thames valley chemotherapy regimens

Thames Valley

Thames Valley Chemotherapy

Regimens Breast Cancer

Thames Valley

Chemotherapy Regimens – Breast Cancer 2 of 86

Notes from the editor These regimens are available on the Network website www.tvscn.nhs.uk Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] 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 Thames Valley 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

© Thames Valley Cancer SCN. All rights reserved. Not to be reproduced in whole or in part without the permission of the copyright owner.

http://www.tvscn.nhs.uk/

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Thames Valley 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

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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 breast

70

Trastuzumab emtansine (Kadcyla) Metastatic breast 72

Vinorelbine 30 (21 day) Metastatic breast 75

Vinorelbine oral Metastatic breast 77

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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: http://tvscn.nhs.uk/networks/cancer/cancer-topics/chemotherapy/ For dose banded chemotherapy standardized product specifications: www.england.nhs.uk/commissioning/spec-services/npc-crg/group-b/b02/dose-banded-chemotherapy-standardised-product-specifications/

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AC (60/600) Indication: Adjuvant or metastatic

DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 600mg/m2

IV bolus DOXORUBICIN 60mg/m2

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 = 450-550mg/m2

(in normal cardiac function) = 400mg/m2(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 109/L ≥100 < 100 Neutrophils x 109/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 Breast PODG Chair Authorisation: Date:

Page 1 of 2 Published: November 2018 Review: November 2020

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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 Breast PODG Chair Authorisation: Date:


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CMF IV (28 day) Indication: High risk adjuvant breast

DRUG REGIMEN Day 1 *CYCLOPHOSPHAMIDE 600mg/m2

IV bolus METHOTREXATE 40mg/m2

IV bolus FLUOROURACIL 600mg/m2

IV bolus Day 8 CYCLOPHOSPHAMIDE* 600mg/m2

IV bolus METHOTREXATE 40mg/m2


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 45 - 60 mL/min give 65% dose GFR 30 - 45 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)

Breast PODG Chair Authorisation: Date:


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Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/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)



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CMF oral (28 day) Indication: High risk adjuvant breast

DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE* 100mg/m2

PO for 14 days METHOTREXATE 40mg/m2


IV bolus Day 8 METHOTREXATE 40mg/m2


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)



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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)



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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/m2

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/m2. 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


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

2) Non urgent blood tests. Tests relating to disease response/progression

Docetaxel Cyclophosphamide



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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 2009. 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



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EC Indication: Metastatic

DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 500mg/m2

IV bolus EPIRUBICIN 75mg/m2


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/m2

(with normal cardiac function) = 650mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation)



Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/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 Breast PODG Chair Authorisation: Date:


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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 Breast PODG Chair Authorisation: Date:


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TRASTUZUMAB Adjuvant 8/6 (21 day)

Indication: Adjuvant treatment of early breast cancer. May be given with concurrent RT.

NICE guidance - www.nice.org.uk 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 45-49 and >10 points from baseline then stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF 45-49 and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF 45-49 and >10 points from baseline stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF > 50 or LVEF 45-49 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



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INVESTIGATIONS Routine Blood test 1) Blood results required 3 monthly

Give Discuss

Hb x g/dL ≥10 < 10


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; 353:1659-1672.

Trastuzumab adjuvant 21 day



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DOCETAXEL CARBOPLATIN TRASTUZUMAB (TCH)

Indication: Her2 positive breast cancer, unsuitable for an anthracycline



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 45-49 and >10 points from baseline then stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF 45-49 and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF 45-49 and >10 points from baseline stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF > 50 or LVEF 45-49 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



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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/m2. 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.


Give Discuss

Hb x g/dL ≥10 < 10


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




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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




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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.



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/m2

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/m2. 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



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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 45-49 and >10 points from baseline then stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF 45-49 and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF 45-49 and >10 points from baseline stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF > 50 or LVEF 45-49 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




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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


Give Discuss

Hb x g/dL ≥10 < 10


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.




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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




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FEC 75/500 Indication: Neoadjuvant / adjuvant and metastatic breast cancer

DRUG REGIMEN Day 1 FLUOROURACIL 500mg/m2


IV bolus CYCLOPHOSPHAMIDE 500mg/m2

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/m2(in patients with cardiac dysfunction or exposed to mediastinal

irradiation) = 1000mg/m2

(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 Breast PODG Chair Authorisation: Date:


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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 0.8-1.5 (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 0.8. 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 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: 1687 – 1717 2. Breast Cancer Adjuvant chemotherapy update, October 07 Dr B A Lavery. TVCN Breast PODG

Lead

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FEC 100 Indication: Neoadjuvant / adjuvant




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/m2(in patients with cardiac dysfunction or exposed to mediastinal


(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

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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/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).


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: 5664-5671 2. Breast Cancer Adjuvant chemotherapy update, October 07 Dr B A Lavery. TVCN Breast PODG

Lead

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Network Chemotherapy Regimens – Breast Cancer 29

FEC 100 - 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.




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/m2

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/m2(in patients with cardiac dysfunction or exposed to mediastinal


(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


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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/m2. 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.


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/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.

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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




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/m2

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.

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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.


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




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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/m2(in patients with cardiac dysfunction or exposed to mediastinal


(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


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/m2. 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




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Give Discuss

Hb x g/dL ≥10 < 10




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


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.




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DOCETAXEL 100 adjuvant (21 day) Indication: Neoadjuvant / adjuvant

First line adjuvant use in cases where anthracyclines cannot be used (previous anthracyclines for a previous breast cancer, serious cardiac problems etc),

NICE guidance approved the use of Docetaxel in the adjuvant setting for node positive women. NICE guidance named TAC as the regime to use, but this has substantial toxicity risks, and high rates of neutropenic sepsis. UK breast groups have opted for the TACT trial regime instead. The French results are the best in the literature, and after consideration at the TVCN Breast PODG it is recommended that the PACS01 schedule is used when an adjuvant taxane based regimen is recommended for node positive cases.

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). (This can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions) DOCETAXEL 100mg/m2

in 250ml* sodium chloride 0.9% infusion over 1 hour * doses 200mg to 360mg in 500ml sodium chloride 0.9%

NB: Routine GCSF as per local policy

Cycle Frequency: Every 21 days 3 cycles when following 3 cycles of FEC 100 (see separate regimen)

DOSE MODIFICATIONS 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 75 mg/m2. 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.

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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 (on the day of chemo go ahead with GCSF support as per

local policy, no chemo dose reductions).



ANTIEMETIC POLICY Low emetogenic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Discuss if severe cutaneous reactions, peripheral neuropathy or fluid retention after previous Course REFERENCES 1. Breast Cancer Adjuvant chemotherapy update, October 07 Dr B A Lavery. TVCN Breast PODG

Lead 2. 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: 1687 – 1717 3. Sequential Adjuvant Epirubicin-based and Docetaxel Chemotherapy for Node positive Breast

Cancer Patients: The FNCLCC PACS 01 Trial. JCO 2006; 24: 5664-5671 4. Epirubicin increases long term survival in adjuvant chemotherapy of patients with poor

prognosis, node-positive, early breast cancer: 10 year follow up results of the French Adjuvant Study Group 05 Randomized Trial. JCO 2005; 23: 2686-2693

5. NICE technology appraisal guidance 109 September 2006

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CAPECITABINE 1000 MONOTHERAPY (1000mg/m2 BD)

Indication: First line monotherapy of metastatic advanced breast cancer NICE guidance – www.nice.org.uk Capecitabine monotherapy is recommended as an option for people with locally advanced or metastatic breast cancer who have not previously received capecitabine in combination therapy and for whom anthracycline and taxane containing regimens have failed or further anthracycline treatment is contraindicated.

DRUG REGIMEN Days 1 to 14 1000mg/m2

twice daily (2000mg/m2/day) po for 14 days followed by a 7 day rest NB the lower starting dose above is used in breast and heavily pretreated patients it may be possible to consider to 1250mg/m2

in patients who tolerate the 1000mg/m2 dose with minimal toxicity ‘However 50% of the patients in the main phase 3 trial required a reduction of capecitabine dose. This dose reduction was not associated with any increased risk of progression or resistance to treatment, in fact there was slightly better controlled disease in those whose dose reduced by 25% in the oral Capecitabine arm (the above dose)’ NB Tablets available as strengths of 150mg and 500mg. Cycle Frequency: Every 21 days until progression or unacceptable toxicity

DOSE MODIFICATIONS Capecitabine Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% dose

30 - 50 give 75% dose <30 contraindicated

Hepatic impairment – SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modifications due to toxicity (including plantar-palmar erythema and gastrointestinal toxicity).

Capecitabine Breast PODG Chair Authorisation: Date:


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Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of starting dose) * Grade 1 Maintain dose level Maintain dose level * Grade 2 - 1st appearance Interrupt until resolved to grade 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75%

INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss

Hb x g/dL ≥10 < 10


Serum creatinine - GFR should be calculated or measured using EDTA

CONCURRENT MEDICATION Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.

Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (handfoot syndrome) causing red palms and soles – treat with pyridoxine 50mg tds Diarrhoea – treat with loperamide or codeine Cardiotoxicity – monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. All patients should be told to report any cardiac symptoms immediately and should be told to stop the medication immediately if any suspicion of cardiac problems.

Capecitabine Breast PODG Chair Authorisation: Date:


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CYCLOPHOSPHAMIDE +/- METHOTREXATE

Indication: Metastatic breast cancer, heavily pre-treated patients

DRUG REGIMEN Days 1 to 7 CYCLOPHOSPHAMIDE 50mg PO Days 1 & 2 METHOTREXATE 2.5mg PO bd

Cycle Frequency: Every 7 days continuously

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar

Methotrexate GFR 45 - 60mL/min give 65% dose GFR 30 - 45mL/min give 50% dose GFR < 30mL/min omit dose Bilirubin 53 - 85micromol/L or ALT//AST > 180 give 75% dose Bilirubin >85 micromol/L omit




2) Non urgent blood tests Tests relating to disease response/progression FBC. U&Es, creatinine, glucose, calcium. LFT's, CGA assessment

CONCURRENT MEDICATION None


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication) Cyclophosphamide may irritate bladder, drink copious volumes of water. Caution with pleural effusions or ascites.

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CAPECITABINE 1250 DOCETAXEL 75 NICE guidance – www.nice.org.uk In the treatment of locally advanced or metastatic breast cancer, capecitabine in combination with docetaxel is recommended in preference to single agent docetaxel in people for whom anthracycline containing regimens are unsuitable or have failed.

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/m2

in 250ml sodium chloride 0.9% infusion over 1 hour Days 1 to 14 CAPECITABINE* 1250mg/m2

bd po (2500mg/m2/day) days 1 to 14 followed by 7 day rest

* The Summary of Product Characteristics recommends a dose of 1250mg/m2 bd.

However 50% of the patients in the main phase 3 trial required a reduction of capecitabine dose. This dose reduction was not associated with any increased risk of progression or resistance to treatment, in fact there was slightly better controlled disease in those whose dose reduced by 25% in the oral Capecitabine arm. Therefore a lower starting dose of 1000*mg/m2

bd may be considered.

NB Capecitabine tablets available as strengths of 150mg and 500mg Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Capecitabine Check CrCl prior to every cycle CrCl (ml/min) >50 give 100% dose

30 - 50 give 75% dose <30 contraindicated

Hepatic impairment – SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modifications due to toxicity (including plantar palmar erythema and gastrointestinal toxicity).

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Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of starting dose) * Grade 1 Maintain dose level Maintain dose level * Grade 2 - 1st appearance Interrupt until resolved to grade 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4 - 1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 - 2nd appearance Discontinue permanently Not applicable 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/m2. 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. Haematology Treatment should only be readministered when the neutrophil count is > 1.5 x 109/L. Patients with neutropenia < 0.5 x 109/L for more than one week, or febrile neutropenia, should have the docetaxel dose reduced from 75mg/m2

to 55mg/m2. If grade 4 neutropenia or febrile neutropenia occurs at 55mg/m2

docetaxel, docetaxel should be discontinued.

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Give Discuss

Hb x g/dL ≥10 < 10


Serum creatinine - GFR should be calculated or measured using EDTA


CONCURRENT MEDICATION Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.

Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR. Docetaxel: Ensure pre-medication is given this can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.

ANTIEMETIC POLICY Low emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (handfoot syndrome) causing red palms and soles – treat with pyridoxine 50mg tds Diarrhoea – treat with loperamide or codeine Cardiotoxicity – monitor cardiac function. To minimise risk of anthracycline induced cardiac failure signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. All patients should be told to report any cardiac symptoms immediately and should be told to stop the medication immediately if any suspicion of cardiac problems.

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CARBOPLATIN Indication: Triple negative or BRCA mutated metastatic breast cancer (case based

discussion)

DRUG REGIMEN Day 1 CARBOPLATIN AUC 6 in 500ml glucose 5% infusion over 60 minutes Dose (mg) = (GFR + 25) x AUC

Ideally GFR is measured using 51Cr-EDTA AUC = 6


DOSE MODIFICATIONS

Previous neutropenic sepsis, discuss with Consultant or Registrar. 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 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5

GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion.

Patients with hydronephrosis or serum creatinine >100 micromol/L need a serum creatinine checked every cycle. All patients have serum creatinine checked 1st and 4th cycle. 2) Non-urgent blood tests Tests relating to disease response/progression


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. Carboplatin 21 days



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ANTI-EMETIC POLICY Moderately emetogenic (routinely dexamethasone and metoclopramide is adequate but 5HT3 antagonist may be required if there is inadequate control).

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity – monitor

REFERENCES 1. Tutt A, et al: The TNT trial. 2014 San Antonio Breast Cancer Symposium. Abstract S3-01.

Presented December 11, 2014. 2. The Lancet Oncology Volume 15, No. 7, p747–756, November 2014 3. Prof Gunter von Minckwitz, MD, Prof Andreas Schneeweiss, MD, Prof Sibylle Loibl, MD,

Christoph Salat, MD, Prof Carsten Denkert, MD, Prof Mahdi Rezai, MD, Prof Jens U Blohmer, MD, Prof Christian Jackisch, MD, Stefan Paepke, MD, Prof Bernd Gerber, MD, Dirk M Zahm, MD, Sherko Kümmel, MD, Holger Eidtmann, MD, Peter Klare, MD, Prof Jens Huober, MD, Prof Serban Costa, MD, Prof Hans Tesch, MD, Claus Hanusch, MD, Prof Jörn Hilfrich, MD, Fariba Khandan, MD, Prof Peter A Fasching, MD, Bruno V Sinn, MD, Knut Engels, MD, Keyur Mehta, MBA, Valentina Nekljudova, PhD, Prof Michael Untch, MD Published Online: 30 April 2014

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http://www.thelancet.com/journals/lanonc/issue/vol15no7/PIIS1470-2045(14)X7165-2

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Thames Valley


DOXORUBICIN 75 Indication: Metastatic breast cancer

DRUG REGIMEN Day 1 DOXORUBICIN 75mg/m2

IV bolus NB Reduce dose for heavily pretreated patients discuss with consultant (e.g. 60mg/m2)


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 cumulative dose = 450-550mg/m2

(in normal cardiac function) = 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation)

INVESTIGATIONS Routine blood test 1) Blood results required before chemotherapy administration

Give Discuss

Hb x g/dL ≥10 < 10



Tests relating to disease response/progression ECG (possible ECHO) required if patient has preexisting cardiac disease (Doxorubicin)



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.

Doxorubicin 75



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DOXORUBICIN 20 (7 day) Indication: Metastatic breast cancer

DRUG REGIMEN Day 1 DOXORUBICIN 20mg/m2

IV bolus NB Dose can be increased in patients who tolerate treatment to the full Doxorubicin (21 day) dose (see separate regimen) discuss with consultant

Cycle Frequency: Every 7 days (number of cycles to be individualized)

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 cumulative dose = 450-550mg/m2

(in normal cardiac function) = 400 mg/m2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation)


Give Discuss

Hb x g/dL ≥10 < 10



Tests relating to disease response/progression ECG (possible ECHO) required if patient has preexisting cardiac disease (Doxorubicin)



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.

Doxorubicin 20 weekly



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EPIRUBICIN 60 Indication: Metastatic breast cancer

DRUG REGIMEN Day 1 EPIRUBICIN 60mg/m2


DOSE MODIFICATIONS Epirubicin Bilirubin 24-50 micromol/L give 50% dose Bilirubin 51-85 micromol/L give 25% dose Bilirubin >85 micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m2 (in patients with cardiac dysfunction or exposed to

mediastinal irradiation) = 1000mg/m2

(with normal cardiac function)


Give Discuss

Hb x g/dL ≥10 < 10







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.

Epirubicin 60 Breast PODG Chair Authorisation: Date:


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EPIRUBICIN 20 (7 day) Indication: Metastatic breast cancer

DRUG REGIMEN Day 1 EPIRUBICIN 20mg/m2

IV bolus Cycle Frequency: Every 7 days (number of cycles to be individualized)

DOSE MODIFICATIONS Epirubicin Bilirubin 24-50 micromol/L give 50% dose Bilirubin 51-85 micromol/L give 25% dose Bilirubin >85 micromol/L omit Dose reduce in severe renal impairment. Maximum lifetime dose = 650mg/m2 (in patients with cardiac dysfunction or exposed to

mediastinal irradiation) = 1000mg/m2

(with normal cardiac function)


Give Discuss

Hb x g/dL ≥10 < 10







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.

Epirubicin 20 weekly



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ERIBULIN Indication: Locally advanced or metastatic breast cancer, previously treated with at least 2 previous lines of chemotherapy for advanced disease (which may include an anthracycline or a taxane, and capecitabine) NICE TA423

DRUG REGIMEN Days 1 and 8

ERIBULIN 1.23mg/m2 in 50ml sodium chloride 0.9% IV infusion over 5 minutes Eribulin equivalent to eribulin mesylate 1.4mg/m2)

Cycle Frequency: Every 21 days until disease progression

DOSE MODIFICATIONS Eribulin In severe renal impairment (Creatinine clearance <40ml/min) may need a dose reduction. Hepatic impairment Mild hepatic impairment (Child-Pugh A (5-6 points)) give 0.97mg/m2. Moderate hepatic impairment (Child-Pugh B (7-9 points)) give 0.62mg/m2. Severe hepatic impairment (Child-Pugh C (10-15 points)) has not been studied but it is expected that a more marked dose reduction is needed if eribulin is used in these patients. The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 indicating the most severe derangement. Measure 1 point 2 points 3 points Total bilirubin μmol/l <34 34-50 >50 Serum albumin g/l >35 28-35 <28 INR <1.7 1.71-2.20 >2.20 Ascites None Mild Severe Hepatic encephalopathy None Grade I-II Grade III-IV (or (or suppressed refractory)

with medication)

Eribulin Breast PODG Chair Authorisation: Date:


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http://en.wikipedia.org/wiki/Bilirubin

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Adverse reaction after previous Eribulin administration Recommended dose Haematological: ANC < 0.5 x 109/l lasting more than 7 days 0.97mg/m2 ANC < 1 x 109/l neutropenia complicated by fever or infection 0.97mg/m2 Platelets < 25 x 109/l thrombocytopenia 0.97mg/m2 Platelets < 50 x 109/l thrombocytopenia complicated by haemorrhage or requiring blood or platelet transfusion 0.97mg/m2 Non-haematological: Any Grade 3 or 4 in the previous cycle 0.97mg/m2 Reoccurrence of any haematological or non-haematological adverse reactions as specified above Despite reduction to 0.97 mg/m2 0.62 mg/m2 Despite reduction to 0.62 mg/m2 Consider discontinuation

Do not re-escalate the eribulin dose after it has been reduced.

INVESTIGATIONS Routine Blood test days 1 and 8 1) Blood results required before chemotherapy administration Give Discuss

Hb x g/dL ≥10 < 10


ECG (possibly ECHO) required if patient has pre-existing cardiac disease



ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Myelosuppression Peripheral neuropathy QT prolongation (caution with other QT prolonging drugs eg ondansetron, domperidone, metoclopramide) REFERENCES

1. SPC March 2011 2. Lancet 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2.

Eribulin Breast PODG Chair Authorisation: Date:


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EVEROLIMUS Indication: Treatment of advanced ER +ve, HER2 –ve metastatic breast cancer, without symptomatic visceral disease, in combination with exemestane, following previous treatment with non-steroidal aromatase inhibitor. No previous treatment with exemestane and no more than 1 line of chemotherapy for the treatment of metastatic disease TA421

DRUG REGIMEN Day 1 Everolimus 10mg orally daily (in combination with exemestane) Cycle Frequency: Daily for 4 weeks continuously until progression

DOSE MODIFICATIONS Everolimus Any dose modifications should be discussed with a Consultant.

Renal impairment No dose adjustment is required in patients with renal impairment.

Hepatic impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in this patient population.

INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration

Give Discuss

Hb x g/dL ≥10 < 10


Routine bloods: FBC, renal function, liver function. Random blood sugar, lipid profile; if elevated to repeat on fasting blood Baseline imaging: CT and/or MRI at baseline and every three months. 2) Non urgent tests Tests relating to disease response/progression

CONCURRENT MEDICATION Check drug interactions, particularly cytochrome inducers and inhibitors and adjust doses accordingly.

Everolimus Breast PODG Chair Authorisation: Date:


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ANTIEMETIC POLICY Minimal emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Increased glucose, lipids and triglycerides Decreased haemoglobin, lymphocytes, neutrophils and platelets Hypersensitivity reactions Pneumonitis, Infections Oral ulceration

REFERENCES 1. SPC May 2010

Everolimus Breast PODG Chair Authorisation: Date:


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FULVESTRANT Indication: ER+ve metastatic breast cancer, following two lines of endocrine therapy Ensure funding is available for patient prior to prescribing. Subject to Trust agreeing funding

DRUG REGIMEN Day 1 FULVESTRANT 500mg IM (2 x 250mg injections) Day 15 FULVESTRANT 500mg IM (2 x 250mg injections) cycle 1 only Fulvestrant should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock Cycle Frequency: Every 28 days

DOSE MODIFICATIONS Fulvestrant Renal impairment No dose adjustments are recommended for patients with mild to moderate renal impairment (creatinine clearance 30 ml/min). Safety and efficacy have not been evaluated in patients with severe renal impairment (creatinine clearance < 30 ml/min), and, therefore, caution is recommended in these patients.

Hepatic impairment No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased, Fulvestrant should be used with caution in these patients.There are no data in patients with severe hepatic impairment


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS The most frequently reported adverse reactions are injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).

REFERENCES Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov, Didier Verhoeven, José L. Pedrini, Iya Smirnova, Mikhail R. Lichinitser, Kelly Pendergrass, Luca Malorni, Sally Garnett, Yuri Rukazenkov, and Miguel Martin J Natl Cancer Inst. 2014 Jan; 106(1): djt337. Published online 2013 Dec 7. doi: 10.1093/jnci/djt337 Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial

Fulvestrant Breast PODG Chair Authorisation: Date:


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http://www.ncbi.nlm.nih.gov/pubmed/?term=Leo%20AD%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Jerusalem%20G%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Petruzelka%20L%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Torres%20R%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bondarenko%20IN%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Khasanov%20R%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Khasanov%20R%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Verhoeven%20D%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pedrini%20JL%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Smirnova%20I%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lichinitser%20MR%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pendergrass%20K%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Pendergrass%20K%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Malorni%20L%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Garnett%20S%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Rukazenkov%20Y%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Martin%20M%5Bauth%5D

http://dx.doi.org/10.1093%2Fjnci%2Fdjt337

Thames Valley


MMM Indication: Metastatic breast cancer

DRUG REGIMEN Day 1 MITOMYCIN 10mg (absolute dose) IV bolus (alternate cycles)

MITOXANTRONE10mg (absolute dose) in 100ml sodium chloride 0.9% infusion over 15 minutes METHOTREXATE 50mg (absolute dose) IV bolus

Day 22 MITOXANTRONE10mg (absolute dose) in 100ml sodium chloride 0.9% infusion over 15 minutes METHOTREXATE 50mg (absolute dose) IV bolus


DOSE MODIFICATIONS Mitoxantrone Bilirubin >60micromol/L and good performance status give 60% dose Bilirubin >60micromol/L and poor performance status omit Maximum cumulative dose = 110mg/m2

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 Mitomycin GFR > 10ml/min give 100% dose GFR < 10ml/min give 75% dose Consider a dose reduction for high doses of Mitomycin when GFR 10-60ml/min




MMM Breast PODG Chair Authorisation: Date:


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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 > 120 micromols/L


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity – monitor cardiac function. Mitoxantrone may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication)

MMM Breast PODG Chair Authorisation: Date:


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DOCETAXEL 100 metastatic (21 day) Indication: Anthracycline resistant breast cancer, metastatic breast cancer

NICE guidance – www.nice.org.uk Docetaxel and paclitaxel are recommended as an option for the treatment of advanced breast cancer where initial cytotoxic chemotherapy (including an anthracycline) has failed or is inappropriate.



in 250ml* sodium chloride 0.9% infusion over 1 hour * doses 200mg to 360mg in 500ml sodium chloride 0.9% NB Reduce docetaxel to 75mg/m2 in heavily pretreated patients or performance status not optimal, in absence of routine used of GCSF in metastatic setting use 100mg/m2 with caution.

Cycle Frequency: Every 21 days usually no more than 6 (subject to tolerance and response)

DOSE MODIFICATIONS 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/m2. 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.


Give Discuss

Hb x g/dL ≥10 < 10



Docetaxel 100 met q21d



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Docetaxel 100 met q21d



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DOCETAXEL 40 (7 day) Indication: Anthracycline resistant breast cancer for patients who cannot tolerate the standard three weekly regimen

DRUG REGIMEN Day 1 Premedication DEXAMETHASONE 8mg BD starting 12 hours before chemotherapy

and continued for a total of 3 doses (for patients who are unable to tolerate high doses of steroids or tolerate docetaxel well 4mg bd may be considered). DOCETAXEL 40mg/m2

in 250ml sodium chloride 0.9 infusion over 1 hour Day 8 Premedication DEXAMETHASONE 8mg BD starting 12 hours before chemotherapy

and continued for a total of 3 doses (for patients who are unable to tolerate high doses of steroids or tolerate docetaxel well 4mg bd may be considered). DOCETAXEL 40mg/m2

in 250ml sodium chloride infusion over 1 hour Day 15 Premedication DEXAMETHASONE 8mg BD starting 12 hours before chemotherapy

and continued for a total of 3 doses (for patients who are unable to tolerate high doses of steroids or tolerate docetaxel well 4mg bd may be considered).

DOCETAXEL 40mg/m2

in 250ml sodium chloride 0.9% infusion over 1 hour Cycle Frequency: Every 28 days for 6 cycles

DOSE MODIFICATIONS 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 give 75% dose 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.


Give Discuss

Hb x g/dL ≥10 < 10



Docetaxel 40 weekly



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CONCURRENT MEDICATION Ensure pre-medication is given this can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions)



Docetaxel 40 weekly



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Thames Valley


GEMCITABINE and CARBOPLATIN Indication: Triple negative or BRCA mutated breast cancer

DRUG REGIMEN Day 1 GEMCITABINE 1000mg/m2

infusion in 250ml sodium chloride 0.9% over 30 minutes CARBOPLATIN AUC 4

in 500ml glucose 5% infusion over 60 minutes

Day 8 GEMCITABINE 1000mg/m2

infusion in 250ml sodium chloride 0.9% over 30 minutes NB In heavily pretreated or elderly patients consider reducing gemcitabine doses to 750mg/m2. Cycle Frequency: Every 21 days for 6 cycles

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Carboplatin If GFR = or < 20ml/min discuss with consultant.

Gemcitabine CrCl <30ml/min consider dose reduction (Clinical decision) If bilirubin > 27 μmol/L, initiate treatment with dose of 800 mg/m2 Neutrophils >1.5x109/L and platelets >100x109/L give 100% dose Neutrophils<1.5x109/L or platelets <100x109/L delay treatment (Day 1) or omit treatment (Day 8) Diarrhoea and/or mucositis Grade 2 toxicity – omit until toxicity resolved then restart at 100% dose Grade 3 toxicity – omit until toxicity resolved then restart at 75% dose Grade 4 toxicity – omit until toxicity resolved then restart at 50% dose

Gemcitabine Carboplatin



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INVESTIGATIONS Pre assessment requirments FBC and biochem – for CrCl pre cycle 1 (biochem and FBC to be done each time) Routine Blood test 1) Blood results required before chemotherapy administration

Give Discuss

Hb x g/dL ≥10 < 10


Liver function tests (LFT)

• GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s discretion. • Patients with hydronephrosis or serum creatinine >= 100 micromol/L need a serum creatinine checked every cycle. All patients have serum creatinine checked 1st and 4th cycle. 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION 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.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Ototoxicity - monitor Neurotoxicity - monitor Diarrhoea – see dose modifications Mucositis – see dose modifications

Gemcitabine carboplatin



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PACLITAXEL 175 (21 day) NICE guidance – www.nice.org.uk Docetaxel and paclitaxel are recommended as an option for the treatment of advanced breast cancer where initial cytotoxic chemotherapy (including an anthracycline) has failed or is inappropriate

DRUG REGIMEN Day 1 PREMEDICATION 30mins prior to infusion:

DEXAMETHASONE 20 mg IV bolus RANITIDINE 50 mg IV bolus CHLORPHENAMINE 10 mg IV bolus PACLITAXEL 175mg/m2

in 500ml* sodium chloride 0.9% infusion over 3 hours * doses 84mg to 144mg in 250ml sodium chloride 0.9% Cycle Frequency: Every 21 days up to 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration If grade >= 2 neuropathy, consider using paclitaxel 135 mg/m2 In the absence of Gilbert's syndrome: Bilirubin <1.25xULN (21micromol/L) and ALT/AST <10xULN dose at 175mg/m2 Bilirubin <26 micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2 Dose escalation possible. 200mg/m2 on second and subsequent cycles if nadir count is satisfactory. Discuss with Consultant or Registrar


Give Discuss

Hb x g/dL ≥10 < 10


Liver function tests (LFT)


Paclitaxel 175 q21d



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CONCURRENT MEDICATION Ensure pre medication given


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS (2% risk of severe hypersensitivity) Reactions range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10 minutes), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment.

Paclitaxel 175 q21d



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PACLITAXEL weekly Indication: Metastatic or locally advanced breast cancer Single agent paclitaxel with trastuzumab for small HER2+ve node-negative cancers (<5mm or less) or where there is a contra-indication to standard chemotherapy e.g. because of age or co-morbidity. Weekly schedule is not licensed treatment.


DEXAMETHASONE 8mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 90mg/m2metastatic in 250ml* sodium chloride 0.9% infusion over 1 hour PACLITAXEL 80mg/m2 adjuvant in 250ml* sodium chloride 0.9% infusion over 1 hour

* doses 162mg to 600mg in 500ml sodium chloride 0.9% Cycle Frequency: Every 7 days for 12 weeks (3 x 28 days) NB Patients who are elderly, had extensive bone irradiation or bone secondaries or having this as 3rd line treatment may require a reduced dose day 1, 8 and 15 every 28 days (see separate regimen)

DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment


Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure pre-medication is given.

Paclitaxel 90 (weekly)



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REFERENCES 1. Andrew D. Seidman, Donald Berry, Constance Cirrincione, Lyndsay Harris, Hyman Muss, P.

Kelly Marcom, Grandella Gipson, Harold Burstein, Diana Lake, Charles L. Shapiro, Peter Ungaro, Larry Norton, Eric Winer and Clifford Hudis. JCO 2008. Randomized Phase III Trial of Weekly Compared With Every-3-Weeks Paclitaxel for Metastatic Breast Cancer, With Trastuzumab for all HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840

2. Joseph A. Sparano, M.D., Molin Wang, Ph.D., Silvana Martino, D.O., Vicky Jones, M.D., Edith A. Perez, M.D., Tom Saphner, M.D., Antonio C. Wolff, M.D., George W. Sledge, Jr., M.D., William C. Wood, M.D., and Nancy E. Davidson, M.D. N Engl J Med. 2008 Apr 17; 358(16): 1663–1671. doi: 10.1056/NEJMoa0707056 Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer

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http://jco.ascopubs.org/search?author1=Andrew+D.+Seidman&sortspec=date&submit=Submit

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http://jco.ascopubs.org/search?author1=Constance+Cirrincione&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Lyndsay+Harris&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Hyman+Muss&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=P.+Kelly+Marcom&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=P.+Kelly+Marcom&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Grandella+Gipson&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Harold+Burstein&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Diana+Lake&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Charles+L.+Shapiro&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Peter+Ungaro&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Peter+Ungaro&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Larry+Norton&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Eric+Winer&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Clifford+Hudis&sortspec=date&submit=Submit

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sparano%20JA%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wang%20M%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Martino%20S%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Jones%20V%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Perez%20EA%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Perez%20EA%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Saphner%20T%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wolff%20AC%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sledge%20GW%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Wood%20WC%255Bauth%255D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Davidson%20NE%255Bauth%255D

http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18420499

http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18420499

http://dx.doi.org/10.1056%2FNEJMoa0707056

Thames Valley


PACLITAXEL 80mg (days 1, 8 and 15) Indication: Metastatic or locally advanced breast cancer (weekly schedule is not licensed treatment). For patients who require a reduced dose e.g. elderly, had extensive bone irradiation or bone secondaries or having this as 3rd line treatment


DEXAMETHASONE 8mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus PACLITAXEL 80mg/m2

in 250ml* sodium chloride 0.9% infusion over 1 hour * doses 162mg to 600mg in 500ml sodium chloride 0.9% Cycle Frequency: Days 1, 8 and 15 every 28 days up to 3 cycles subject to tolerance and response

DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. In the absence of Gilbert's syndrome: Bilirubin >51micromol/L stop treatment


Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Ensure pre-medication is given.

Paclitaxel 80mg weekly q28d



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Paclitaxel 80mg weekly q28d



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PACLITAXEL albumin bound

Indication: Metastatic breast cancer, only patients who have received previous treatment and who cannot tolerate either docetaxel or solvent bound paclitaxel.

DRUG REGIMEN Day 1 PACLITAXEL ALBUMIN BOUND 260mg/m2 IV infusion over 30 minutes

Cycle Frequency: Every 21 days up to 6 cycles subject to tolerance and response

DOSE MODIFICATIONS If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. Hepatic - Mild to moderate hepatic impairment there is insufficient data. Patients with severe hepatic impairment should not be treated with paclitaxel. Renal - Insufficient data to recommend dose modifications in patients with renal impairment.


Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Liver function tests (LFT)




ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Hypersensitivity - discontinue immediately Sensory neuropathy Cardiotoxicity

REFERENCES 1. SPC July 2011 2. MOBBB recommendation July 2011

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PACLITAXEL CARBOPLATIN 21 day

Indication: Triple negative recurrent / metastatic breast cancer

DRUG REGIMEN Day 1 PRE-MEDICATION 30mins prior to paclitaxel DEXAMETHASONE 20mg IV bolus RANITIDINE 50mg IV bolus CHLORPHENAMINE 10mg IV bolus

PACLITAXEL 175mg/m2 in 500ml* sodium chloride 0.9% infusion over 3 hours (PVC free) CARBOPLATIN AUC 6 (EDTA) in 500ml Glucose 5% infusion over 60 minutes Dose (mg) = (GFR + 25) x AUC * doses 84mg to 144mg in 250ml sodium chloride 0.9% Cycle Frequency: Every 21 days for 6 cycles (may be given for 8 cycles in certain circumstances)

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Carboplatin If GFR/CrCl = or <20ml/min discuss with consultant. Paclitaxel If patient complains of tinnitus, tingling of fingers and/or toes or motor weakness discuss with Consultant or Registrar before administration. If grade II or > neuropathy, consider using paclitaxel 135mg/m2. Bilirubin <1.25xULN (21micromol/L) and AST <10xULN dose at 175mg/m2 Bilirubin <26micromol/L give 135mg/m2 Bilirubin 27-51micromol/L give 75mg/m2 Bilirubin >51micromol/L give 50mg/m2

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a. Liver function tests (LFTs) b. GFR assessed using 51Cr-EDTA result or calculated creatinine clearance at the Consultant’s

discretion. (Carboplatin) c. Patients with hydronephrosis or serum creatinine > 100micromol/L need a serum creatinine

checked every cycle. All patients have serum creatinine checked 1st and 4th cycle -Carboplatin. 2) Non-urgent blood tests Tests relating to disease response/progression

CONCURRENT MEDICATION Paclitaxel – ensure pre medication is given Carboplatin - Anaphylaxis treatment should be prescribed if the patient has had an anaphylactic episode previously. Carboplatin should be given at a slower rate e.g. 2-4 hours.

ANTIEMETIC POLICY Moderately emetogenic (routinely dexamethasone and metoclopramide is adequate but 5HT3 antagonist may be required if there is inadequate control).

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS 2% risk of severe hypersensitivity. Reactions to paclitaxel range from mild hypotension (light-headedness) to full cardiac collapse (anaphylactic shock). Discontinue infusion and resuscitate appropriate to reaction. If reaction is mild and settles promptly (i.e. within 5-10mins), cautiously restart at a slower rate under close supervision. If further reactions occur stop treatment. Ototoxicity - monitor Neurotoxicity – monitor

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PERTUZUMAB TRASTUZUMAB DOCETAXEL

The first line treatment of locally advanced or metastatic breast cancer where all the following criteria are met: Locally advanced or metastatic breast cancer 3. HER2 3+ or FISH positive breast cancer 4. ECOG PS 0 or 1 5. Any adjuvant HER2 therapy should have been completed more than 12 months prior to metastatic diagnosis 6. No prior treatment with chemotherapy or HER2 therapy for metastatic disease 7. The patient will receive pertuzumab as first line treatment in combination with docetaxel and IV trastuzumab. The use of pertuzumab is only funded when given with intravenous trastuzumab. Use of pertuzumab with subcutaneous trastuzumab will not be funded 8. Pertuzumab will otherwise be used as set out in its SPC. If a patient commences 1st line treatment with docetaxel and has a severe allergic reaction to the docetaxel and is re-challenged with docetaxel unsuccessfully, chemotherapy with the combination of paclitaxel, pertuzumab and intravenous trastuzumab can be used but only in these specific circumstances. *Not to be used beyond first disease progression outside the CNS. Do not discontinue if disease progression is within the CNS alone.

DRUG REGIMEN Cycle 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) Day 1 Pertuzumab 840mg in 250ml sodium chloride 0.9% IV infusion over 1 hour Day 2 Docetaxel 75mg/m2 in 250ml sodium chloride 0.9% IV infusion over 1 hour Day 2 Trastuzumab 8mg/kg in 250ml sodium chloride 0.9% IV infusion

Cycle 2 onwards 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) Day 1 Docetaxel 75mg/m2**in 250ml* sodium chloride 0.9% IV infusion over 1 hour cycles 2 to 6 Day 1 Pertuzumab 420mg in 250ml sodium chloride 0.9% IV infusion Day 1 Trastuzumab 6mg/kg in 250ml sodium chloride 0.9% IV infusion **Docetaxel dose may be increased to 100mg/m2 from cycle 2 * doses 200mg to 360mg in 500ml sodium chloride 0.9%

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, Docetaxel for 6 cycles only, pertuzumab and trastuzumab continue until disease progression Pertuzumab Trastuzumab Docetaxel


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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 give 75% dose 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. 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. For docetaxel dose modifications, see docetaxel summary of product characteristics (SmPC). For trastuzumab, dose reductions are not recommended, see trastuzumab summary of product characteristics (SmPC). 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 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.

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INVESTIGATIONS

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 2) Non urgent blood tests - Tests relating to disease response / progression - Baseline weight and every 3 months - Monitor cardiac function (ECG/ECHO/MUGA) of all patients before and during treatment, aiming for assessments every 3 months.


ANTIEMETIC POLICY Low emetic 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. Discuss if severe cutanous reactions, peripheral neuropathy or fluid retention after previous course.

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TRASTUZUMAB 4/2 (7 day)

Indication: Metastatic breast (HER3+ or FISH+)

NICE guidance - www.nice.org.uk Trastuzumab is used in combination with paclitaxel for people with tumours with excessive human epidermal growth factor receptor 2 (HER2) at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline treatment is inappropriate. Trastuzumab monotherapy is recommended for women with tumours with excessive HER2 at levels of 3+ who have had at least two chemotherapy treatments for metastatic breast cancer. Previous chemotherapy must have included at least an anthracycline drug and a taxane drug where these treatments are appropriate. It should also have included hormonal therapy in patients sensitive to oestrogen.

DRUG REGIMEN Cycle 1 only Day 1 Loading dose (to be given once only)

*TRASTUZUMAB 4mg/kg in 250ml sodium chloride 0.9% infusion over 90 minutes Cycles 2 to 24 Day 1 Maintenance dose

TRASTUZUMAB 2mg/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: Every 7 days up to 24 cycles in the first instance subject to tolerance and response. Not to be continued beyond progression.

DOSE MODIFICATIONS No dose reduction or cessation of Trastuzumab is required if patient has acute reversible neutropenia If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 4mg/kg.


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Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests


Baseline weight and every 3 months

Monitor cardiac function (ECG/ECHO) of all patients before and during treatment, aiming for assessments every 3 months



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. NB Patients need to remain on the ward/day unit for monitoring for 6 hours post first dose and for 2 hours post maintenance doses.

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TRASTUZUMAB metastatic 8/6 (21 day)

Indication: Metastatic breast (HER3+ or FISH +) if weekly administration is inconvenient or

impractical


DRUG REGIMEN Cycle 1 Day 1 Loading dose (to be given once 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: Every 21 days up to 18 cycles in the first instance to tolerance and response. Not to be continued beyond progression.

DOSE MODIFICATIONS No dose reduction or cessation of Trastuzumab is required if patient have acute reversible neutropenia If trastuzumab infusion is delayed by more than 7 days the patient should be reloaded at 8mg/kg.

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Give Discuss

Hb x g/dL ≥10 < 10




Baseline weight and every 3 months Monitor cardiac function (ECG/ECHO) of all patients before and during treatment,

aiming for assessments every 3 months



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.

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TRASTUZUMAB Sub-cutaneous Indication: Adjuvant, neoadjuvant and metastatic breast (HER3+ or FISH +)


DRUG REGIMEN Day 1 TRASTUZUMAB 600mg subcutaneously over 5 minutes

NB. *Patients should be observed for four hours after the first injection for signs or symptoms of administration-related reactions If the first cycle was well tolerated, following the 2nd and 3rd cycles patients should be observed on the ward / day unit for 30 minutes after the completion of trastuzumab injection. If the 2nd and 3rd cycles were well tolerated, after the 4th and subsequent cycles patients do not need to be observed following completion of trastuzumab injection. Patients should be warned of the possibility of delayed reactions and instructed to seek medical advice immediately should this occur.

Cycle Frequency: Every 21 days Early breast cancer for up to 18 cycles Metastatic breast cancer until disease progression

DOSE MODIFICATIONS No dose reduction or cessation of Trastuzumab is required if patient have acute reversible neutropenia If the patient misses a dose of Trastuzumab subcutaneous formulation, it is recommended to administer the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between consecutive Trastuzumab subcutaneous formulation administrations should not be less than three weeks.

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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 45-49 and >10 points from baseline then stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF 45-49 and >10 EF points from baseline hold trastuzumab, repeat LVEF in 3 weeks. If repeat LVEF <44 or LVEF 45-49 and >10 points from baseline stop trastuzumab. If repeat LVEF 45-49 and <10 points from baseline or LVEF >49 resume trastuzumab. • If LVEF > 50 or LVEF 45-49 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.


Give Discuss

Hb x g/dL ≥10 < 10






CONCURRENT MEDICATION Trastuzumab should not be given concurrently with anthracyclines for metastatic or adjuvant treatment and only with low dose anthracyclines in chemo naïve neoadjuvant treatment. Subcutaneous trastuzumab should not be given with pertuzumab. Trastuzumab infusion related chills and/or fevers – treat with paracetamol and chlorphenamine.


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.

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TRASTUZUMAB EMTANSINE (Kadcyla) Indication: HER2+ve locally advanced unresectable or metastatic (stage IV) breast cancer. Progression during or after the most recent treatment for advanced stage disease or within 6 months of completing treatment for early stage disease, having had previous treatment with a taxane and previous treatment with trastuzumab, left ventricular ejection fraction of 50% or more. PS 0 or 1 Not to be used beyond first disease progression outside the CNS. Do not discontinue if disease progression is within the CNS alone Ensure individual funding has been obtained prior to prescribing.

DRUG REGIMEN Day 1 TRASTUZUMAB EMTANSINE 3.6mg/kg IV in 250ml sodium chloride 0.9% infusion over 90 minutes If the prior infusion was well tolerated subsequent infusions may be administered over 30 minutes and observed for at least 30 minutes after infusion. Cycle Frequency: Every 21 days until disease progression or unacceptable toxicity

DOSE MODIFICATIONS Dose reduction schedule

Dose reduction schedule (Starting dose is 3.6 mg/kg)

Dose to be administered

First dose reduction 3 mg/kg

Second dose reduction 2.4 mg/kg

Requirement for further dose reduction Discontinue treatment

Dose modification guidelines for increased transaminases

(AST/ALT) Grade 2 (> 2.5 to ≤ 5 × the ULN)

Grade 3 (> 5 to ≤ 20 × the ULN)

Grade 4 (> 20 × the ULN)

No dose modification is required. Do not administer trastuzumab emtansine until AST/ALT recovers to Grade ≤ 2 (>2.5 to <5 x ULN), and then dose reduce.

Discontinue trastuzumab emtansine.

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Dose modification guidelines for hyperbilirubinemia

Grade 2 (> 1.5 to ≤ 3 × the ULN)

Grade 3 (> 3 to ≤ 10 × the ULN)

Grade 4 (> 10 × the ULN)

Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤ 1 (>ULN to 1.5x ULN). No dose modification is required.

Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤ 1 (>ULN to 1.5x ULN), and then dose reduce.


Dose modification guidelines for thrombocytopenia

Grade 3 (Platelets: 25,000 to < 50,000/mm3)

Grade 4 (Platelets: < 25,000/mm3)

Do not administer trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (i.e. platelets ≥ 75,000/mm3). No dose modification is required.

Do not administer trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (i.e. platelets ≥ 75,000/mm3), and then dose reduce

Dose modifications for left ventricular dysfunction

LVEF < 40% LVEF > 45% LVEF 40% to ≤ 45% and

decrease is < 10% points

from baseline

LVEF 40% to ≤ 45% and decrease is ≥ 10%

points from baseline

Symptomatic CHF

Do not administer trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks. If LVEF

< 40% is confirmed, discontinue trastuzumab emtansine.

Continue treatment

with trastuzumab emtansine.

Continue treatment with trastuzumab emtansine.

Repeat LVEF assessment

within 3 weeks.

Do not administer trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks. If the LVEF

has not recovered to within 10% points from baseline, discontinue

trastuzumab emtansine.


Peripheral neuropathy Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be considered according to the dose reduction schedule.




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Renal impairment No adjustment to the starting dose is needed in patients with mild or moderate renal impairment. The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully. Hepatic impairment The safety and efficacy have not been studied in patients with hepatic impairment. No specific dose recommendations can be made.


Give Discuss Hb x g/dL ≥10 < 10








ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Urinary tract infection Hypokamaemia Neuropathy, dizziness Stomatitis Rash Arthralgia, myalgia Increased transaminases Thrombocytopenia




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VINORELBINE 30 (21 day)

NICE guidance – www.nice.org.uk Vinorelbine monotherapy is not recommended as a first line treatment for advanced breast cancer. Vinorelbine monotherapy is recommended as one option for second line or later therapy for the treatment of advanced breast cancer when anthracycline based regimens have failed or are unsuitable.

DRUG REGIMEN Day 1 VINORELBINE 30mg/m2

(maximum 60mg) IV infusion in 50ml sodium chloride 0.9% over 10 minutes Day 8 VINORELBINE 30mg/m2

(maximum 60mg) IV infusion in 50ml sodium chloride 0.9% over 10 minutes

Administration should always be followed by a 250ml sodium chloride 0.9% infusion to flush the vein.

NB For heavily pretreated patients or patients with poor performance status, consider giving in a four weekly cycle or reduce dose to 25mg/m2 discuss with consultant

Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar If patients have a neutrophil count <1.5 on day 8, this dose can be delayed to day 15.

AST/ALT ≤5xULN and bilirubin <1.55xULN give 100% dose AST/ALT 5.1-20xULN and bilirubin <1.5-3xULN postpone and reassess (if liver toxicity persists for more than 3 weeks discontinue treatment). AST/ALT 20xULN and bilirubin >3xULN discontinue Elevation of creatinine ≤2.5xULN give 100% dose Elevation of creatinine ≥2.6xULN postpone dosing and reassess 1 week later (if after a 2 week delay the creatinine is still elevated by ≥2.6ULN discontinue treatment).


Give Discuss

Hb x g/dL ≥10 < 10

Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 2) Non urgent blood tests. Tests relating to disease response/progression

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CONCURRENT MEDICATION Caution with drugs affecting CYP 3A4 isoenzyme (e.g. omeprazole, fluoxetine, erythromycin, amiodarone, carbamazepine, phenytoin) Consider concomitant laxatives particularly in patients with a history of constipation or those receiving opioid analgesics.


ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS

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VINORELBINE oral NICE guidance – www.nice.org.uk Vinorelbine monotherapy is not recommended as a first line treatment for advanced breast cancer. Vinorelbine monotherapy is recommended as one option for second line or later therapy for the treatment of advanced breast cancer when anthracycline based regimens have failed or are unsuitable.

DRUG REGIMEN Cycle 1 Days 1 and 8 VINORELBINE 60mg/m2

PO Cycle 2 onwards if cycle 1 tolerated may be increased to 80mg/m2 see dose modifications Cycle Frequency: Every 21 days

NB: total dose should never exceed 120mg for 60mg/m2 or 160mg for 80mg/m2 per week. Capsules available in 20mg and 30mg strengths and must be stored in fridge.

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar.

From cycle 2, consider increasing dose to 80mg/m2 days 1,8except for patients in whom neutrophils dropped <0.5x109/L once or patients in whom neutrophils dropped between 0.5-x109/L during first cycle.

For any administration at 80mg/m2, if neutrophils <0.5x109/L, administration should be delayed until recovery and the dose reduced to 60mg/m2 for the next three administrations. See product literature for dose re-escalation guidelines.

No prospective study is available in order to establish guidelines for the dose reduction of Vinorelbine capsules in hepatic impairment. If there is significant hepatic impairment the dose of Vinorelbine soft capsules should be reduced. In patients with massive liver metastases (i.e. >75% of liver volume replaced by the tumour) it is empirically suggested that the dose be reduced by 25% and the haematological parameters closely monitored.

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Give Discuss

Hb x g/dL ≥10 < 10



CONCURRENT MEDICATION Caution with drugs affecting CYP 3A4 isoenzyme (e.g. omeprazole, fluoxetine, erythromycin, amiodarone, carbamazepine, phenytoin) Consider concomitant laxatives particularly in patients with a history of constipation or those receiving opioid analgesics.

ANTIEMETIC POLICY Moderate emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Neurosensory disorders

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