Early Invasive Breast Cancer Neo-adjuvant and … regimens v7 01... · Neo-adjuvant and Adjuvant Chemotherapy Node Positive/High Risk Node Negative 1. ... Neoadjuvant Breast Cancer

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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: 24th October 2012 Last corrected: 24th 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: 74/1227 10 Poor Response/No Response to 3-4 cycles of FEC-75 5. FEC-75/DOC100 (3+3) CTIS: 74/649 11 Diabetic Patients (less steroids than docetaxel) 6. AC 60/600 x4/ Paclitaxel-90 weekly x 12 CTIS: 496/1099 11/12 Options for elderly

7. AC 60/600 1 day x 4-6 CTIS: 496/1226 13 8. FEC-60 1 day x 4-6 CTIS: 567 14 Avoid alopecia (non anthracycline) 9. CMF IV Day 1+8 x 6 CTIS: 71/1200 14

Monoclonal antibodies; Adjuvant/Neoadjuvant 10. Trastuzumab CTIS: 1157/1158 15


Metastatic Breast Cancer Chemotherapy Page Anthracycline regimens

11. AC 60/600 1 day CTIS: 496 16 12. Epirubicin-30 weekly CTIS: 1323 17 13. MC-60/600 (Myocet (lipo Dox) plus cyclo) CTIS: 1361 17

Taxane regimens

14. Docetaxel 75-100 CTIS: 19 15. Docetaxel/Capecitabine CTIS: 1317 19 16. Paclitaxel-90 weekly CTIS: 1099 20 17. Paclitaxel/Gemcitabine CTIS: 1291 21 Additional Private Care 18. Abraxane-260; Paclitaxel Albumin 3 weekly CTIS: 23 19. Abraxane-100; Paclitaxel-Albumin-100 weekly CTIS: 24

Bevacizumab Additional Private Care

20. Bevacizumab/Paclitaxel CTIS: 25 21. Bevacizumab/Capecitabine CTIS Vinorelbine

21. Vinorelbine-30 Day 1 and 8 CTIS: 223 30 22. Vinorelbine two weekly CTIS: 703 30 23. Vinorelbine-60 ORAL CTIS: 1230 31

Capecitabine

24. Capecitabine 2000 CTIS: 200 33

Carboplatin 25. MV-Carbo CTIS: 1164 34

Gemcitabine/Carboplatin see page 36(Local approval required) CTIS:

CMF (Non classical) 26. CMF-750 IV CTIS: 1229 35

Gemcitabine

27. Gemcitabine/Carboplatin (Local approval required) 36 Paclitaxel/Gemcitabine see page 21 CTIS: 1291

Lapatinib

28. Lapatinib/capecitabine (Cancer Drugs Fund) CTIS: 38 29. 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: 788/787 51


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: 24th October 2012 Last corrected: 24th 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 x109/L x109/L Day 1 � 1.0 and �100 0.5 - 0.9 and 75 - 99

Full dose all drugs Continue treatment at full dose with GCSF support starting 24 hours after end of each chemotherapy cycle


Results on Day of Chemo Adjuvant/Neo-adjuvant Dose Modification <0.5 or 75-99 Any and <75 Day 8 �1.0 and �100 <1.0 and/or <100 Neutropenic Sepsis

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. Full dose 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 x109/L x109/L Day 1 � 1.5 and � 100 <1.5 and/or <100

Recurrence of toxicity Day 8 � 1.5 and � 100 <1.5 and/or <100

Full dose all drugs 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. 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 Full dose Omit day 8 chemo. Next cycle to commence day 29 subject to blood counts.


Results on Day of Chemo Metastatic Dose Modification Bone marrow failure secondary to metastatic infiltration Febrile Neutropenia (FN)

1st episode FN

Recurrent FN

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. 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/m2 IV bolus Day 1 Epirubicin 100mg/m2 IV bolus Day 1 Cyclophosphamide 500mg/m2 IV over 30 mins/bolus Day 1 NB. Cyclophosphamide dose is reduced to 500mg/m2 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)

Your chemotherapy record (NWLCN red book) Chemotherapy alert card (NWLCN)

Macmillan drug specific information sheet(s) and information prescriptions as appropriate

Neutropenia DVD (NWLCN)


Additional information: 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

Fluorouracil Full dose Full dose Do not give regimen

Epirubicin Full dose Full dose Do not give regimen

Cyclophosphamide Full dose 25% dose reduction Discuss with consultant

Hepatic Function Bilirubin and AST micromols/L 21-51 or 2-4 x ULN 51-85 or >4 x ULN >85 and Any Bilirubin micromols/L <85 >85 Bilirubin Serum micromols/L Transaminases or ALP >17 or >2-3 x ULN

See below See below Do not give Full dose Do not give See above

50% dose reduction 75% dose reduction Do not give See above Do not give See above

See below See below Do not give See below See below 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.

Mucositis/Stomatitis CTC Grade 1 (Imperial) Grade 2 (SPC) �Grade 3

Full dose Delay chemo until recovery then give 25% dose reduction all drugs Delay chemo until recovery then give 40% dose reduction all drugs


Side effect: FEC Dose Modification Nausea/Vomiting Refractory to antiemetics therapy CTC Grade

� Grade 1 � Grade 2

Full dose 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/m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy, dexamethasone as above

Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (NWLCN red book)

Chemotherapy alert card (NWLCN) Macmillan drug specific information sheet(s) and information prescriptions as appropriate

Neutropenia DVD (NWLCN) Additional information: 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


Renal Function Mild/Moderate

Severe

No dose reduction necessary in mild/moderate renal impairment Discuss with consultant


Side effect: Docetaxel Dose Modification 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

Full dose 25% dose reduction (ie reduce to 75mg/m2 from 100mg/m2) Do not give

Cutaneous Reactions Severe or cumulative cutaneous reactions (SPC)

Reduce dose from 100mg/m2 to 75mg/m2 or from 75mg/m2 to 60mg/m2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel

Neuropathy Severe peripheral neuropathy (SPC)

Reduce dose from 100mg/m2 to 75mg/m2 or from 75mg/m2 to 60mg/m2 if already reduced. If patient continues to experience severe reactions, discontinue docetaxel

Allergic Reactions (SPC) Mild

Severe

Rechallenge

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/m2 IV over 1 hour Day 1 Cyclophosphamide 600mg//m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines of as per local policy, dexamethasone as above




Neutropenia DVD (NWLCN) Additional information: 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): 1177-1183 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/m2 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/m2 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


• Angina pectoris requiring medication • Clinically significant valvular disease • Evidence of transmural infarction on

ECG • Poorly controlled hypertension

Tests to OK/Confirm each cycle of chemo: 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.

Supportive drugs with each cycle: Cycles 1-6;High risk anti-emetics as per NWLCN guidelines or as per local policy, Dexamethasone as above



Neutropenia DVD (NWLCN) Additional information: 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/m2 IV bolus Day 1 Epirubicin 75mg/m2 IV bolus Day 1 Cyclophosphamide 600mg/m2 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


Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy



Neutropenia DVD (NWLCN) Additional information:

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-75 5. Docetaxel-100 (CTIS: 1207/1208) Dexamethasone 8mg Oral Twice a day For 3 days starting the day before docetaxel Docetaxel 100mg/m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy, dexamethasone as above




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


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/m2) Cycles 1 to 4 AC-60/600 1 day (CTIS: 496/1226) Doxorubicin 60mg/m2 IV bolus Day 1

Cyclophosphamide 600mg/m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN





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/m2 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/m2) 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 Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN


Your chemotherapy record (NWLCN red book)




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/m2 IV 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN





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):1483-96 Table: AC Side effect: AC Dose Modification Haematology

See relevant haematological toxicity table page 3/4

Renal Function (WLCN 2009)


<10mls/min

Doxorubicin Full dose Full dose Do not give. Discuss with consultant

Cyclophosphamide

Full dose 25% dose reduction Do not give. Discuss with consultant


Side effect: AC Dose Modification Hepatic Function (BC Cancer Agency North London) Bilirubin AST/ALT micromol/L >17 or 2-3 x ULN 20-51 or >3 x ULN 51-85 - >85 -

Doxorubicin 25% dose reduction 50% dose reduction 75% dose reduction Do not give See above

Cyclophosphamide 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/m2 IV bolus Day 1 Epirubicin 60mg/m2 IV bolus Day 1 Cyclophosphamide 600mg/m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN




Neutropenia DVD (NWLCN) Additional information: 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/m2 IV over 30 mins/bolus Day 1 and 8 Methotrexate 40mg/m2 IV bolus Day 1 and 8 5-Fluorouracil 600mg/m2 IV bolus Day 1 and 8 Interval between cycles: Repeat every 28 days Number of cycles: 6 cycles


Tests before starting course of chemo: FBC, U&Es, LFTs Tests to OK/Confirm each cycle of chemo: Day 1: FBC, U&Es, LFTs Day 8: FBC, U&Es Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN





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


Tests to OK/Confirm each cycle of chemo: 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

Supportive drugs with each cycle: None Patient information: 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.


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 3rd 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 re-challenge with anthracycline 11. AC-60/600 1 day (CTIS: 496/1263) Doxorubicin 60mg/m2 IV 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 Supportive drugs with each cycle: 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):1483-96 12. Epirubicin-30-weekly (CTIS:1232) Epirubicin 30mg/m2 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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN






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


Liver function (NLCN 2009) <23 micromol/L

24-51 micromol/L 81-85 micromol/L

>85 micromol/L

Full dose 50% dose reduction 75% dose reduction Do not give

Renal Function �30mls/min <30mls/min

Full dose Do not give. Discuss with consultant

Non Haematological Toxicities �Grade 2

Delay chemo until resolved. Restart with 25% dose reduction

13. Myocet-Cyclo 60/600 (CTIS: 1361) Liposomal Doxorubicin (Myocet) Cyclophosphamide 600mg/m2 IV over 30 minutes Day 1 Liposomal Doxorubicin (Myocet) 60mg/m2 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






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


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

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

Hepatic function (SPC) Bilirubin AST < ULN and Normal < ULN and Raised Bilirubin > ULN but <50micromol/L > 50micromol/L

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

Mucositis Grade 1 Grade 2 Grade 3 Grade 4

Full dose. 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/m2 IV over 1 hour Day 1 *Docetaxel dose may be increased to 100mg/m2

Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs






Neutropenia DVD (NWLCN) Additional information: Administration notes: See notes for Docetaxel-100 page 7

Dose modifications: See Docetaxel table page 7 15. Docetaxel-75 plus Capecitabine-2000 (CTIS;1317) Dexamethasone 8mg Oral twice a day For 3 days starting the day before docetaxel Docetaxel 75mg/m2 IV over 1 hour Day 1 Capecitabine 1000mg*/m2 Oral twice a day Day 1 to 14 Ie 2000mg/m2/day

October 2012; capecitabine dose reduced to 2000mg/ m2/day in line with LCA. (Previously 2500mg/ m2/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 Supportive drugs with each cycle: High risk antiemetics as per NWLCN

guidelines or as per local policy Loperamide, chlorhexidine mouthwash. Patient information: Chemotherapy treatment booklet (local information/Macmillan)




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


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/m2 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//m2







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 Dose Modification (www trial) Haematology Neutrophils Platelets x109/L x109/L � 1.0 and � 75 <1.0 or <75

Grade 4 Neutropenia last �7days (N <0.5)

Thrombocytopenia <25 x 109/L

Febrile neutropenia N <0.5 and fever >38oC

Or

Full dose. 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


Side effect: Paclitaxel Dose Modification (www trial) Sepsis with grade 3/4

neutropenia Delay until recovered then give Paclitaxel 20% dose reduction

Renal function (NLCN 2007) Crcl � 30mls/min < 30mls/min

No dose adjustment necessary Discuss with consultant

Hepatic function (NLCN 2009)

Discuss with consultant

Non Haematological Toxicities (excluding alopecia)

�Grade 1 Grade 2 Grade 3

Grade 4

Full dose Delay until recovered, then discuss with consultant. Delay until recovered to Grade 1 then give Paclitaxel 20% dose reduction Stop paclitaxel. Discuss with consultant.

Peripheral Neuropathy �Grade 1 Grade 2 �Grade 3

Full dose 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/m2 IV over 3 hours Day 1 Gemcitabine 1250mg/m2 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






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.


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

Full dose Do not give

Hepatic Function (NLCN 2009) Bilirubin (micromol/L)

<17 micromol/L 17-26 micromol/L 27-51 micromol/L

>51 micromol/L BCCA Bilirubin Transaminases <1.25xULN and <10xULN

Paclitaxel Full dose Paclitaxel 135mg/m2 Paclitaxel 75mg/m2 Discuss with consultant. Consider paclitaxel 50mg/m2 Paclitaxel 175mg/m2

Gemcitabine Full dose Full dose Gemcitabine 800mg/m2 Discuss with consultant No data

Lethargy Grade 3-4

Consider gemcitabine: 25% dose reduction If does not respond to dose reduction: Stop treatment

Oedema 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/m2 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 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 Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN

policy or as per local guidelines Patient information: Chemotherapy treatment booklet (local information/Macmillan)


Macmillan drug specific information sheet(s) and information prescriptions as appropriate Neutropenia DVD (NWLCN)

Additional information: 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.


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 Dose Modification (SPC) Haematology Neutrophils Platelets x109/L x109/L �1.5 and �100 Severe neutropenia Neutrophils <0.5 x 109 for one week or longer

1st Occurrence

2nd Occurrence

Full dose Do not treat below these levels. Wait until recovered before re-treatment. (SPC 26/07/11) Wait until recovered to �1.5 x 109/L then restart with reduced dose; Abraxane 220mg/m2 for subsequent cycles (15% dose reduction). Wait until recovered to �1.5 x 109/L then restart with reduced dose; Abraxane 180mg/m2 for subsequent cycles (30% dose reduction

Renal function (SPC) Studies in this group have not been performed. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion

Hepatic function (SPC) Mild to moderate impairment

Severe impairment

Insufficient data to recommend dose modifications. Do not treat with Abraxane

Sensory neuropathy Grade 1 or 2 Grade 3+

1st Occurrence

2nd Occurrence

3rd Recurrence despite dose reduction

Dose reduction not generally required. Withhold treatment until resolved to grade 1 or 2, then restart with Abraxane 220mg/m2 Withhold treatment until resolved to grade 1 or 2 then restart with Abraxane 180mg/m2 Discuss with consultant


19. Abraxane: Paclitaxel Albumin- 125 weekly with break For ‘Additional Private Care’ unless NDP approved/PCT agreement to fund Paclitaxel Albumin 125mg/m2 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

Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN/local policy


Chemotherapy alert card (NWLCN) Macmillan drug specific information sheet(s) and information prescriptions as appropriate Neutropenia DVD (NWLCN)

General advice on EGFR related skin reactions Additional information: 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) 850-6

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/m2 IV over 1 hour Day 1, 8 and 15 October 2012: Paclitaxel dose reduced to 80mg/m2 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


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 Supportive drugs with each cycle: 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 Additional information: 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 Dec27. 357;26 p2666-2676 ECOG E2100 Trial Avastin SPC September 2009


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

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.

Haemorrhage Grade 1 and 2 Grade 3 or 4 (first occurrence)

No schedule modifications Discontinue bevacizumab and institute appropriate treatment

Proteinuria First occurrence of proteinuria:

1+ (dipstick)

2+, 3+ and 4+ dipstick

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.


Side effect: Bevacizumab Dose modification (SPC) Second and subsequent occurrence of �2+ proteinuria (dipstick)

2+ (dipstick)

3+ and 4+ (dipstick):

Nephrotic Syndrome (Grade 4)

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

Gastro-intestinal perforation Gastro-intestinal perforation or dehiscence

Discontinue bevacizumab permanently and institute appropriate treatment

Wound healing complications Prevention of wound healing complications Wound healing complications

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.

Fistula or intra-abdominal abscess Fistula or intra-abdominal abscess

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


Side effect: Bevacizumab Dose modification (SPC) Grade 1 Hypertension Asymptomatic, transient (<24hr) increase >20mmHg (diastolic) or to >150/100mmHg if previously within normal limits. Grade 2 Hypertension Recurrent or persistent (>24hrs) increase by 20mmHg (diastolic) or to >150/100mmHg if previously within normal limits Grade 3 Hypertension Requiring more than one anti-hypertensive or more intensive therapy than previously. Grade 4 Hypertension Life threatening consequence eg. hypertensive crisis

Continue with bevacizumab

Monotherapy of antihypertensive may be indicated. Withhold bevacizumab. Once BP controlled to <150/100mmHg patient may restart bevacizumab. Withhold bevacizumab for persistent or symptomatic hypertension, until BP controlled. If hypertension is not controlled with medication; permanently discontinue bevacizumab. Stop bevacizumab permanently.

Infusion-related or allergic reactions � Grade 2 Infusion related reactions eg. fever, chills, headaches, nausea. Allergic reactions eg. fever, rash, urticaria, bronchospasm

Grade 3

If infusion related reactions occur with any infusion: Administer the next dose with premedication over the same time period (ie. do not reduce infusion time for next dose). If next dose with premedication is well tolerated, then the subsequent infusion time may be reduced by 30 minutes (+/- 10mins) provided premedication is still used ie. 90 minute infusion reduced to 60 minutes. If infusion related reactions occur with the reduced infusion time with premedication then all subsequent doses must be administered over the previous longer infusion time with premedication. eg. if infusion related reactions occur with a 60 minute infusion all subsequent doses should be administered over 90 minutes (+/- 15mins) with premedication. eg. if infusion related reactions occur with 30 minute infusion, all subsequent doses should be administered over 60 minutes (+/- 10mins) with premedication Stop bevacizumab infusion. DO NOT restart on that day. Discuss with consultant to decide if bevacizumab should be permanently discontinued or reinstituted with premedication over 90 minutes (+/- 15mins). If the reaction occurred at the 90 minute rate, initially challenge at a slower rate and gradually increase to 90 minutes. When bevacizumab reinstituted, the patient should be monitored for a duration comparable to duration of previous reaction.


Side effect: Bevacizumab Dose modification (SPC)

Grade 4 If suspected anaphylactic reactions during bevacizumab infusion STOP bevacizumab infusion, institute usual medical response to reaction, consider application of tourniquet proximal to the injection site to slow systemic absorption of bevacizumab (do not obstruct arterial flow in the limb)

21. Bevacizumab-10/ Capecitabine weekly

Secure Cancer Drugs Fund approval before starting treatment Bevacizumab 15mg/kg IV over 90 mins* Day 1 Capecitabine 1000mg/m2 Oral Twice a day Days 1 to 14 *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 21 days Number of cycles: For Additional Private care only

For first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with bevacizumab/capecitabine combination

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 perforations, wound healing, hypertension, proteinuria, thromboembolism, haemorrhage, CNS metastases, congestive heart failure.

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs, BP, dipstick proteinuria, Crcl calculated

Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN guidelines or as per local policy

Chlorhexidine mouthwash 10mls QDS Loperamide 2-4mg QDS PRN (Max 16mg/day)


Chemotherapy alert card (NWLCN)



General advice on EGFR related skin reactions Additional information: Bevacizumab see administration notes page 26

Capecitabine see administration notes page 35 Dose Modification; Bevacizumab see dose modification table page 27

Capecitabine see dose modification table page 35 Reference Avastin SPC, Roche Products Ltd. 14th September 2012. Trial AVF3694g

Other Options/Regimens Used 3rd or 4th line after anthracyclines and taxanes but may be earlier if poor LFTs/not fit for taxanes/previous anthracyclines Vinorelbine IV The SPC recommended dose for IV vinorelbine is 25-30mg/m2 weekly. In heavily pre-treated patients, it may be more appropriate to give the dose on alternate weeks or on a Day 1 and 8 basis every 21 days. 21. Vinorelbine Day 1 + 8 IV (CTIS: ) Vinorelbine 25mg/m2 (max 60mg) IV minibag over 10mins Day 1 & 8 Interval between cycles: Repeat every 21 days Number of cycles: 4 cycles Tests before starting course of chemo: FBC, U&Es, LFTs

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: Low risk antiemetics as per NWLCN

guidelines or as per local policy Consider prophylactic laxatives



Neutropenia DVD (NWLCN) Additional information: See below

Dose modifications: See below 22. Vinorelbine IV Two Weekly (CTIS: 703) Vinorelbine 25mg/m2 (max 60mg) IV minibag over 10minutes Day 1 Interval between cycles: Repeat every 14 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs



Patient information: Chemotherapy treatment booklet (local information/Macmillan)





Administration notes: Vinorelbine is a vesicant and must be administered according to NWLCN administration policy. It should be administered as a slow IV bolus with 0.9% sodium chloride and injected into a free-running saline drip. It should be flushed in with 250ml of 0.9% sodium chloride.

Dose modifications: See table below Table: Vinorelbine IV Side effect: Vinorelbine IV Dose Modification Haematology


Renal function (NLCN 2009) �30ml/min <30ml/min

Full dose Discuss with consultant

Hepatic Function (BC Cancer Agency) Bilirubin

�35micromol/L 36-50micromol/L

>50micromol/L

Transaminases (Pierre Fabre SPC) >5 x ULN

Full dose Delay and reassess 1 week later Consider vinorelbine 50% dose reduction If toxicity persists for more than 3 weeks, discontinue treatment Do not give Vinorelbine 33% dose reduction Monitor haematological toxicity closely

23. Vinorelbine ORAL Single Agent (SPC regimen)

Subject to local approval of oral formulation (usually where IV vinorelbine can not be administered due to poor venous access).

First three weeks administration (week 1,2 and 3) (CTIS: ) Vinorelbine 60mg/m2 (max 160mg/week) Oral once Day 1 (repeat every 7 days for first 3 weeks) Subsequent administration (cycle 4 onwards) (CTIS: ) Do NOT increase dose if neutrophils have dropped once below 0.5 x 109/L or have dropped more than once between 0.5 to 1.0 x 109/L Vinorelbine 80mg/m2 (max 160mg/week) Oral once Day 1 (repeat every 7 days) Interval between cycles: Repeat every 7 days Dose for first 3 administrations is 60mg/m2 Dose may be increased for cycle 4 onwards as outlined above Number of cycles: Usually 2-4 cycles (max 6 cycles) Subject to local approval of oral formulation Tests before starting course of chemo: FBC, U&Es, LFTs







Capsules should be swallowed whole with water, do not suck or chew as contents of the capsule is irritant. Recommended to take the capsule with some food. SPC: based on clinical studies Oral vinorelbine 80mg/m2 corresponds to IV vinorelbine 30mg/m2 Oral vinorelbine 60mg/m2 corresponds to IV vinorelbine 25mg/m2

Absolute bioavailability of oral vinorelbine is approximately 40% Dose modifications: See table page 32 Vinorelbine dose table from SPC

Body Surface Area m2

Dose for 60mg/m2

mg Dose for 80mg/m2

mg 0.95 – 1.04 60 80 1.05 – 1.14 70 90 1.15 – 1.24 70 100 1.25 – 1.34 80 100 1.35 – 1.44 80 110 1.45 – 1.54 90 120 1.55 – 1.64 100 130 1.65 – 1.74 100 140 1.75 – 1.84 110 140 1.85 – 1.94 110 150

≥ 1.96 120 160 Even patients with BSA ≥ 2.0 m2 should not exceed 160mg/day

Table: Vinorelbine Oral Single Agent Side effect: Vinorelbine Oral

Dose Modification

Haematology (SPC) Neutrophils Platelets x10/9/L x109/L �1.5 �100 <1.5 <100 Neutrophil count during first three administrations of 60mg/m2

>1.0 x10/9/L

�0.5 and <1.0 x10/9/L (1 episode) �0.5 and <1.0 x10/9/L (2 episodes)

<0.5 x10/9/L

Full dose Delay until recovery then dose as below Recommended dose for Dose for next administration Vinorelbine 80mg/m2 Repeat every 7 days Vinorelbine 80mg/m2 Repeat every 7 days Vinorelbine 60mg/m2 Repeat every 7 days Vinorelbine 60mg/m2 Repeat every 7 days


Side effect: Vinorelbine Oral

Dose Modification

Neutrophil count beyond the 4th administration of 60mg/m2

>1.0 x10/9/L

�0.5 and <1.0 x10/9/L (1 episode) �0.5 and <1.0 x10/9/L (2 episodes)

<0.5 x10/9/L

Vinorelbine 80mg/m2 Repeat every 7 days Vinorelbine 80mg/m2 Repeat every 7 days Vinorelbine 60mg/m2 Repeat every 7 days Vinorelbine 60mg/m2 Repeat every 7 days It is possible to re-escalate the dose from 60mg/m2 to 80mg/m2 if the neutrophil count did not once drop below 0.5 or more than once drop between 0.5 and 1.0 during previous three consecutive administrations given at 60mg/m2

Renal function (NLCN 2009) �30ml/min <30ml/min

No dose reduction necessary Discuss with consultant

Hepatic function (BC Cancer Agency) Bilirubin

�35micromol/L 36-50micromol/L

>50micromol/L Transaminases (Pierre Fabre SPC)

>5 x ULN

Full dose Delay and reassess 1 week later. Consider vinorelbine 50% dose reduction. If toxicity persists for more than 3 weeks discontinue treatment Do not give Vinorelbine 33% dose reduction

Capecitabine 24. Capecitabine 2500 (CTIS: 200)

Capecitabine 1250mg/m2 Oral twice a day Days 1 to 14 ie 2500mg/m2/day with water after ie 28 doses in Food total NB: In frail patients, consider starting dose at 2000mg/m2/day ie 1000mg/m2 twice a day

October 2012: starting dose increased in line with LCA guidelines to 2500mg/m2/day.

Previously from Sep-11 to Sep-12, starting dose was 2000mg/m2/day for all patients. Tablets only available as 500mg and 150mg.

Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, Crcl (calculated), LFTs

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Crcl (calculated, LFTs Supportive drugs with each cycle: Low risk antiemetics as per NWLCN

guidelines or as per local policy Loperamide if necessary, chlorhexidine

mouthwash Patient information: Chemotherapy treatment booklet (local information/Macmillan)




Neutropenia DVD (NWLCN) Capecitabine patient diary Additional information:

Administration notes: Capecitabine Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. 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 tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol.

Dose modifications: See Breast/capecitabine table below Table: Breast/Capecitabine Side Effects

Dose Modification

Haematology

See relevant haematological toxicity table page 3/4

Renal Function (SPC) Crcl � 51mls/min 30-50mls/min <30mls/min

Full dose 25% dose reduction recommended Omit capecitabine

Hepatic function (SPC) Bilirubin (treatment related elevation >3x ULN Amino transferases (treatment related elevation) >2.5 x ULN

Stop capecitabine until elevation resolved and discuss with consultant Stop capecitabine until elevation resolved and discuss with consultant

Hand-foot Syndrome and Diarrhoea (SPC) NCIC GRADE (SPC) Grade 1 Grade 2 1st appearance 2nd appearance 3rd appearance 4th appearance Grade 3 1st appearance 2nd appearance 3rd appearance Grade 4 1st appearance

DURING CYCLE Continue Interrupt until resolved to grade 0-1 Interrupt until resolved to grade 0-1 Interrupt until resolved to grade 0-1 Discontinue permanently Interrupt until resolved to grade 0-1 Interrupt until resolved to grade 0-1 Discontinue permanently Discontinue permanently. If in best interest of patient to continue:- Interrupt until resolved to Grade 0-1

NEXT CYCLE Full dose Full dose 25% dose reduction 50% dose reduction 25% dose reduction 50% dose reduction 50% dose reduction


Carboplatin 25. MV-Carbo (CTIS )

Mitomycin C 8mg/m2 IV bolus Day 1 Vinblastine 6mg/m2 (max 10mg) IV minibag over 10mins Day 1 and 22 Carboplatin 5(GFR+25)mg IV over 1 hour Day 1 and 22 October 2012: Mitomycin dose increased to 8mg/m2 in line with LCA guidelines, (previously 6mg//m2) Interval between cycles: Repeat every 42 days.

Some versions administer mitomycin day 1 and 22 for 1st cycle only then just day 1 on subsequent cycles.

Number of cycles: Up to 3 cycles depending on response (6 treatments) Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs. Redo EDTA if rising creatinine. If bilirubin raised and haemoglobin lowered or haemolysis is suspected do urgent blood film for haemolysis pre chemo.

Do not give mitomycin unless: • Creatinine within normal range • Bilirubin <30micromol/L • WBC �3.0x109/L • Neutrophils �1.5x109/L • Platelets �100x109/L • No red blood cell fragmentation seen in

blood film Supportive drugs with each cycle: High risk antiemetics as per NWLCN





Haemolytic Uraemic Syndrome (HUS) is extremely rare at this dose but is usually fatal. Seek specialist advice

Dose modifications: See table below Table: MV-Carbo Side effect

Dose Modification (Adapted from Focus Trial)

Haematology


Renal function Crcl

�60 mls/min

50-59 mls/min

Carboplatin dose as per GFR Mitomycin: Full dose Carboplatin dose as per GFR Mitomycin: Discuss with consultant

Hepatic function Bilirubin >30micromol/L

Do not give mitomycin and discuss with consultant


CMF If no prior alkylating agent 26. CMF 750 Day 1 (CTIS: 1229) Cyclophosphamide 750mg/m2 IV over 30 mins/bolus Day 1 Methotrexate 40mg/m2 IV bolus Day 1 5-Fluorouracil 600mg/m2 IV bolus Day 1

LCA guidelines include classical CMF (see page 14) instead of above. The CMF-750 IV regimen above allows the patient to spend less time attending hospital appointments.







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 below Table: CMF Side effect: CMF Dose Modification Haematology

See relevant haematological toxicity table page 4 Cyclophosphamide Full dose Full dose

Methotrexate (50mg/m2)

Full dose Consider dose reduction. Advice varies from 50% dose reduction to give full dose.

5FU Full dose Full dose

Renal Functions (NLCN) Crcl �60mls/min

30-59mls/min

<30mls/min Discuss with consultant Hepatic Function


Non Haematological Toxicity eg. mucositis CTC � Grade 2

Delay until recovery then 25% dose reduction all drugs


Gemcitabine 27. Gemcitabine – Carboplatin (CTIS: )

For ‘Additional Private Care’ unless local NDP approved/PCT agreement to fund Gemcitabine * 1000mg/m2 IV over 30 mins Days 1 and 8 Carboplatin * 5x (GFR+25)mg IV over 1 hour Day 1 * Due to haematological toxicity, reduce starting doses in heavily pre-treated patients to Gemcitabine 800mg/m2 days 1 and 8 plus, Carboplatin 4x (GFR+25)mg day 1. Interval between cycles: Repeat every 21 days Number of cycles: Triple negative (oestrogen negative, progestogen negative, HER2 negative)

Metastatic breast Cancer: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs, EDTA, Test to OK/Confirm each cycle if chemo: FBC, U&Es, LFTs, Crcl (calculated).

Supportive drugs with each cycle: High risk antiemetics as per NWLCN guidelines or as per local policy




Administration notes Carboplatin may cause allergic reactions and can occur within minutes of Administration. Gemcitabine should be administered over 30 minutes.

Dose modifications: See table Gem/Carbo below Reference: Laessiq et al. BJCancer 1994 Nov; 70 (5):990-3

• Recommended lower doses for pre-treated patients Nasr et al. Clin breast Cancer 2004 5 (no 2): 117-122

• Reduced carboplatin to 4.5AUC due to haematological toxicity Chan et al. Online publication 25-Aug-2010. Invest.new drugs DOI 10.1007/s10637-0099305x

• Recommended lower starting doses due to significant haematological toxicity


Table Gemcitabine-Carboplatin Side effect: Gem/Carbo Dose Modification (Adapted from OII trial) Haematology Neutrophils Platelets x109/L x109/L Day 1 �1.5 and �100 <1.5 or <100

If �1 week delay:

If delay >1week but �2 weeks } Or Neutropenic fever }

Or Platelets <25 x109/L }

If further recurrence despite 1st dose reduction

If recurrence despite 2nd dose reduction Day 8 �1.5 and �100 1.0-1.4 or 75-99 <1.0 or <75

Full dose Do not treat below these limits. Delay until recovered then dose according to duration of delay as outlined below. Once recovered give full dose all drugs Once recovered reduce dose Gemcitabine: 20% dose reduction day 1 and 8 Carboplatin: 4AUC Once recovered give Gemcitabine: Day 1: 20% dose reduction Day 8: omit dose Carboplatin 4AUC Discuss with consultant Gemcitabine Day 8 - full dose Gemcitabine Day 8 - 50% dose reduction Gemcitabine Day 8 - omit dose

Renal Function (NLCN 2009) GFR �30mls/min <30mls/min

Carboplatin dose according to Calvert formula Do not give either drug. Discuss with consultant

Hepatic Function (NLCN) Bilirubin �27micromol/L >27micromol/L

Gemcitabine limited data available Full dose all drugs Discuss with consultant

Lapatinib 28. Lapatinib plus Capecitabine 2000 (CTIS: )

Secure Cancer Drugs Fund approval prior to starting treatment Lapatinib 1250mg (five tablets) ONCE a day as a single dose Days 1 to 21 Ie continuously Capecitabine 1000mg/m2 Oral twice a day Days 1 to 14 ie 2000mg/m2/day with water after food ie 28 doses in total

Tablets only available as 500mg and 150mg. Interval between cycles: Repeat every 21 days Number of cycles: Apply to Cancer Drugs Fund for HER2 positive advanced or metastatic breast cancer patients who have progressed following anthracycline and taxane therapy and trastuzumab in the metastatic setting: Continue until disease progression


Tests before starting course of chemo: FBC, U&Es, Crcl (calculated), LFTs SPC states do not give to patients with LVEF below lower limit of normal

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Crcl (calculated, LFTs Monitor for signs of pulmonary toxicity (dyspnoea, fever, cough) including interstitial lung disease and pneumonitis.

Supportive drugs with each cycle: Low risk antiemetics as per NWLCN guidelines or as per local policy

Loperamide if necessary, chlorhexidine mouth wash




Administration notes: Capecitabine Patients must receive specific capecitabine counselling prior to treatment from a capecitabine trained nurse/pharmacist as per local policy. 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 tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin and therefore patients on these drugs must have their blood levels monitored more regularly. Capecitabine is contraindicated with allopurinol. Lapatinib The lapatinib daily dose should not be divided. Lapatinib should be taken either at least one hour before, or at least one hour after food. To minimise the variability in the individual patient, administration of lapatinib should be standardised in relation to food intake, for example always be taken before a meal. Missed doses should NOT be replaced and the dosing should resume with the next scheduled daily dose. Interactions with lapatinib: Lapatinib is predominantly metabolised by CYP3A and is a substrate for the transport of proteins Pgp and BCRP. See SPC for drugs that are affected if co-administered. Solubility of lapatinib is pH dependent. Avoid substances that increase gastric pH as lapatinib absorption may be affected. Lapatinib inhibits CYP3A4 and CYP2C8. See SPC for drug interactions. Bioavailability of lapatinib is increased up to 4 times by food depending on eg. the fat content in the meal. Avoid grapefruit juice during treatment with lapatinib.

Dose modifications: See table below Table: Lapatinib Side Effects Dose Modification

Lapatinib Capecitabine Haematology (lapatinib EAP) Neutrophils Platelets Hb x109/L x109/L g/dL

Full dose lapatinib

Full dose capecitabine


Side Effects Dose Modification �1.5 and �100 and �9.0 <1.5 or <100 or <9.0

1st appearance

2nd appearance

3rd appearance

4th appearance

Interrupt lapatinib until resolved to above these levels. Once recovered: Resume at full dose Resume at full dose or dose reduce to 1000mg/day Resume at full dose or dose reduce to 1000mg/day or 750mg/day Discontinue regimen

Interrupt capecitabine until resolved to above these levels. Once recovered; Resume at full dose or with 25% dose reduction Resume with 25% dose reduction Resume with 50% dose reduction

Discontinue permanently

Renal Function (lapatinib EAP) Crcl


<30mls/min

1st appearance 2nd appearance

3rd appearance

Full dose lapatinib Full dose lapatinib Interrupt lapatinib until recovered to above this level; Once recovered: Resume at full dose Resume at full dose or dose reduce to 1000mg/day Resume at full dose or dose reduce to 1000mg/day or 750mg/day

Full dose capecitabine 25% dose reduction in pre-treated patients Omit capecitabine if GFR <30 mls/min

Hepatic Function (lapatinib EAP) Bilirubin

� 3xULN

> 3xULN

1st appearance

2nd appearance

3rd appearance

4th appearance Amino transferases (treatment related elevation) >2.5 x ULN

Lapatinib Full dose lapatinib Interrupt lapatinib until recovered to above this level, then once recovered dose as follows; Resume at full dose Resume at full dose or dose reduce to 1000mg/day Resume at full dose or dose reduce to 1000mg/day or 750mg/day Discuss with consultant Discuss with consultant

Capecitabine Full dose capecitabine Interrupt capecitabine until resolved to above these levels, then once recovered dose as follows; Resume at full dose or 25% dose reduction Resume with 25% dose reduction Resume with 50% dose reduction

Discontinue permanently Stop capecitabine until elevation resolved and discuss with consultant


Side Effects Dose Modification Stop lapatinib, consult lapatinib SPC and discuss with consultant


Cardiac Events Asymptomatic Cardiac Events Decreased left ventricular ejection fraction Symptomatic Cardiac Events Interstitial Lung disease or Pneumonitits

Stop lapatinib, consult lapatinib SPC and discuss with consultant


Lapatinib

Full dose

Capecitabine

Full dose

Consider loperamide • Loperamide 4mg stat then 2mg every four hours or after each

unformed stool • Continue loperamide until patient free of diarrhoea for � 12

hours • If mild to moderate diarrhoea persists after 24 hours, increase

loperamide to 2mg every two hours and start oral antibiotics • If diarrhoea unresolved after 48 hours start codeine 30mg TDS • Drink 8-10 large glasses of clear liquids/day • Avoid dairy products, alcohol, spicy and fried foods • Eat frequent small meals eg rice pasta toast

Lapatinib Full dose Full dose Interrupt until resolved to grade 0-1 then resume with 1250mg/day or reduce to 1000mg/day Interrupt until resolved to grade 0-1 then resume with 1000mg/day

Capecitabine Interrupt until resolved to grade 0-1 then restart with full dose. Interrupt until resolved to grade 0-1 then restart with 25% dose reduction. Interrupt until resolved to grade 0-1 then restart with 50% dose reduction Discontinue treatment permanently

Diarrhoea (GSK Guide) If patient experiences grade 1 or 2 diarrhoea with complicating factors e.g. cramping, severe nausea/ vomiting reduced PS, fever, sepsis, grade 3 / 4 neutropenia, dehydration manage as grade 3 or 4 diarrhoea Diarrhoea Grade 1

Diarrhoea Grade 2 1st appearance

2nd appearance

3rd appearance

4th appearance

Diarrhoea Grade 2 supportive care

As grade 1


Side Effects Dose Modification Lapatinib

Interrupt treatment (for up to 14 days) until resolved to grade 0-1. Then restart with 1250mg/day or reduce to 1000mg/day. As for 1st appearance Discontinue treatment

Capecitabine Interrupt until resolved to grade 0-1. Then restart with 25% dose reduction Interrupt until resolved to grade 0-1. Then restart with 50% dose reduction. Discontinue permanently

• Initiate loperamide if not already initiated • Administer antibiotics as needed especially if there is

fever or grade 3-4 neutropenia or symptoms persist >24 hours

• Consider electrolyte restoring therapy • Discontinue intervention when diarrhoea-free for 24 hours • Use IV fluids • Consider hospital administration for patients at risk of life

threatening complications

Lapatinib Interrupt until resolved to grade 0-1. Restart at reduced dose or consider discontinuing permanently. Discontinue treatment

Capecitabine Discontinue treatment permanently. If consultant considers it in the patient’s best interests to continue. Interrupt until resolved to grade 0-1 then resume with 50% dose reduction. Discontinue treatment permanently.

Diarrhoea Grade 3

1st appearance

2nd appearance

3rd appearance

Diarrhoea Grade 3 supportive care

Diarrhoea Grade 4 1st appearance

2nd appearance

Diarrhoea grade 4 supportive care As for grade 3

Hand Foot Syndrome (GSK Guide)

Hand Foot Syndrome supportive care

Avoid prolonged exposure to hot water and/or heat eg. sun, saunas, in front of a fire. Avoid activities that cause friction on the feet eg. jogging, aerobics. Avoid activities that require one to press hard with one’s hands eg. using tools and household equipment. Avoid contact with chemicals eg. detergents, cleaning fluids. Avoid vigorous rubbing of the skin eg. with a towel. Use cool compresses (15-20 mins at a time) Gently apply mild skin care creams to keep skin moist.


Side Effects Dose Modification Lapatinib

Full dose

Capecitabine Full dose

Full dose Full dose Full dose Discuss with consultant

Interrupt until resolved to grade 0-1. Resume at full dose. Interrupt until resolved to grade 0-1. Resume with 25% dose reduction. Interrupt until resolved to grade 0-1. Resume with 50% dose reduction. Discontinue treatment

Full dose Full dose Discontinue regimen

Interrupt until resolved to grade 0-1. Resume with 25% dose reduction. Interrupt until resolved to grade 0-1. Resume with 50% dose reduction Discontinue treatment

Hand Foot Syndrome (GSK Guide) Grade 1 Grade 2 1st appearance

2nd appearance

3rd appearance

4th appearance Grade 3 1st appearance

2nd appearance

3rd appearance

Grade 4 1st appearance

2nd appearance

Discuss with consultant Discontinue regimen

Discontinue treatment permanently, or if consultant considers it is in the patient’s best interest to continue, interrupt until resolved to grade 0-1 and then resume with 50% dose reduction. Discontinue treatment

• Avoid Prolonged exposure to sunlight • Use broad spectrum sunscreen (containing titanium

oxide or zinc oxide) with high sun protection factor • Use hypoallergenic moisturisers and emollients that do

not contain perfumes or preservatives eg Vaseline.

Lapatinib

Full dose

Capecitabine

Full dose

Rash/Desquamation Supportive Care (GSK Guide)

Rash/Desquamation (GSK Guide)

Grade 1

Supportive treatment

Consider • Aqueous cream and emollients where dry skin

component • Mild to moderate steroid cream. Note topical steroids

can result in irritation/dryness and exacerbate symptoms • Topical antibiotics eg. clindamycin gel 1% for pustular


Side Effects Dose Modification rash

• Systemic antibiotics eg. doxycycline for pustular rash • Oral antihistamines may be useful where lesions are

pruritic • Topical and oral retinoids are NOT recommended

(lapatinib rash different to patho-physiology of acne vulgaris)

• Avoid prolonged exposure to sunlight. • Use broad spectrum sunscreen • Use hypoallergenic moisturiser

Lapatinib Continue treatment, If not improved after 2 weeks interrupt treatment for up to 14 days until resolved to grade 0-1. If resolved, start with 1250mg/day. If symptoms recur, interrupt treatment until resolved to � grade 1 then restart with 1000mg/day

Capecitabine

Full dose

As grade 1

Lapatinib Interrupt treatment. If symptoms resolve within 14 days, restart at full dose 1250mg/day

If symptoms recur, interrupt treatment until resolved to � grade 1 then restart with 1000mg/day

Capecitabine Full dose

As for Grade 1 • Consider short course of oral corticosteroids for

maculopapular rash • Consult dermatologist for difficult to treat or unresponsive

skin rashes

Rash/Desquamation (GSK Guide) Grade 2 Lapatinib SPC states that discontinuation or interruption of lapatinib should be considered for events � grade 2. Dosing may be restarted at 1250mg/day when toxicity improved to � grade 1. If toxicity recurs restart at 1000mg/day. Expanded guidance in this table is provided by GSK based on information from the clinical development programme.

Supportive treatment Rash/Desquamation (GSK Guide) Grade 3 See notes for grade 2

Grade 3 Supportive treatment

Rash/Desquamation (GSK Guide) Grade 4 Grade 4 rash has not been reported

Lapatinib

Interrupt treatment. If resolved within 14 days restart with 1250mg/day If symptoms recur interrupt treatment until resolved to � grade 1 and restart at 1000mg/day.

Capecitabine

Full dose


Side Effects Dose Modification Rash/Desquamation (GSK Guide)

Grade 4 Supportive treatment

As for Grade 3

Other Toxicities (SPC) NCICTC Any toxicity � grade 2

Lapatinib

Discuss with consultant Consider interruption or discontinuation of lapatinib. Dose can be restarted at 1250mg/day when toxicity resolves to grade 1 or less. If toxicity recurs, then interrupt until resolved then lapatinib can be restarted at lower dose (1000mg/day).

Capecitabine


28. Lapatinib plus Aromatase Inhibitor (CTIS: )

Secure Cancer Drugs Fund approval prior to starting treatment Lapatinib 1500mg (six tablets) ONCE a day as a single dose Days 1 to 21 ie continuously Aromatase Inhibitor according to standard option for clinical setting

Interval between cycles: Continuous treatment, repeat test every 21 days Number of cycles: Apply to Cancer Drugs Fund for Postmenopausal patients with HER2 positive hormone receptor positive, metastatic breast cancer for whom chemotherapy is not currently intended.

Continue until disease progression Tests before starting course of chemo: FBC, U&Es, Crcl (calculated), LFTs

SPC states do not give to patients with LVEF below lower limit of normal

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Crcl (calculated, LFTs Monitor for signs of pulmonary toxicity (dyspnoea, fever, cough) including interstitial lung disease and pneumonitis.

Supportive drugs with each cycle: Low risk antiemetics as per NWLCN guidelines or as per local policy

Loperamide if necessary, chlorhexidine mouth wash





Additional information: Administration notes: Lapatinib The lapatinib daily dose should not be divided. Lapatinib should be taken either at least one hour before, or at least one hour after food. To minimise the variability in the individual patient, administration of lapatinib should be standardised in relation to food intake, for example always be taken before a meal. Missed doses should NOT be replaced and the dosing should resume with the next scheduled daily dose. Interactions with lapatinib: Lapatinib is predominantly metabolised by CYP3A and is a substrate for the transport of proteins Pgp and BCRP. See SPC for drugs that are affected if co-administered. Solubility of lapatinib is pH dependent. Avoid substances that increase gastric pH as lapatinib absorption may be affected. Lapatinib inhibits CYP3A4 and CYP2C8. See SPC for drug interactions. Bioavailability of lapatinib is increased up to 4 times by food depending on eg. the fat content in the meal. Avoid grapefruit juice during treatment with lapatinib.

Dose modifications: See table page 29. Eribulin 1.4 Day 1+8 (Halaven)

Secure Cancer Drugs Fund approval prior to starting treatment Eribulin Mesylate 1.4mg/m2 IV bolus Day 1 and 8 All doses expressed in mg of eribulin mesylate 1.4mg eribulin mesylate is equivalent to 1.23mg/m2 eribulin

Interval between cycles: Repeat every 21 days Number of cycles: Secure approval from Cancer Drugs Fund for patients with locally advanced or metastatic breast cancer who have progressed after at least two chemo regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane (unless patient was unsuitable for these treatments) 6 cycles Tests before starting course of chemo: FBC, U&Es, Mg, LFTs

SPC says do not initiate eribulin unless neutrophils �1.5 x 109/L and platelets �100 x 109/L SPC recommends ECG monitoring if eribulin is initiated in patients with congestive heart failure bradyarrhythmias, medicines known to prolong QT interval. See SPC for information. Hypokalemia and hypomagnesemia should be corrected before starting treatment.

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, Mg, LFTs. Monitor for signs of peripheral neuropathy.

Supportive drugs with each cycle: Moderate risk antiemetics as per NWLCN guidelines of as per local policy


Chemotherapy alert card (NWLCN)




Dose: The USA prescribing information refers to doses of eribulin as the mesylate salt; ie full dose: eribulin mesylate 1.4mg/m2 and reduced doses of 1.1mg/m2 and 0.7mg/m2. In the phase III EMBRACE trial and the corresponding publication (Lancet 2011; 377: 914-23), the doses referred to throughout are also that of the eribulin mesylate. However the EU prescribing information refers to doses as 1.23mg/m2 eribulin (equivalent to 1.4mg/m2 eribulin mesylate). The vial is labelled with the mg/ml of eribulin NOT eribulin mesylate. Administration notes: SPC states there is no experience of using eribulin with anti HER2 therapy in clinical trials. Eribulin is eliminated through biliary excretion (up to 70%). Transport protein involved is not known. It is not recommended to use inhibitors of hepatic transport proteins with eribulin. See SPC. Concomitant treatment with enzyme inducers is not recommended. See SPC

Dose modifications: Table: Eribulin Side-Effect: Eribulin Dose Modification (SPC 25.03.11) Haematology Neutrophils Platelets x109/L x109/L �1.0 and �75 <1.0 or <75 Neutrophils <0.5x109/L } lasting more than 7 days } OR } Neutrophils <1.0x109/L, } neutropenia complicated by fever or } infection } OR } Platelets <25x109/L thrombocytopenia } OR } Platelets <50x109/L } thrombocytopenia complicated by }haemorrhage or requiring blood or platelet transfusionhaemorrhage or requiring blood or } platelet transfusion }

Full dose. Do not treat below these levels Delay treatment until recovered to above these levels then reduce according to criteria below. 1st Occurrence Delay until recovered to above levels then resume with eribulin mesylate 1.1mg/m2 2nd Occurrence If adverse reactions recurs despite dose reduction to 1.1mg/m2. Delay until recovered to neutrophils �1.0 and platelets �75 then resume with eribulin mesylate 0.7mg/m2. 3rd Occurrence If adverse reaction recurs despite dose reduction to 0.7mg/m2. Consider discontinuation of eribulin.

Renal Impairment Crcl �40mls/min

<40mls/min

Full dose SPC states dose reduction may be required. Optimal dose in this group of patients not established.


Side-Effect: Eribulin Dose Modification (SPC 25.03.11) Hepatic Impairment Impaired liver function due to metastases Mild hepatic impairment; due to metastases. Child-Pugh A Moderate hepatic impairment due to metastases. Child-Pugh B Severe hepatic impairment due to liver metastases. Child-Pugh C Impaired liver function due to cirrhosis

Bilirubin >1.5 x ULN

ALT or AST >3.0 x ULN

Dose reduce to eribulin mesylate 1.1mg/m2 day 1 and 8 Dose reduce to eribulin mesylate 0.7mg/m2 day 1 and 8 This group has not been studied so no dose recommendations can be made. SPC states: This group has not been studied. Doses used above in liver impairment due to metastases may be used in mild to moderate impairment but close monitoring is advised as doses may need to be adjusted. SPC states these patients have higher incidence of Grade 4 neutropenia – but data are limited. SPC states these patients experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Non Haematological Side Effects including peripheral neuropathy Any grade 3 or 4 side-effect in previous cycle

1st occurrence. Delay until recovery then resume with eribulin mesylate 1.1mg/m2 day 1 and 8 2nd occurrence despite dose reduction to 1.1mg/m2. Delay until recovered then resume with Eribulin mesylate 0.7mg/m2 day 1 and 8. 3rd occurrence despite dose reduction to 0.7mg/m2 Consider discontinuation

Peripheral Neuropathy

Dose reduce as above for none haematological side effect. In clinical trials patients with pre-existing neuropathy > grade 2 were excluded. Eribulin trial patients with pre existing neuropathy grade 1 or 2 were no more likely to develop new or worsening symptoms than those who entered study without the condition.


31. Everolimus F or ‘Additional Private Care’ unless local NDP approved/PCT agreement to fund

Everolimus 10mg Oral once a day Days 1 to 28 Swallow whole with glass of water Exemestane 25mg Oral once a day Day 1 to 28 After the same meal each day Interval between cycles: Continuous treatment of both drugs until progression

Repeat tests every 28 days Number of cycles: Patients with hormone receptor positive, HER2 negative

advanced breast cancer in combination with exemestane in post menopausal women without symptomatic visceral disease after recurrence or progression following non steroidal aromatase inhibitor.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Tests before starting course of chemo: FBC, U&Es, LFTs, fasting blood glucose, chest X-Ray, serum cholesterol and

triglycerides. Hep-B serology in all patients at risk of Hep-B infection, (eg IV drug users). Treat existing infections before commencing treatment.

Tests to OK/confirm each cycle of chemo: FBC, U&Es, LFTs (everolimus) Fasting blood glucose every 4 weeks

Serum cholesterol and triglycerides every 4 weeks. Chest X-Ray every 4 weeks. If new respiratory symptoms do CT scan and pulmonary function tests in view of risk of pneumonitis

Supportive drugs with each cycle: No routine supportive drugs Patient information: Chemotherapy treatment booklet (local information/Macmillan) Your chemotherapy record (NWLCN red book) NWLCN Chemotherapy alert card

Macmillan drug specific information sheets and information prescriptions as appropriate NWLCN Neutropenia DVD

Additional information: Everolimus Swallow everolimus whole with a glass of water, with or without food, at the same time each day. Do not crush or chew. If a dose is missed, do not take and additional dose but take the usual prescribed next dose. Everolimus has immunosuppressant properties and may predispose patients to infections including opportunistic pathogens. Infections are very common in patients taking everolimus, these may include pneumonia, other bacterial infections, invasive fungal infections and viral infections including reactivation of Hepatitis B virus Refer Hep-B carriers to Hepatology team for consideration of antiviral prophylaxis. Patient should be advised to report promptly any new/worsening respiratory symptoms. Avoid live vaccines during treatment. Patient advice; ensure patient has patient information leaflet covering

• Signs and symptoms of infection, anaemia, thrombocytopenia • Dietary and exercise advice for lipid abnormalities


• Signs and symptoms of raised blood glucose levels • Seek medical advice if become short of breath or difficulty breathing • Encourage good oral hygiene avoid alcohol based mouthwashes. • Hygiene advice because at increased risk of infection eg hand washing, avoid raw

foods, avoid cleaning up after pets/cat litter, avoid visits to developing countries • Emphasise importance of prompt reporting of signs and symptoms of rash

Dose modifications: Table: Everolimus Side Effect (Everolimus) Dose Modification (Ref: Novartis a practical guide to afinitor) Haematology Neutrophils (x109/L) �1.0 0.5-0.9 1st occurrence

Recurrence

<0.5 1st occurrence

Recurrence

Platelets (x109/L) �75 �50-74 1st occurrence

Recurrence

�25-49 1st occurrence

Recurrence

<25 1st occurrence

Haemoglobin �9 g/dL <9 g/dL

Full dose. Withhold treatment until platelets �75 and neutrophils �1.5, then restart at initial full dose If recurs withhold until platelets �75 and neutrophils �1.5 then resume at reduced dose everolimus 5mg once a day For febrile neutropenia withhold until platelets �75 and neutrophils �1.5, then resume at reduced dose. If neutropenia recurs discontinue treatment Withhold treatment until platelets �75 and neutrophils �1.5 then restart at reduced dose everolimus 5mg once a day. If recurs (neutrophils <1.0), discontinue treatment. For febrile neutropenia (life threatening), discontinue treatment. Full dose. Withhold treatment until platelets �75 and neutrophils �1.0 then restart at initial full dose If recurs withhold until platelets �75 and neutrophils �1.5 then resume at reduced dose everolimus 5mg once a day Withhold treatment until platelet �75 and neutrophils �1.0 then restart at reduced dose everolimus 5mg once a day. If recurs (platelets 25-49), discontinue treatment. Discontinue treatment Full dose. Do not give until recovered to above this level

Renal Function CrCl �25mls/min

SPC states no dose adjustment required

Hepatic Function Child-Pugh Class B

(Moderate hepatic impairment)

Child-Pugh Class C (Severe hepatic impairment)

Reduce dose to Everolimus 5mg once a day Everolimus not recommended. Consider Hep-B reactivation as cause of deranged LFTs on treatment


Side Effect (Everolimus) Dose Modification (Ref: Novartis a practical guide to afinitor) Non Infectious Pneumonitis See SPC for diagnosis

Grade 1

Grade 2

Grade 3

Grade 4

Continue everolimus. Monitor as per trust guidelines. CT scan and pulmonary function test (PFT). Repeat chest X-ray/CT scan every 2 cycles until to baseline Everolimus; Reduce dose to 5mg once a day until improvement to � grade 1; consider interruption if symptoms are troublesome. Discontinue everolimus if recovery to � grade 1 is not evident within in 3 weeks. Treat symptomatically; prescribe corticosteroids if cough is troublesome. Monitor as per trust guidelines/specialist advice. CT scan and PFTs. Repeat chest X-ray/CT scan every 2 cycles until to baseline. Consider bronchoscopy. Everolimus; Interrupt treatment improvement to � grade 1; Restart everolimus within 2 weeks at reduced dose (5mg once a day) if clinical benefit is evident. Treatment; Prescribe corticosteroids if infectious aetiology is ruled out. Taper as clinically indicated. Monitor as per trust guidelines/specialist advice. CT scan and PFTs. Repeat chest X-ray/CT scan every 2 cycles until to baseline. Bronchoscopy required Everolimus; Discontinue everolimus Treatment; Prescribe corticosteroids if infectious aetiology is ruled out. Taper as clinically indicated. Monitor as per trust guidelines/specialist advice. CT scan and PFTs. Repeat chest X-ray/CT scan every 2 cycles until to baseline. Bronchoscopy required

Infections NB. Check SPC for drug interactions between antibacterials, antifungals and antivirals Infections Before treatment On treatment Grade 1 Be aware of risk of atypical infections Grade 2 Treat localised infection with local intervention indicated Be aware of risk of atypical infections

Be aware of risk of atypical infections Be aware of risk of reactivation of Hepatitis B Treat appropriately BEFORE starting treatment. Refer Hep-B carriers to Herpetology team for consideration of antiviral prophylaxis. Everolimus; Continue with same dose, No treatment necessary. Everolimus; Maintain dose if tolerable. If not tolerated, withhold until recovered to � grade 1, then restart with same dose. If symptoms return to grade 2, withhold until recovered to � grade 1, then restart with reduced dose everolimus 5mg once a day. If withheld >21 days, discontinue treatment.


Side Effect (Everolimus) Dose Modification (Ref: Novartis a practical guide to afinitor) Infections Grade 3 IV antibiotics as indicated, antifungal or antiviral intervention Be aware of risk of atypical infections Grade 4 Life threatening consequences such as septic shock, hypotension, acidosis or necrosis. Be aware of risk of atypical infections

Everolimus; Withhold until recovered to � grade 1, then restart with reduced dose everolimus 5mg once a day. If withheld >21 days, discontinue treatment. Discontinue everolimus treatment Institute appropriate therapy with ID advice

Stomatitis Grade 1 Minimal, normal diet Grade 2 Symptomatic; able to eat and swallow modified diet Grade 3 Symptomatic; unable to eat and swallow modified diet Grade 4 Symptomatic associated with life threatening consequences

Everolimus full dose. Symptoms; Non alcoholic mouthwash or 0.9& salt water Avoid alcohol and peroxide containing mouthwashes . Everolimus; Maintain dose if tolerable. If not tolerated, withhold until recovered to � grade 1, then restart with same dose. Symptoms; Topical analgesic mouth treatments. Topical corticosteroids. Antiviral therapy if herpetic infection confirmed. Antifungal therapy (topical preferred) may be administered on case by case basis. Avoid hydrogen peroxide, iodine and thyme derivatives. Everolimus; Withhold until recovered to � grade 1, then restart with reduced dose everolimus 5mg once a day. Symptoms; Topical analgesic mouth treatments. Topical corticosteroids. Antiviral therapy if herpetic infection confirmed. Antifungal therapy (topical preferred) may be administered on case by case basis. Avoid hydrogen peroxide, iodine and thyme derivatives. Discontinue everolimus treatment Institute appropriate therapy with ID advice (see grade 3)

Rash Grade 1

Grade 2

Everolimus; continue full dose. Mild lesions may resolve spontaneously; no specific treatment required Everolimus; Maintain dose if tolerable. If patient is unable to tolerate the toxicity, withhold until recovered to � grade 1, then restart with same dose. If toxicity returns to grade 2, withhold until recovered to � grade 1, then restart with reduced dose everolimus 5mg once a day. Treatment; Topical treatment with a product containing benzoyl peroxide and antibiotic initially (discuss with ID). Some patient with acne before starting everolimus, benefit from topical as well as oral antibiotic therapy (discuss with ID). Avoid retinoids as they may disrupt skin integrity and introduce infection.


Side Effect (Everolimus) Dose Modification (Ref: Novartis a practical guide to afinitor) Rash

Grade 3

Grade 4

Everolimus; Withhold until recovered to � grade 1, then restart with reduced dose everolimus 5mg once a day Treatment; As grade 2 above Everolimus; Discontinue everolimus Treatment; As grade 2 above

Lipids Hypercholesterolaemia (HCE) Hypertriglyceridaemia (HT) Grade 1 HCE >ULN-7.75mmol/L and/or HT > ULN – 2.5xULN Grade 2 HCE 7.75-10.34mmol/L and/or HT 2.5-5.0xULN Grade 3 HCE 10.34-12.92mmol/L and/or HT 5.0-10xULN Grade 4 HCE >12.90mmol/L and/or HT >10xULN

Monitor and institute therapy to correct abnormalities. Full dose everolimus Treat hyperlipidaemia in line with trust guidelines. Triglycerides >5.6mmol/L are at risk of pancreatitis, treat urgently. Maintain dose if tolerated. If not tolerated, hold until recovered to � grade 1 then restart at same dose. Treat hyperlipidaemia in line with trust guidelines. Triglycerides >5.6mmol/L are at risk of pancreatitis, treat urgently. Withhold until recovered to � grade 1 then restart at reduced dose everolimus 5mg once a day or discontinue as per clinical judgement. Treat hyperlipidaemia in line with trust guidelines. Triglycerides >5.6mmol/L are at risk of pancreatitis, treat urgently. Discontinue everolimus

Blood Glucose Hyperglycaemia At all grades treat according to Trust hyperglycaemia guidelines Grade 1 ULN-8.9mmol/L Grade 2 8.9-13.9mmol/L Grade 3 13.9-27.8mmol/L Grade 4 >27.8mmol/L

Monitor and institute therapy to correct abnormalities. Hyperglycaemia prior to treatment commencing should be corrected if possible before starting everolimus. Full dose everolimus All grades treat in line with Trust hyperglycaemia guidelines Treat hyperglycaemia in line with trust guidelines. Maintain dose if tolerated. If not tolerated, withhold until recovered to � grade 1 then restart at same dose. Treat hyperglycaemia in line with trust guidelines. Withhold until recovered to � grade 1 then restart at reduced dose or discontinue as per clinical judgement Treat hyperglycaemia in line with trust guidelines. Discontinue everolimus


Side Effect (Everolimus) Dose Modification (Ref: Novartis a practical guide to afinitor) Interactions Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided

See SPC for guidance

Wound Healing

Everolimus is associated with impaired wound healing. Care should be exercised in pre surgical patients or patients with other wounds

Monoclonal Antibodies – Metastatic Breast Cancer Trastuzumab (Herceptin), Anti-c-erbB2/Her2 epidermal growth factor receptor antibody Available according to NICE guidance; either with taxane/paclitaxel as first line metastatic treatment where anthracyclines are not appropriate, or single agent as 3rd line after anthracyclines and taxanes (and endocrine therapy if ER positive). Not to be used beyond progression except where progression is limited to the CNS. 32a. Trastuzumab weekly (CTIS Load:788 Maint:787) Trastuzumab 4mg/kg IV infusion Day 1 only loading dose Trastuzumab 2mg/kg IV infusion Day 8 then weekly as Repeat once each week. maintenance 32b. Trastuzumab every 2 weeks (CTIS Load:343 Maint:342) Trastuzumab 6mg/kg IV infusion Day 1 only loading dose Trastuzumab 4mg/kg IV infusion Day 14 then every 14 days as Repeat every 14 days. maintenance 32c. Trastuzumab every 3 weeks (CTIS Load:802 Maint:801) Trastuzumab 8mg/kg IV infusion Day 1 only loading dose Trastuzumab 6mg/kg IV infusion Day 21 then every 21 days as Repeat every 21 days. maintenance Interval between cycles: As above Number of cycles: SPC recommends until progression of disease. Test before starting course of chemo: Baseline cardiac assessment ECHO – see SPC

for action if cardiac function deteriorates. FBC Tests to OK/confirm chemo: FBC and cardiac assessment as per adjuvant; at 4

months (cycle 6) and 8 months (cycle 12) then every 6 months or as clinically indicated. See LCA clinical guidelines.

Supportive drugs with each cycle: None Patient information: Chemotherapy treatment booklet (local information/Macmillan)





Additional information: Scheduling:

If given with chemotherapy (SPC refers to paclitaxel) the SPC recommends the first dose of trastuzumab is given the day before the chemotherapy, if well tolerated then on subsequent cycles the Paclitaxel dose may be given immediately after the trastuzumab dose.

Cardiotoxicity (SPC): Trastuzumab is associated with cardiotoxicity. The risk of cardiotoxicity is greatest when combined with anthracyclines. Do not use concurrently with anthracyclines except in well-controlled clinical trial with cardiac monitoring (SPC). Avoid anthracyclines for 24 weeks after trastuzumab (SPC).

Administration notes: Infusion reactions may occur including dyspnoea, hypotension, wheezing, bronchospasm, anaphylaxis, respiratory distress, tachycardia, angioedema and urticaria. Usually mild to moderate and occurs within 2.5 hours of staring the first infusion. The patient should be observed for 6 hours after the 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 the subsequent doses.

Dose Modifications: (SPC) No reductions in the dose of trastuzumab were made during clinical trials. Patients

may continue trastuzumab during periods of reversible chemotherapy induced myelosuppression.

BREAST CANCER Section by: Dr Suzy Cleator, Dr Pippa Riddle, Dr Charles Lowdell, Professor Charles Coombes, Professor Justin Stebbing, Dr Riz Ahmed, Dr Carlo Palmieri Version control sheet Version Date Author Status Comment

1.00 23.11.05 Susan Whear Draft 1.01 23.11.05 Susan Whear Replaced Previously approved version 2.00 Susan Whear Draft 3.00 27.02.07 Susan Whear Draft 3.01 10.07.07 Susan Whear Replaced Previously approved version 3.02 25.09.07 Susan Whear Replaced Previously approved version 4.00 04.06.08 Susan Whear Draft 4.01 04.06.08 Susan Whear Replaced Previously approved version 5.00 05.10.09 Susan Whear Draft 5.01 14.07.10 Susan Whear Draft 5.02 22.07.10 Susan Whear Replaced Previously approved version 6.00 20.09.10 Susan Whear Draft 6.01 20.09.10 Susan Whear Draft 7.00 08.10.12 Susan Whear Draft Version control box added.

Haematology dose modifications made clearer Generic liver function dose adjustments removed and added to each regimen Neo-adjuvant & adjuvant regimens combined Miltefosine removed Trastuzumab monitoring frequency adjusted in line with LCA Docetaxel/Capecitabine; capecitabine dose reduced in line with LCA Abraxane added


Bevacizumab/Docetaxel removed Bevacizumab/Paclitaxel; paclitaxel dose reduced in line with LCA Bevacizumab/capecitabine added Vinorelbine SPC weekly regimen removed Single agent capecitabine starting dose increased back to 2500mg/sqm/day in line with LCA MV-Carbo; Mitomycin dose increased in line with LCA Gemcitabine-Carboplatin starting doses increased (but reduce in heavily pre-treated) Lapatinib/capecitabine now CDF and more detailed dose modification tables Eribulin added via CDF Everolimus-exemestane added for additional private care Everolimus dose reductions in line with Novartis ‘A practical guide to afinitor’ Lapatinib-AI added in line with CDF.

7.01 24.10.12 Susan Whear APPROVED 24.10.12 approved Dr S Cleator

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