or vomiting, do a set of obs. Give hydrocortisone 100mg IV, chlorpheniramine 10mg IV. Ototoxicity - monitor Neurotoxicity - monitor Docetaxel Carboplatin Pertuzumab Trastuzumab Page 4 of 4 Published: November 2018 Chemotherapy Regimens Breast Cancer 24 of 86

25 FEC 75/500 Indication: Neoadjuvant / adjuvant and metastatic breast cancer DRUG REGIMEN Day 1 FLUOROURACIL 500mg/m 2 IV bolus EPIRUBICIN 75mg/m 2 IV bolus CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus GCSF as per local policy Cycle Frequency: Every 21 days for 6 cycles (review after 4 cycles) DOSE MODIFICATIONS Previous neutropenic sepsis, Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant Epirubicin Bilirubin 24-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) = 1000mg/m 2 (with normal cardiac function) Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose FEC 75/500 Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 25 of 86

26 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L (on the day of chemo go ahead with GCSF support as per local policy for 7 days starting at least 24 hours after chemotherapy, no chemo dose reductions). <0.8 wait until neutrophils ) Non urgent blood tests Tests relating to disease response/progression ECG (possible ECHO) required if patient has preexisting cardiac disease (Epirubicin) CONCURRENT MEDICATION Patients who have had previous neutropenic sepsis should go ahead without dose reduction but with prophylactic GCSF support as per local policy (discuss with Consultant). ANTIEMETIC POLICY Moderately emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Cardiotoxicity monitor cardiac function. Epirubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. Cyclophosphamide may irritate bladder, drink copious volumes of water. REFERENCES 1. Effects of Chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. EBCTG. Lancet 2005; 365: Breast Cancer Adjuvant chemotherapy update, October 07 Dr B A Lavery. TVCN Breast PODG Lead FEC 75/500 Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 26 of 86

27 FEC 100 Indication: Neoadjuvant / adjuvant DRUG REGIMEN Day 1 FLUOROURACIL 500mg/m 2 IV bolus EPIRUBICIN 100mg/m 2 IV bolus CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus Cycle Frequency: Every 21 days for 6 cycles (4 cycles if unable to cope) Neoadjuvant / adjuvant 3 cycles of FEC 100 followed by 3 of Docetaxel (100mg/m2) see separate FEC-docetaxel regimen. DOSE MODIFICATIONS Previous neutropenic sepsis, Symptoms including diarrhoea, mucositis and leucopenia, discuss with Registrar or Consultant Epirubicin Bilirubin 24-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) = 1000mg/m 2 (with normal cardiac function) Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose FEC 100 Page 1 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 27 of 86

28 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 <1.5 (on the day of chemo go ahead with GCSF support as per local policy, no chemo dose reductions). 2) Non urgent blood tests Tests relating to disease response/progression ECG (possible ECHO) required if patient has preexisting cardiac disease (Epirubicin) CONCURRENT MEDICATION Patients who have had previous neutropenic sepsis should go ahead without dose reduction but with prophylactic GCSF support as per local policy (discuss with Consultant). ANTIEMETIC POLICY Highly emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (handfoot syndrome) causing red palms and soles treat with pyridoxine 50mg tds Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Cardiotoxicity monitor cardiac function. Epirubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cardiotoxicity - special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with fluorouracil. Cyclophosphamide may irritate bladder, drink copious volumes of water. REFERENCES 1. Sequential Adjuvant Epirubicin-based and Docetaxel Chemotherapy for Node positive Breast Cancer Patients: The FNCLCC PACS 01 Trial. JCO 2006; 24: Breast Cancer Adjuvant chemotherapy update, October 07 Dr B A Lavery. TVCN Breast PODG Lead FEC 100 Page 2 of 2 Published: November 2018 Chemotherapy Regimens Breast Cancer 28 of 86

29 FEC DOCETAXEL Indication: Neoadjuvant breast cancer and adjuvant node positive good performance status <= 65 years breast cancer. Consider use in >65 years only if extremely good performance status. DRUG REGIMEN Day 1 FLUOROURACIL 500mg/m 2 IV bolus EPIRUBICIN 100mg/m 2 IV bolus CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus Cycle Frequency: Every 21 days for 3 cycles followed by Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy (or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered). (This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) DOCETAXEL 100mg/m 2 in 250ml* glucose 5% or sodium chloride 0.9% infusion over 1 hour * doses 200mg to 360mg in 500ml sodium chloride 0.9% Cycle Frequency: Every 21 days for 3 cycles NB: Routine GCSF as per local policy Clinicians and Nurses may review alternate cycles. DOSE MODIFICATIONS Epirubicin Bilirubin 24-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) = 1000mg/m 2 (with normal cardiac function) Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose FEC 100/ docetaxel Page 1 of 2 Published: November 2018 Version 2.2 Network Chemotherapy Regimens Breast Cancer 29

30 Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: recommended dose is 75mg/m 2. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 (on the day of chemo go ahead with GCSF support),as per local policy no dose reductions 2) Non urgent blood tests Tests relating to disease response/progression 3) ECG (possible ECHO) required if patient has preexisting cardiac disease (Epirubicin) CONCURRENT MEDICATION Ensure pre-medication is given before docetaxel ANTIEMETIC POLICY FEC - Highly emetogenic Docetaxel Low emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Mucositis see dose modifications Diarrhoea see dose modifications Cardiotoxicity monitor cardiac function. Epirubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Cyclophosphamide may irritate bladder, drink copious volumes of water. FEC 100/ docetaxel Page 2 of 2 Published: November 2018 Version 2.2 Network Chemotherapy Regimens Breast Cancer 30

31 FEC 100 DOCETAXEL PERTUZUMAB TRASTUZUMAB Indication: The neoadjuvant treatment of locally advanced, inflammatory or early breast cancer at high risk of recurrence where all the following criteria are met (NICE TA424): Treatment being given with neoadjuvant intent, Newly diagnosed locally advanced, inflammatory or early breast cancer at high risk of recurrence (i.e must have stage T2-T4b and M0 disease) HER2 3+ by IHC or FISH/CISH positive disease, Baseline LVEF greater than or equal to 55% No prior treatment with chemotherapy or HER2 therapy for this breast cancer Given in combination with docetaxel-containing chemotherapy plus intravenous trastuzumab*. *Trastuzumab should be given IV when given in combination with Pertuzumab but trastuzumab may be given IV or SC when given as a single agent in the adjuvant phase. NOTE: The application should be made immediately prior to commencing pertuzumab when given with single agent docetaxel chemotherapy plus trastuzumab as part of sequential anthracycline/docetaxel regimen and not at the start of the anthracycline based component DRUG REGIMEN Day 1 FLUOROURACIL 500mg/m 2 IV bolus EPIRUBICIN 100mg/m 2 IV bolus CYCLOPHOSPHAMIDE 500mg/m 2 IV bolus Cycle Frequency: Every 21 days for 3 cycles followed by Day 1 PREMEDICATION: DEXAMETHASONE 8mg BD starting 24 hours before chemotherapy (or 20mg IV on day of chemotherapy) and 8mg bd post-chemotherapy for 2 days (for patients who are unable to tolerate high doses of steroids 4mg doses may be considered). (This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) DOCETAXEL 75mg/m 2 in 250ml* glucose 5% or sodium chloride 0.9% infusion over 1 hour PERTUZUMAB 840mg in 250ml sodium chloride 0.9% IV infusion cycle 4 PERTUZUMAB 420mg in 250ml sodium chloride 0.9% IV infusion cycles 5 to 7 * doses 200mg to 360mg in 500ml sodium chloride 0.9% Cycle Frequency: Every 21 days for 4 cycles Day 1 TRASTUZUMAB 8mg/kg in 250ml sodium chloride 0.9% infusion over 90 minutes cycle 4 TRASTUZUMAB 6mg/kg in 250ml sodium chloride 0.9% infusion over 30** to 90 minutes cycles 5 to 21 *may be switched to trastuzumab SC from cycle 8 NB: Routine GCSF as per local policy Clinicians and Nurses may review alternate cycles. FEC 100 Docetaxel Pertuzumab Trastuzumab Page 1 of 4 Published: November 2018 Network Chemotherapy Regimens Breast Cancer 31

32 NB. ** If loading dose is tolerated cycle 2 may be given over 60 minutes and cycle 3 onwards over 30 minutes. SPC states patients need to be monitored for 6 hours after the start of the first dose and 2 hours after the start of subsequent doses. Monitor for 3.5 hours post start of infusion (2 hours after completion) of the first dose, if the patient tolerates the previous cycles then cycles 2 and 3 may be monitored for 30 minutes post infusion and cycle 4 onwards does not require monitoring however this is unlicensed and the patient needs to be informed and consented DOSE MODIFICATIONS Trastuzumab Patients with renal impairment Dose adjustments of Pertuzumab are not needed in patients with mild or moderate renal impairment. No dose recommendations can be made for patients with severe renal impairment because of the limited pharmacokinetic data available. Patients with hepatic impairment The safety and efficacy of Pertuzumab have not been studied in patients with hepatic impairment. No specific dose recommendations can be made. No dose reduction or cessation of Trastuzumab is required if patient has acute reversible neutropenia Refer to TVCN adjuvant Trastuzumab guidelines If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg. Continuation and discontinuation of trastuzumab based on interval LVEF assessment If LVEF <44 hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline then stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF and >10 points from baseline stop trastuzumab. If repeat LVEF and <10 points from baseline or LVEF >49 resume trastuzumab. If LVEF > 50 or LVEF and <10 EF points from baseline continue trastuzumab. New LVEF assessment results should be available by the day of the next scheduled trastuzumab administration and a decision to give or hold the dose must be made based on this algorithm. Pertuzumab Dose reductions are not recommended for Pertuzumab. Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppression but they should be monitored carefully for complications of neutropenia during this time If trastuzumab treatment is discontinued, treatment with Pertuzumab should be discontinued. If docetaxel is discontinued, treatment with Pertuzumab and trastuzumab may continue until disease progression or unmanageable toxicity. Left ventricular dysfunction FEC 100 Docetaxel Pertuzumab Trastuzumab Breast PODG Chair Authorisation: Page 2 of 4 Published: November 2018 Network Chemotherapy Regimens Breast Cancer 32

33 Pertuzumab and trastuzumab should be withheld for at least 3 weeks for any of the following: - signs and symptoms suggestive of congestive heart failure (Pertuzumab should be discontinued if symptomatic heart failure is confirmed) - a drop in left ventricular ejection fraction (LVEF) to less than 40% - a LVEF of 40%-45% associated with a fall of = 10% points below pre-treatment values. Pertuzumab and trastuzumab may be resumed if the LVEF has recovered to > 45% or 40-45% associated with < 10% points below pretreatment value. If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, discontinuation of Pertuzumab and trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks Infusion reactions The infusion rate may be slowed or interrupted if the patient develops an infusion reaction (see section 4.8 of SmPC). The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists, antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms. The infusion should be discontinued immediately if the patient experiences a NCI- CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome Epirubicin Bilirubin 24-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) = 1000mg/m 2 (with normal cardiac function) Fluorouracil Consider dose reduction in severe renal impairment (ie GFR <30ml/min) Bilirubin <85micromol/L or ALT/AST <180 give 100% dose Bilirubin >85micromol/L or ALT/AST >180 omit Cyclophosphamide GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose Docetaxel Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Hepatic impairment: Patients who have both elevations of transaminases (ALT and/or AST) > 1.5 x ULN and ALP > 2.5 x ULN: recommended dose is 75mg/m 2. Patients with serum bilirubin > ULN and/or ALT and AST > 3.5 x ULN associated with ALP > 6 x ULN: docetaxel should not be used unless strictly indicated FEC 100 Docetaxel Pertuzumab Trastuzumab Page 3 of 4 Published: November 2018 Network Chemotherapy Regimens Breast Cancer 33

34 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 2) Non urgent blood tests Tests relating to disease response/progression Baseline weight and every 3 months U&Es & LFTs Monitor cardiac function (ECG/ECHO/MUGA) of all patients baseline and at 3, 6, 9, 12 months during treatment and at 6, 12 and 24 months following cessation after treatment. Restage with CT staging every 3 cycles CONCURRENT MEDICATION Trastuzumab infusion related chills and/or fevers treat with paracetamol and chlorphenamine. ANTIEMETIC POLICY Minimal emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Epirubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous course. Trastuzumab infusion related chills and/or fevers are commonly observed during the first infusion (but infrequently with subsequent infusions). Other symptoms may include nausea, hypertension, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. Some adverse reactions to trastuzumab infusion including dyspnoea, hypotension, wheezing, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. If symptoms of back ache, nausea or vomiting, do a set of obs. Give hydrocortisone 100mg IV, chlorphenamine 10mg IV. Mucositis see dose modifications Diarrhoea see dose modifications Cyclophosphamide may irritate bladder, drink copious volumes of water. FEC 100 Docetaxel Pertuzumab Trastuzumab Page 4 of 4 Published: November 2018 Network Chemotherapy Regimens Breast Cancer 34