Neo-adjuvant and Adjuvant Chemotherapy Node Positive/High Risk Node Negative 1. FEC-T: FEC-100/DOC100 (3+3) CTIS: 1210/1207 5/7

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1 Breast Cancer Chemotherapy Protocols Section by: Dr Suzy Cleator, Dr Pippa Riddle, Dr Charles Lowdell, Professor Charles Coombes, Professor Justin Stebbing, Dr Riz Ahmed, Dr Carlo Palmieri Version; Breast Regimens v7.01 NWLCN 24Oct12 Section last updated: 24 th October 2012 Last corrected: 24 th October 2012 Approved by Oncology Breast Lead Clinician Dr S Cleator Date: Approved by NWLCN Breast Tumour Group: Mr W Teh Date: 7 Nov 2012 Review date: October 2014 I N D E X Page Haematological toxicity Dose Modifications and GCSF for Adjuvant/Neo-adjuvant & Metastatic Regimens 3-5 Early Invasive Breast Cancer Neo-adjuvant and Adjuvant Chemotherapy Node Positive/High Risk Node Negative 1. FEC-T: FEC-100/DOC100 (3+3) CTIS: 1210/1207 5/7 Node positive/high Risk Node Negative and Anthracycline Contraindicated 2. TC: Docetaxel/Cyclophos (x 4-6) CTIS: 8 3. TCH: Doce/Carbo/Trastuzumab (if HER2 Positive) x 6 CTIS: 9 Node Negative/Low Risk Node Positive 4. FEC-75 IV 1 day x 6 CTIS: 74/ Poor Response/No Response to 3-4 cycles of FEC FEC-75/DOC100 (3+3) CTIS: 74/ Diabetic Patients (less steroids than docetaxel) 6. AC 60/600 x4/ Paclitaxel-90 weekly x 12 CTIS: 496/ /12 Options for elderly 7. AC 60/600 1 day x 4-6 CTIS: 496/ FEC-60 1 day x 4-6 CTIS: Avoid alopecia (non anthracycline) 9. CMF IV Day 1+8 x 6 CTIS: 71/ Monoclonal antibodies; Adjuvant/Neoadjuvant 10. Trastuzumab CTIS: 1157/ Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 1 of 57

2 Metastatic Breast Cancer Chemotherapy Page Anthracycline regimens 11. AC 60/600 1 day CTIS: Epirubicin-30 weekly CTIS: MC-60/600 (Myocet (lipo Dox) plus cyclo) CTIS: Taxane regimens 14. Docetaxel CTIS: Docetaxel/Capecitabine CTIS: Paclitaxel-90 weekly CTIS: Paclitaxel/Gemcitabine CTIS: Additional Private Care 18. Abraxane-260; Paclitaxel Albumin 3 weekly CTIS: Abraxane-100; Paclitaxel-Albumin-100 weekly CTIS: 24 Bevacizumab Additional Private Care 20. Bevacizumab/Paclitaxel CTIS: Bevacizumab/Capecitabine CTIS Vinorelbine 21. Vinorelbine-30 Day 1 and 8 CTIS: Vinorelbine two weekly CTIS: Vinorelbine-60 ORAL CTIS: Capecitabine 24. Capecitabine 2000 CTIS: Carboplatin 25. MV-Carbo CTIS: Gemcitabine/Carboplatin see page 36(Local approval required) CTIS: CMF (Non classical) 26. CMF-750 IV CTIS: Gemcitabine 27. Gemcitabine/Carboplatin (Local approval required) 36 Paclitaxel/Gemcitabine see page 21 CTIS: 1291 Lapatinib 28. Lapatinib/capecitabine (Cancer Drugs Fund) CTIS: Lapatinib plus Aromatase inhibitor (Cancer Drugs Fund) 45 Eribulin 30. Eribulin D1+8 (Cancer Drugs Fund) CTIS: 46 Everolimus 31. Everolimus plus Exemestane (Additional private care) 49 Monoclonal Antibodies 32. Trastuzumab CTIS: 788/ Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 2 of 57

3 Breast Cancer Chemotherapy Protocols Section by: Dr Suzy Cleator, Dr Pippa Riddle, Dr Charles Lowdell, Professor Charles Coombes, Professor Justin Stebbing, Dr Riz Ahmed, Dr Carlo Palmieri Version: Breast Regimens v7.01 NWLCN 24Oct12 Section last updated: 24 th October 2012 Last corrected: 24 th October 2012 Approved by Oncology Breast Lead Clinician: October 2012 Approved by NWLCN Breast Tumour Group: October 2012 Review date: October 2014 Dosage Modifications All modifications are only a guide and must be authorised by consultant/spr. Different strategies may apply in the case of curative (adjuvant) and metastatic regimens. Adjuvant/Neo-adjuvant Regimens: Haematological Toxicity: There is evidence that maintaining dose intensity of adjuvant/neo-adjuvant chemotherapy improves the outcome following chemotherapy in breast cancer (Citron et al). Therefore the secondary use of GCSF is recommended in adjuvant and neo-adjuvant chemotherapy to maintain dose at 100% with no delays. GSCF in Adjuvant/Neoadjuvant Breast Cancer Regimens Primary GCSF is recommended only with FEC100-T. Primary GCSF is NOT recommended with any other breast chemotherapy regimen currently in use. Secondary GCSF prophylaxis is recommended in adjuvant and neo-adjuvant breast cancer regimens as described in table below Where required, GCSF should start 24 to 72 hours after end of chemotherapy. Do NOT give GCSF immediately prior to chemotherapy. Choice of GCSF product depends on the number of days of GCSF required; o If 4 days of GSCF required use daily injections of ordinary GCSF (NON-pegylated). o If 5 or more days of GCSF required, use a single dose of pegfilgrastim (Neulasta). o DO NOT use Pegfilgrastim with weekly chemotherapy use standard once daily filgrastim or lenograstim. Pegfilgrastim should only be used with chemotherapy with an interval of 14 days or more. Pegfilgrastim (neulasta) should NOT be used to treat neutropenic sepsis. NEVER use Pegfilgrastim during the week before chemotherapy. Results on Day of Chemo Adjuvant/Neo-adjuvant Dose Modification Consideration must be given to blood counts, prior events (eg. febrile neutropenia) and clinical assessment of patient s ability to tolerate chemotherapy. Introduce GCSF and/or dose reduction as appropriate Neutrophils Platelets x10 9 /L x10 9 /L Day and 100 all drugs and Continue treatment at full dose with GCSF support starting 24 hours after end of each chemotherapy cycle Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 3 of 57

4 Results on Day of Chemo <0.5 or Any and <75 Day and 100 <1.0 and/or <100 Neutropenic Sepsis Adjuvant/Neo-adjuvant Dose Modification Discuss with consultant. Consider a treatment delay until platelets recover to 100 and restart with FULL DOSE Consider future dose reductions if recurrent thrombocytopenia. Delay until platelets 100, then restart with 20% dose reduction on subsequent cycles. Omit day 8. Next cycle to commence Day 29 subject to blood counts. A delay in treatment may be necessary to allow patient recovery. In cases of severe sepsis, a dose reduction of 25% may be considered in addition to GCSF support on all subsequent cycles Metastatic Regimens: Haematological Toxicity GCSF in Metastatic Breast Cancer GCSF should NOT be use routinely in the metastatic setting. Results on Day of Chemo Metastatic Dose Modification Consideration must be given to blood counts, prior events (eg. febrile neutropenia), clinical assessment of patient s ability to tolerate chemotherapy, the quality of life of the patient. Neutrophils Platelets x10 9 /L x10 9 /L Day and 100 all drugs <1.5 and/or <100 Delay chemotherapy until counts recovered to ANC 1.5 and platelets 100 (maximum 2 weeks) then resume treatment with 25% dose reduction. If no recovery within 2 weeks chemotherapy regimen should be discontinued. Recurrence of toxicity If haematological toxicity recurs even with 25% dose reduction Delay chemotherapy until counts recovered ANC 1.5 and platelets 100 (maximum 2 weeks) then resume treatment with 50% dose reduction all drugs. (40% reduction in case of docetaxel) OR the chemotherapy regimen may be discontinued Day and 100 <1.5 and/or <100 Omit day 8 chemo. Next cycle to commence day 29 subject to blood counts. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 4 of 57

5 Results on Day of Chemo Bone marrow failure secondary to metastatic infiltration Metastatic Dose Modification Discuss with consultant. Administration of chemotherapy in the setting of bone marrow failure, secondary to metastatic infiltration is a special situation and dose constraints need to be set on an individual basis by the consultant or senior SpR. Febrile Neutropenia (FN) 1 st episode FN Recurrent FN Routine use of GCSF is NOT recommended in the metastatic setting. Only treat if ANC 1.5 and platelets >100 then give 25% dose reduction. Wait until recovery then consider further dose reductions and/or a change in regimen. Adjuvant and Neoadjuvant Chemotherapy Regimens Neoadjuvant Breast Cancer Regimens Chemotherapy followed by surgery. Adjuvant Breast Cancer Regimens Surgery followed by radiotherapy then chemotherapy then (in oestrogen receptor positive patients only) followed by endocrine therapy. Node Positive/High Risk Node Negative 1. FEC-T: FEC-100/Docetaxel-100 FEC-100 for 3 cycles followed by docetaxel-100 for 3 cycles. Cycles 1 to 3 FEC-100 (CTIS: 1210/1209) 5-Fluorouracil 500mg/m 2 IV bolus Day 1 Epirubicin 100mg/m 2 IV bolus Day 1 Cyclophosphamide 500mg/m 2 IV over 30 mins/bolus Day 1 NB. Cyclophosphamide dose is reduced to 500mg/m 2 in FEC100 Interval between cycles: Repeat every 21 days Number of cycles: High risk adjuvant: 3 cycles only followed by 3 cycles of docetaxel-100 Tests before starting course of chemo: FBC, U&Es, LFTs, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs for each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 5 of 57

6 Administration notes: Epirubicin is a vesicant and must be administered according to NWLCN administration policy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered, but success is limited by prolonged circulation time of cyclophosphamide. Dose of cyclophosphamide is below that which is likely to cause haemorrhagic cystitis, and mild symptoms of dysuria may be treated by increasing fluid intake and regular voiding of urine. Dose modifications: See FEC table Table: FEC-100 Side effect: FEC Dose Modification Haematology See relevant haematological toxicity table page 3 Renal Function (NLCN) Crcl 20mls/min 10-20mls/min <10mls/min Hepatic Function Bilirubin and AST micromols/l or 2-4 x ULN or >4 x ULN >85 and Any Fluorouracil Do not give regimen See below See below Do not give Epirubicin Do not give regimen 50% dose reduction 75% dose reduction Do not give Cyclophosphamide 25% dose reduction Discuss with consultant See below See below Do not give Bilirubin micromols/l <85 >85 Do not give See above Do not give See below See below Bilirubin Serum micromols/l Transaminases or ALP >17 or >2-3 x ULN Mucositis/Stomatitis CTC Grade 1 (Imperial) Grade 2 (SPC) Grade 3 See above See above Delay chemo until recovery then give 25% dose reduction all drugs Delay chemo until recovery then give 40% dose reduction all drugs Clinical decision. SPC Pharmacia 04/02/10 states not recommended. In such cases dose should be reduced. BC Cancer Agency states no dose adjustment necessary. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 6 of 57

7 Side effect: FEC Nausea/Vomiting Refractory to antiemetics therapy CTC Grade Grade 1 Grade 2 Dose Modification all drugs Delay chemotherapy until recovery then give 25% dose reduction all drugs Cycles 4 to 6 Docetaxel-100 (CTIS: 1207/1208) Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 100mg/m 2 IV over 1 hour Day 1 Interval between cycles: Repeat every 21 days Number of cycles: 3 cycles after 3 cycles of FEC-100 Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy, dexamethasone as above Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before, the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity reactions; therefore, the patient must be discharged with enough dexamethasone to take before their next cycle. Ensure patient understands how to take their steroids at home. Diabetic patients will need to monitor blood sugar levels more regularly and inform their doctor if they are having problems with the control of their blood sugar levels. IV dexamethasone should not be given to replace oral doses. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered. Dose modifications: See Docetaxel table Table: Docetaxel Side effect: Docetaxel Dose Modification Haematology See relevant haematological toxicity table page 3 Renal Function Mild/Moderate Severe No dose reduction necessary in mild/moderate renal impairment Discuss with consultant Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 7 of 57

8 Side effect: Docetaxel Hepatic Function (Sanofi-Aventis SPC 24/11/11) Bilirubin ALT/AST ALK Phos Any and <1.5 x ULN and <2.5 x ULN Any and >1.5 x ULN and >2.5 x ULN >ULN and >3.5 x ULN and >6 x ULN Cutaneous Reactions Severe or cumulative cutaneous reactions (SPC) Neuropathy Severe peripheral neuropathy (SPC) Allergic Reactions (SPC) Mild Severe Rechallenge Dose Modification 25% dose reduction (ie reduce to 75mg/m 2 from 100mg/m 2 ) Do not give Reduce dose from 100mg/m 2 to 75mg/m 2 or from 75mg/m 2 to 60mg/m 2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel Reduce dose from 100mg/m 2 to 75mg/m 2 or from 75mg/m 2 to 60mg/m 2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe reactions should not be rechallenged with docetaxel. Discuss with consultant. Extreme caution is required as cross reactivity occurs with taxanes. Node Positive/High Risk Node Negative and Anthracycline Contraindicated 2. TC: Docetaxel-75/Cyclophosphamide-600 (CTIS: ) For Additional Private Care unless local NDP approval/pct agreement to fund Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 75mg/m 2 IV over 1 hour Day 1 Cyclophosphamide 600mg//m 2 IV bolus/over 30minutes Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Node positive/high risk node negative patients with cardiac problems which prevent anthracycline administration. 4-6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines of as per local policy, dexamethasone as above Patient information: Chemotherapy treatment booklet (local information/macmillan) Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 8 of 57

9 Administration notes: See notes for Docetaxel-100 page 7 Dose of cyclophosphamide is below that which is likely to cause haemorrhagic cystitis, and mild symptoms of dysuria may be treated by increasing fluid intake and regular voiding of urine. Dose modifications: See Docetaxel table page 7 Reference: J. Clin Oncology 2009; 27(8): Node Positive/High Risk Node Negative, HER2 Positive Anthracycline Contraindicated 3. TCH: Docetaxel-75/Carboplatin 6AUC/Trastuzumab (CTIS: ) For Additional Private Care unless local NDP approved/pct agreement to fund, pending publication of BCIRG006 results Cycle 1 Trastuzumab 8mg/kg IV infusion Day 1 first cycle only loading dose Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 75mg/m 2 IV over 1 hour Day 2 Carboplatin 6(GFR+25)mg IV over 1 hour Day 2 Cycle 2 to 6 Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 75mg/m 2 IV over 1 hour Day 1 Carboplatin 6(GFR+25)mg IV over 1 hour Day 1 Trastuzumab 6mg/kg IV infusion Day 1 Cycle 7-18 Trastuzumab 6mg/kg IV infusion Day 1 Interval between cycles: Repeat every 21 days 21 day regimen adapted from BCIRG006 Number of cycles: Subject to local approval pending publication of BCIRG006 Node positive patients with cardiac problems which prevent anthracycline administration; Docetaxel/Carboplatin/Trastuzumab 6 cycles Followed by Trastuzumab alone 12 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Cardiac function should be assessed prior to the commencement of therapy (ECHO). See London Cancer Alliance LCA recommendations for baseline cardiac assessments before chemotherapy. Do not treat if patient has any of the following: Left ventricular ejection fraction (LVEF) of 55% History of documented congestive heart failure High risk uncontrolled arrhythmias Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 9 of 57

10 Tests to OK/Confirm each cycle of chemo: Patient information: Angina pectoris requiring medication Clinically significant valvular disease Evidence of transmural infarction on ECG Poorly controlled hypertension During chemo; FBC, U&Es LFT. During trastuzumab maintenance; FBC every 3 months. Cardiac assessment at 4 months (cycle 6) and 8 months (cycle 12). If LVEF drops by 10% (ejection) points or more from baseline and to below 50% then trastuzumab treatment should be suspended and discussed with consultant. Cycles 1-6;High risk anti-emetics as per NWLCN guidelines or as per local policy, Dexamethasone as above Chemotherapy treatment booklet (local information/macmillan) Administration notes: Docetaxel see page 7 Trastuzumab: Infusion reactions may occur including dyspnoea, hypotension, wheezing, bronchospasm, anaphylaxis, respiratory distress, tachycardia, angioedema and urticaria. Usually mild to moderate and occur within 2.5 hour of starting the first infusion. The patient should be observed for 6 hours after start of the first dose and anaphylaxis drugs readily available. Interrupt treatment if infusion reactions occur and seek medical advice. Patients should be observed for 2 hours after the start of subsequent doses. Dose modifications: (SPC) See Docetaxel table page 7 No reductions in the dose of trastuzumab Reference: BCIRG006 regimen amended for 3 weekly trastuzumab Node Negative/Low Risk Node Positive 4. FEC-75 1 day (CTIS: 74) 5 Fluorouracil 600mg/m 2 IV bolus Day 1 Epirubicin 75mg/m 2 IV bolus Day 1 Cyclophosphamide 600mg/m 2 IV over 30mins/bolus Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Node negative/low risk node positive; 6 cycles If no/poor response after 3 cycles, switch to docetaxel-100 page 11 Tests before starting course of chemo: FBC, U&Es, LFTs, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 10 of 57

11 High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: See notes for FEC-100 page 6 Dose modifications: See FEC table page 6 Node Negative/Low Risk Node Positive if poor response to FEC Docetaxel-100 (CTIS: 1207/1208) Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 100mg/m 2 IV over 1 hour Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Node negative/low risk node positive When no or poor response after 3-4 cycles of FEC 3 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy, dexamethasone as above Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before, the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity reactions; therefore, the patient must be discharged with enough dexamethasone to take before their next cycle. Ensure patient understands how to take their steroids at home. Diabetic patients will need to monitor blood sugar levels more regularly and inform their doctor if they are having problems with the control of their blood sugar levels. IV dexamethasone should not be given to replace oral doses. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered. Dose modifications: See Docetaxel table page 7 Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 11 of 57

12 Diabetic Patients (reduced steroids compared to docetaxel) 6. AC60/600/Paclitaxel-90 AC60/600 for 4 cycles followed by Paclitaxel-90 weekly for 12 weeks. (NB; LCA regimen is paclitaxel 80mg/m 2 ) Cycles 1 to 4 AC-60/600 1 day (CTIS: 496/1226) Doxorubicin 60mg/m 2 IV bolus Day 1 Cyclophosphamide 600mg/m 2 IV over 30 mins/bolus Day 1 Interval between cycles: Repeat every 21 days Number of cycles: Neoadjuvant diabetic patients; 4 cycles only followed by 12 weekly doses of paclitaxel-90 Tests before starting course of chemo: FBC. LFTs, U&Es, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, LFTs, U&Es High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Doxorubicin is a vesicant and must be administered according to NWLCN administration policy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered, but success is limited by prolonged circulation time of cyclophosphamide. Dose of cyclophosphamide is below that which is likely to cause haemorrhagic cystitis, and mild symptoms of dysuria may be treated by increasing fluid intake and regular voiding of urine. Dose modifications: See table AC page 13 Reference: Cycles 5 onwards. Paclitaxel-90-weekly (CTIS: 1099) Dexamethasone 8mg* IV bolus Day 1 Chlorphenamine 10mg IV bolus Day 1 Ranitidine 50mg IV bolus Day 1 Paclitaxel 90mg/m 2 IV over 1 hour Day 1 *Cycle 2 onwards if paclitaxel well tolerated, dexamethasone may be reduced to 4mg (NB; LCA regimen is Paclitaxel 80mg/m 2 ) Interval between cycles: Repeat every 7 days Number of cycles: Neoadjuvant diabetic patients; 12 weekly doses of paclitaxel-90 after 4 cycles of AC60/600 Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Moderate risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 12 of 57

13 Administration notes: Paclitaxel is a vesicant and must be administered according to NWLCN administration policy. Ensure patient has received appropriate pre-medication to prevent hypersensitivity reactions. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Dose modifications: See table on page 21 Adjuvant; Regimens for the Elderly/Frail 7. AC-60/600 1 day (CTIS: 496/1226) Doxorubicin 60mg/m 2 IV bolus Day 1 Cyclophosphamide 600mg/m 2 IV over 30 mins/bolus Day 1 Interval between cycles: Repeat every 21 days Number of cycles: 4 cycles Tests before starting course of chemo: FBC. LFTs, U&Es, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, LFTs, U&Es High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Doxorubicin is a vesicant and must be administered according to NWLCN administration policy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered, but success is limited by prolonged circulation time of cyclophosphamide. Dose of cyclophosphamide is below that which is likely to cause haemorrhagic cystitis, and mild symptoms of dysuria may be treated by increasing fluid intake and regular voiding of urine. Dose modifications: See table AC/EC below Reference: J. Clin Oncol 1990;8(9): Table: AC Side effect: AC Dose Modification Haematology See relevant haematological toxicity table page 3/4 Renal Function (WLCN 2009) 20mls/min 10-20mls/min <10mls/min Doxorubicin Do not give. Discuss with consultant Cyclophosphamide 25% dose reduction Do not give. Discuss with consultant Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 13 of 57

14 Side effect: AC Hepatic Function (BC Cancer Agency North London) Dose Modification Doxorubicin Cyclophosphamide Bilirubin AST/ALT micromol/l >17 or 2-3 x ULN or >3 x ULN >85-25% dose reduction 50% dose reduction 75% dose reduction Do not give See above SPC Pharmacia 04/12/10 states not recommended. In such cases dose should be reduced. BC Cancer Agency states no dose adjustment necessary. Clinical decision. See below See below See below Non Haematological Toxicity CTC Grade Grade 2 Delay chemo until resolved Restart with 25% dose reduction in all drugs 8. FEC-60 1 day (CTIS: 567) 5 Fluorouracil 600mg/m 2 IV bolus Day 1 Epirubicin 60mg/m 2 IV bolus Day 1 Cyclophosphamide 600mg/m 2 IV over 30mins/bolus Day 1 Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, cardiac assessment. Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) See FEC-100 page 6 Dose modifications: See FEC table page 6 Reference: Non Anthracycline Regimen (avoids alopecia or if unable to receive anthracyclines) 9. CMF IV Day 1 and 8 (CTIS: 71) Cyclophosphamide 600mg/m 2 IV over 30 mins/bolus Day 1 and 8 Methotrexate 40mg/m 2 IV bolus Day 1 and 8 5-Fluorouracil 600mg/m 2 IV bolus Day 1 and 8 Interval between cycles: Number of cycles: Repeat every 28 days 6 cycles Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 14 of 57

15 Tests before starting course of chemo: Tests to OK/Confirm each cycle of chemo: Patient information: FBC, U&Es, LFTs Day 1: FBC, U&Es, LFTs Day 8: FBC, U&Es Moderate risk antiemetics as per NWLCN guidelines or as per local policy Chemotherapy treatment booklet (local information/macmillan) Administration notes: Prior to treatment, discuss hair loss and liaise with wig fitter (due to moderate hair thinning). If the patient is prescribed folinic acid it should be prescribed to start 24hr after methotrexate. Dose of cyclophosphamide is below that which is likely to cause haemorrhagic cystitis, and mild symptoms of dysuria may be treated by increasing fluid intake and regular voiding of urine. Dose modifications: See CMF table page 36 Monoclonal Antibodies; Adjuvant and Neoadjuvant Adjuvant Trastuzumab (Herceptin) Available according to NICE guidance 107 (August 2006) for early stage HER-2 positive breast cancer following surgery, chemotherapy (neo-adjuvant or adjuvant) and radiotherapy if applicable. 10. Trastuzumab every 3 weeks (Load CTIS: 1157, Maintenance 1158) Trastuzumab 8mg/kg IV infusion Day 1 only loading dose Trastuzumab 6mg/kg IV infusion Day 21 then repeated every 21 days as maintenance Interval between cycles: Loading dose then repeat maintenance dose every 21 days Number of cycles: 1 year treatment. 18 doses (1 loading dose and 17maintenance doses) or until disease recurrence if earlier. Tests before starting each course of chemo: Cardiac function should be assessed prior to the commencement of therapy (ECHO). See London Cancer Alliance (LCA) recommendation for baseline cardiac assessments before chemotherapy. In line with LCA; Do not treat if patient has any of the following: Left ventricular ejection fraction (LVEF) of 50%. Discuss with consultant if less than 50% History of documented congestive heart failure High risk uncontrolled arrhythmias Angina pectoris requiring medication Clinically significant valvular disease Evidence of transmural infarction on ECG Poorly controlled hypertension Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 15 of 57

16 Tests to OK/Confirm each cycle of chemo: Patient information: FBC every 3 months. Cardiac assessment at 4 months (cycle 6) and 8 months (cycle 12) See LCA clinical guidelines. If LVEF drops by 10% (ejection) points or more from baseline and to below 50% then trastuzumab treatment should be suspended and discussed with consultant None Chemotherapy treatment booklet (local information/macmillan) Administration notes: Infusion reactions may occur including dyspnoea, hypotension, wheezing, bronchospasm, anaphylaxis, respiratory distress, tachycardia, angioedema and urticaria. Usually mild to moderate and occur within 2.5 hour of starting the first infusion. The patient should be observed for 6 hours after start of the first dose and anaphylaxis drugs readily available. Interrupt treatment if infusion reactions occur and seek medical advice. Patients should be observed for 2 hours after the start of subsequent doses. Dose modifications: (SPC) No reductions in the dose of trastuzumab were made during clinical trials. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 16 of 57

17 Metastatic Breast Cancer Regimens Metastatic/Locally Advanced Breast Cancer Chemotherapy Regimens Treatment will include some/all of the following: a) Chemotherapy - All patients where indicated b) Monoclonal antibodies - Trastuzumab (Herceptin) for HER2 positive patients, as per NICE: Either with taxane chemotherapy as first line metastatic treatment where anthracyclines not appropriate or as single agent as 3 rd line after anthracycline and taxane (and endocrine therapy if ER positive). c) Endocrine therapy - Oestrogen receptor positive patients only. d) Bisphosphonates - Determined by the presence and burden of metastatic bone disease Anthracycline Regimens If no prior anthracycline or if >3-5 years since anthracycline chemotherapy given, consider rechallenge with anthracycline 11. AC-60/600 1 day (CTIS: 496/1263) Doxorubicin 60mg/m 2 IV bolus Day 1 Cyclophosphamide 600mg/m 2 IV over 30 mins/bolus Day 1 Interval between cycles: Repeat every 21 days Number of cycles: 4-6 cycles Tests before starting course of chemo: FBC. LFTs, U&Es, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, LFTs, U&Es High antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: See notes for AC 60/600 1 day page 13 Dose modifications: See table AC page 13 Reference: J. Clin Oncol 1990;8(9): Epirubicin-30-weekly (CTIS:1232) Epirubicin 30mg/m 2 IV bolus Day 1 Interval between cycles: Repeat every 7 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 17 of 57

18 Administration notes: Epirubicin is a powerful vesicant and must be administered according to NWLCN administration policy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered. Dose modifications: See Epirubicin table below Table: Epirubicin Side effect: Epirubicin Dose Modification Haematology See relevant haematological toxicity table page 4 Liver function (NLCN 2009) <23 micromol/l micromol/l micromol/l >85 micromol/l Renal Function 30mls/min <30mls/min Non Haematological Toxicities 50% dose reduction 75% dose reduction Do not give Do not give. Discuss with consultant Grade 2 Delay chemo until resolved. Restart with 25% dose reduction 13. Myocet-Cyclo 60/600 (CTIS: 1361) Liposomal Doxorubicin (Myocet) Cyclophosphamide 600mg/m 2 IV over 30 minutes Day 1 Liposomal Doxorubicin (Myocet) 60mg/m 2 IV over 1 hour Day 1 Interval between cycles: Repeat every 21 days (for patients with cardiac problems) Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, cardiac assessment Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Liposomal doxorubicin (myocet) should be considered an irritant and must be administered according to NWLCN administration policy. When infused rapidly acute reactions associated with liposomal infusions have been reported. Reported symptoms have included flushing, dyspnoea, fever, facial Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 18 of 57

19 swelling, headache, back pain, chills, tightness in the chest and throat, and/or hypotension. This acute reaction may be avoided by using a 1-hour infusion time. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered Dose modifications: See table below Table: Myocet-Cyclophosphamide Side effect Dose Modification (SPC) Haematology See relevant haematological toxicity table page 4 Renal Function Doxorubicin Cyclophosphamide (NLCN) >20mls/min 10-20mls/min <10mls/min Hepatic function (SPC) Bilirubin AST < ULN and Normal < ULN and Raised Bilirubin > ULN but <50micromol/L > 50micromol/L Mucositis Grade 1 Grade 2 Grade 3 Grade 4 Doxorubicin is metabolised largely by the liver and excreted in the bile. Therefore dose modification is not required for patients with renal function impairment Full Dose 25% dose reduction Discuss with consultant Full Dose Consider 25% dose reduction 50% dose reduction Discuss with consultant. Avoid if possible as no information and dose based on extrapolation; 75% dose reduction. Delay one week. If recovered restart at full dose. Delay one week and if resolved restart at 25% dose reduction. Delay one week and if resolved restart at 50% dose reduction. Taxanes If relapse after anthracycline or if relapse within 1 year of anthracycline: 14. Docetaxel-75 (Taxotere) (CTIS: ) Dexamethasone 8mg Oral Twice a day For three days starting the day before docetaxel Docetaxel 75*mg/m 2 IV over 1 hour Day 1 *Docetaxel dose may be increased to 100mg/m 2 Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 19 of 57

20 Administration notes: See notes for Docetaxel-100 page 7 Dose modifications: See Docetaxel table page Docetaxel-75 plus Capecitabine-2000 (CTIS;1317) Dexamethasone 8mg Oral twice a day For 3 days starting the day before docetaxel Docetaxel 75mg/m 2 IV over 1 hour Day 1 Capecitabine 1000mg*/m 2 Oral twice a day Day 1 to 14 Ie 2000mg/m 2 /day October 2012; capecitabine dose reduced to 2000mg/ m 2 /day in line with LCA. (Previously 2500mg/ m 2 /day) Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, Crcl, U&Es, LFTs, ECG in the case of previous cardiac history Tests to OK/Confirm each cycle of chemo: FBC, Crcl (calculated), U&Es, LFTs High risk antiemetics as per NWLCN guidelines or as per local policy Loperamide, chlorhexidine mouthwash. Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Docetaxel Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before, the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity reactions, therefore, the patient must be discharged with enough dexamethasone to take before their next cycle. Ensure patient understands how to take their steroids at home. Diabetic patients will need to monitor blood sugar levels more regularly and inform their doctor if they are having problems with the control of their blood sugar levels. IV dexamethasone should not be given to replace oral doses. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered. Capecitabine Patients must attend a nurse capecitabine clinic prior to cycles 1 and 2. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient s GP. Capecitabine interacts with warfarin Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 20 of 57

21 and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol. Dose modifications: See capecitabine SPC for specific guidance on dose reductions in combination with docetaxel. 16. Paclitaxel-90-weekly (CTIS: 1099) Dexamethasone 8mg* IV bolus Day 1 Chlorphenamine 10mg IV bolus Day 1 Ranitidine 50mg IV bolus Day 1 Paclitaxel 90mg/m 2 IV over 1 hour Day 1 *Cycle 2 onwards if paclitaxel well tolerated, dexamethasone may be reduced to 4mg LCA metastatic paclitaxel regimen is 70-90mg//m 2 Interval between cycles: Repeat every 7 days Number of cycles: 18 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Moderate risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Paclitaxel is a vesicant and must be administered according to NWLCN administration policy. Ensure patient has received appropriate pre-medication to prevent hypersensitivity reactions. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Dose modifications: See table below Table: Paclitaxel Side effect: Paclitaxel Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.0 and 75 <1.0 or <75 Grade 4 Neutropenia last 7days (N <0.5) Thrombocytopenia <25 x 10 9 /L Febrile neutropenia N <0.5 and fever >38 o C Or Dose Modification (www trial). Do not treat below these levels Delay until recovered Delay until recovered then give Paclitaxel 20% dose reduction Delay until recovered then give Paclitaxel 20% dose reduction Delay until recovered then give Paclitaxel 20% dose reduction Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 21 of 57

22 Side effect: Paclitaxel Renal function (NLCN 2007) Crcl Hepatic function (NLCN 2009) Sepsis with grade 3/4 neutropenia Non Haematological Toxicities (excluding alopecia) Peripheral Neuropathy 30mls/min < 30mls/min Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Dose Modification (www trial) Delay until recovered then give Paclitaxel 20% dose reduction No dose adjustment necessary Discuss with consultant Discuss with consultant Delay until recovered, then discuss with consultant. Delay until recovered to Grade 1 then give Paclitaxel 20% dose reduction Stop paclitaxel. Discuss with consultant. Next cycle give paclitaxel 20% dose reduction Stop paclitaxel. Discuss with consultant 17. Paclitaxel-Gemcitabine (CTIS 1291) Dexamethasone 20mg Oral before 6pm on the evening before paclitaxel dose Dexamethasone 20mg Oral morning of paclitaxel dose Ranitidine 50mg IV bolus 30mins pre-paclitaxel Chlorphenamine 10mg IV bolus Pre-paclitaxel Paclitaxel 175mg/m 2 IV over 3 hours Day 1 Gemcitabine 1250mg/m 2 IV over 30mins Day 1 and 8 Interval between cycles: Repeat every 21 days Number of cycles: As NICE for metastatic breast cancer 6 cycles patients only when docetaxel monotherapy or docetaxel/capecitabine are also considered Tests before starting course of chemo: Day 1: FBC, U&Es, LFTs Day 8: FBC, U&Es Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Moderate risk antiemetics as per NWLCN guidelines or as per local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) Administration notes: Paclitaxel: See Paclitaxel page 20 Gemcitabine: must be administered over 30 minutes. In the case of injection site reaction (vein irritation) the infusion may be slowed down slightly after agreement with the medical team but must not be infused over more than one hour. Prolonged infusion increases the treatment toxicity and should be avoided. Peripheral venous comfort may be increased with warming the arm with a heat pad. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 22 of 57

23 Dose modifications: See table below Table: Gemcitabine/Paclitaxel Side effect: Gemcitabine/Paclitaxel Dose Modification Haematology See relevant haematological toxicity table page 4 Renal Function Crcl 40mls/min <40mls/min Hepatic Function (NLCN 2009) Bilirubin (micromol/l) <17 micromol/l micromol/l micromol/l >51 micromol/l BCCA Bilirubin Transaminases <1.25xULN and <10xULN Lethargy Oedema Do not give Paclitaxel Paclitaxel 135mg/m 2 Paclitaxel 75mg/m 2 Discuss with consultant. Consider paclitaxel 50mg/m 2 Paclitaxel 175mg/m 2 Gemcitabine Gemcitabine 800mg/m 2 Discuss with consultant No data Grade 3-4 Consider gemcitabine: 25% dose reduction If does not respond to dose reduction: Stop treatment Grade 3-4 Dipstick test for protein If positive do 24 hour urine protein estimation 18. Abraxane: Paclitaxel Albumin-260 (every 3 weeks) For Additional Private Care unless NDP approved/pct agreement to fund Paclitaxel Albumin 260mg/m 2 IV over 30 mins Day 1 (Abraxane) Interval between cycles: Repeat every 21 days Number of cycles: Metastatic breast cancer where steroids cannot be given Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs up to 6 cycles Moderate risk antiemetics as per NWLCN policy or as per local guidelines Patient information: Chemotherapy treatment booklet (local information/macmillan) Each dose contains approximately 425mg sodium. Licensed for Monotherapy treatment of metastatic breast cancer who have failed first line treatment for metastatic breast cancer for whom standard anthracycline containing regimens is not indicated. Funding must be secured before treatment starts. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 23 of 57

24 SPC sates that Abraxane should not be used in combination with other anti-cancer agents. Do not shake the dose. Dose modifications: See table Abraxane below Reference: Celgene Ltd. Abraxane SPC 26/07/11 Table Abraxane-260 Side-effect: Abraxane-260 Haematology Neutrophils Platelets x10 9 /L x10 9 /L 1.5 and 100 Severe neutropenia Neutrophils <0.5 x 10 9 for one week or longer 1 st Occurrence Renal function (SPC) 2 nd Occurrence Hepatic function (SPC) Mild to moderate impairment Dose Modification (SPC) Do not treat below these levels. Wait until recovered before re-treatment. (SPC 26/07/11) Wait until recovered to 1.5 x 10 9 /L then restart with reduced dose; Abraxane 220mg/m 2 for subsequent cycles (15% dose reduction). Wait until recovered to 1.5 x 10 9 /L then restart with reduced dose; Abraxane 180mg/m 2 for subsequent cycles (30% dose reduction Studies in this group have not been performed. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion Insufficient data to recommend dose modifications. Sensory neuropathy Grade 1 or 2 Grade 3+ Severe impairment 1 st Occurrence 2 nd Occurrence Do not treat with Abraxane Dose reduction not generally required. Withhold treatment until resolved to grade 1 or 2, then restart with Abraxane 220mg/m 2 Withhold treatment until resolved to grade 1 or 2 then restart with Abraxane 180mg/m 2 3 rd Recurrence despite dose reduction Discuss with consultant Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 24 of 57

25 19. Abraxane: Paclitaxel Albumin- 125 weekly with break For Additional Private Care unless NDP approved/pct agreement to fund Paclitaxel Albumin 125mg/m 2 IV over 30 mins Day 1, 8 and 15 Interval between cycles: Repeat every 28 days Number of cycles: Metastatic breast cancer where steroids cannot be given Up to 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs Moderate risk antiemetics as per NWLCN/local policy Patient information: Chemotherapy treatment booklet (local information/macmillan) General advice on EGFR related skin reactions See Abraxane page 23 Dose Modifications: Discuss with consultant; dose modifications are made according to tolerability in particular neuropathy Reference; JL Blum et al. Clin Breast Cancer 2007, Dec 7 (11) Bevacizumab (Avastin) 20. Bevacizumab-10/ Paclitaxel-80 weekly Secure Cancer Drugs Fund approval before starting treatment Bevacizumab 10mg/kg IV over 90 mins* Day 1 and 15 Dexamethasone 8mg IV bolus Day 1, 8 and 15 Chlorphenamine 10mg IV bolus Day 1, 8 and 15 Ranitidine 50mg IV bolus Day 1, 8 and 15 Paclitaxel 80mg/m 2 IV over 1 hour Day 1, 8 and 15 October 2012: Paclitaxel dose reduced to 80mg/m 2 in line with LCA guidelines. *First infusion of bevacizumab should be infused over 90 minutes. If this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. Interval between cycles: Repeat every 28 days Number of cycles: Secure Cancer Drugs Funding for First line metastatic breast cancer with Either triple negative tumours and/or prior taxane therapy continue all drugs until disease progression or unacceptable toxicity Tests before starting course of chemo: FBC, U&Es, LFTs, CrCl (calculated), INR. Blood pressure, dipstick for proteinuria Do not administer bevacizumab within 28 days of surgery, see breast page 27 See SPC for other cautions with bevacizumab eg. gastro intestinal Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 25 of 57

26 perforations, wound healing, hypertension, proteinuria, thromboembolism, haemorrhage, CNS metastases, congestive heart failure. Tests to OK/confirm each cycle of chemo: Day 1: FBC, U&Es, LFTs, BP, dipstick proteinuria, Crcl calculated Day 8: FBC, U&Es, BP, dipstick proteinuria, calculated Crcl Day 15: FBC, U&Es, BP, dipstick proteinuria, calculated Crcl Moderate risk antiemetics as per NWLCN guidelines or as per local policy Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN (Max 16mg/day) Patient information: Chemotherapy treatment booklet (local information/macmillan) General advice on EGFR related skin reactions Administration notes: Bevacizumab: Bevacizumab should be administered diluted with normal saline. Do NOT mix bevacizumab with any other fluids. Where other fluids follow bevacizumab infusion, flush first with normal saline then flush with the other fluid. Bevacizumab first infusion is administered over 90 minutes. If this first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated all subsequent infusions may be administered over 30 minutes. See dose modifications table for action if dose not tolerated. Paclitaxel: See page 21 Dose modifications/cautions: Bevacizumab: Bevacizumab dose reduction for adverse events is not recommended (SPC). If indicated, bevacizumab therapy should either be permanently discontinued or temporarily suspended until toxicity resolves. Chemotherapy alone may continue if bevacizumab toxicity/side effects dictate that bevacizumab should be withheld. Paclitaxel See breast page 21 Reference: NEJM 2007 Dec ;26 p ECOG E2100 Trial Avastin SPC September 2009 Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 26 of 57

27 Table: Bevacizumab Side effect: Bevacizumab Dose modification (SPC) All toxicities graded according to CTCAE v3.0 guidelines Thrombosis/Embolism Venous thromboembolic event Grade 3 or incidentally discovered pulmonary embolus (first occurrence) Symptomatic Grade 4 venous thromboembolic event (first occurrence) Arterial thromboembolic event any grade Haemorrhage Grade 1 and 2 Grade 3 or 4 (first occurrence) Proteinuria First occurrence of proteinuria: 1+ (dipstick) 2+, 3+ and 4+ dipstick Hold bevacizumab for 2 weeks. Bevacizumab may be resumed after initiation of therapeutic-dose anticoagulant therapy as soon as all of the following criteria are met: The patient must be on a stable dose of anticoagulant and, if on an oral coumarin-derivative, have an INR within the target range (usually between 2 and 3) prior to restarting bevacizumab. Permanently discontinue bevacizumab Permanently discontinue bevacizumab if patient develops any grade of arterial thromboembolic event. No schedule modifications Discontinue bevacizumab and institute appropriate treatment Administer bevacizumab as scheduled. NO additional evaluation is required. Administer bevacizumab as scheduled and collect 24- hour urine to determine the total protein within 3 days prior to the next scheduled dose. If 24-hour proteinuria 2g: Administer bevacizumab as scheduled 24-hour proteinuria >2g: Bevacizumab treatment should be withheld pending next 24 hour total protein. If Repeat 24 hour urine protein 2g: Administer bevacizumab as schedule. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to 1g/24 hour. Repeat 24-hour urine protein > 2g: Bevacizumab dose should be withheld until 24- hour protein has decreased to 2g. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to 1g/24 hour. Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 27 of 57

28 Side effect: Bevacizumab Second and subsequent occurrence of 2+ proteinuria (dipstick) 2+ (dipstick) 3+ and 4+ (dipstick): Nephrotic Syndrome (Grade 4) Gastro-intestinal perforation Gastro-intestinal perforation or dehiscence Wound healing complications Prevention of wound healing complications Wound healing complications Fistula or intra-abdominal abscess Fistula or intra-abdominal abscess Dose modification (SPC) Administer bevacizumab as scheduled. NO additional evaluation is required. Administer bevacizumab as scheduled and collect 24- hour urine to determine the total protein within 3 days prior to the next scheduled dose is required: If 24-hour proteinuria 2g: Administer bevacizumab as scheduled 24-hour proteinuria >2g: Bevacizumab treatment should be withheld pending next 24 hour total protein. If Repeat 24 hour urine protein 2g: Administer bevacizumab as schedule. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to 1g/24 hour. Repeat 24-hour urine protein > 2g: Bevacizumab dose should be withheld until 24- hour protein has decreased to 2g. 24-hour protein should be further monitored prior to each administration of bevacizumab until it has decreased to 1g/24 hour. Discontinue bevacizumab treatment Discontinue bevacizumab permanently and institute appropriate treatment Bevacizumab therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. Bevacizumab therapy should be withheld for at least 28 days before elective surgery. In patients who experience wound healing complications during bevacizumab treatment, bevacizumab should be withheld until the wound is fully healed. Patients who develop a fistula or intra-abdominal abscess should discontinue bevacizumab Hypertension Patients should be monitored for development of, or worsening hypertension by frequent blood pressure measurement. BP measurement should be taken after the patient has been in a resting position for 5 minutes. Repeated measurement of BP for verification should be taken of the initial reading is 140mmHg systolic and/or 90mmHg diastolic blood pressure Breast regimens v7 01 NWLCN 24Oct12.doc Breast Page 28 of 57