breast regimens v5.2 nwlcn 22jul10

Breast regimens v5.2 NWLCN 22Jul10 Breast of 38

Breast Cancer Chemotherapy Protocols Section by: Dr Suzy Cleator, Dr Pippa Riddle, Dr Charles Lowdell, Professor Charles Coombes, Professsor Robert Leonard, Dr Justin Stebbing, Dr Riz Ahmed, Dr Carlo Palmeri Section last updated: 14th July 2010 Last corrected: 22nd July 2010 Approved by Oncology Breast Lead Clinican Dr S Cleator Date: Approved by NWLCN Breast Tumour Group: Mr R Al Mufti Date: Review date: June 2011 I N D E X Page 1. Dose Modifications and GCSF Adjuvant/Neo-adjuvant & Metastatic Regimens 3-5 Early Invasive Breast Cancer Neo-adjuvant Chemotherapy 2. First line; a) FEC-75 IV CTIS: 74/1227 5 3. FEC Failure; a) Docetaxel-100 CTIS: 649 6

4. Neoadjuvant Monoclonal antibodies see adjuvant 7 Adjuvant Chemotherapy5. Node positive first line taxane

a) FEC-100/Docetaxel-100 CTIS: 1210/1207 8 b) TC Docetaxel/Cyclophos (Additional Private Care) 9 c) TCH Doce/Carbo/Trastuzumab (Additional Private Care) 9

6. Node negative a) FEC-75-1 day CTIS: 74 11

7. Options for elderly a) AC 60/600 1 day CTIS: 496 11

b) FEC-60 CTIS: 567 12 8. Avoid alopecia (non anthracycline)

a) CMF Day 1+8 CTIS: 71/1200 12

9. Adjuvant Monoclonal antibodies a) Trastuzumab CTIS: 1157/1158 13

10. Locally Recurrent Breast Cancer a) Miltefosine topical solution 6mg/ml (6%) 14


Page Metastatic Breast Cancer Metastatic Chemotherapy 15 11. Anthracycline regimens

a) AC 60/600 1 day CTIS: 496 15 b) Epirubicin-30 weekly CTIS: 1323 16 c) MC-60/600 (Cyclo plus Lipo Dox/myocet) CTIS: 1361 16

12. Taxane regimens

a) Docetaxel 75-100 CTIS: 17 b) Docetaxel/Capecitabine CTIS 18 c) Paclitaxel-90 weekly CTIS: 1099 19 d) Paclitaxel/Gemcitabine CTIS: 1291 20 e) Bevacizumab/Docetaxel (Additional Private Care) 21 f) Bevacizumab/Paclitaxel (Additional Private Care) 22

13. Vinorelbine

a) Vinorelbine 25 IV weekly CTIS: 26 b) Vinorelbine-30 Day 1 and 8 CTIS: 223 26

c) Vinorelbine two weekly CTIS: 703 27 d) Vinorelbine-60 ORAL CTIS: 1230 27

14. Capecitabine a) Capecitabine 2500 CTIS: 200 29

15. Carboplatin a) MV-Carbo CTIS: 1164 31 Gemcitabine/Carboplatin see page 33

16. CMF (Non classical) a) CMF-750 IV CTIS: 1229 32

17. Gemcitabine a) Gemcitabine/Carboplatin (Additional Private Care) 33

Paclitaxel/Gemcitabine (see page 19)

18. Lapatinib a) Lapatinib/capecitabine (Additional Private Care) 34

19. Monoclonal Antibodies a) Trastuzumab CTIS: 788/787 37


Breast Cancer Chemotherapy ProtocolsSection by: Dr Suzy Cleator, Dr Pippa Riddle, Dr Charles Lowdell, Professor Charles Coombes, Professor Robert Leonard, Dr Justin Stebbing, Dr Riz Ahmed, Dr Carlo Palmeri Section last updated: 22nd July 2010 Last corrected: 22nd July 2010 Approved by Oncology Breast Lead Clinican: July 2010 Approved by NWLCN Breast Tumour Group: July 2010 Review date: June 2011 1. 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 NOT recommended with any 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 For all adjuvant/neoadjuvant docetaxel use a single dose of pegfilgrastim (neulasta).

• Pegfilgrastim (neulasta) should NOT be used to treat neutropenic sepsis. • 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.

• 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 < 1.0 and <100

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 CancerGCSF 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 1.0-1.49 and/or 75-99

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.

Liver Function TestsAnthracycline or docetaxel containing regimens

Bilirubin Transaminases Alkaline Phosphate

% Dose Reduction

<1.5 x ULN And/or <2.0 x ULN and/or <2.5 x ULN Full dose 1.5 - 2.0 x ULN And/or 2.0 - 3.5 x ULN and/or 2.5 - 6.0 x ULN 25% reduction >2.0 x ULN And/or >3.5 x ULN and/or >6.0 x ULN Omit drugs 2. Neo-adjuvant Chemotherapy Regimens First Line 2a. FEC-75 (CTIS: 74/1227) 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: 6 cycles. Switch to docetaxel after 4 cycles if response is sub-

optimal or node positive Tests before starting course of chemo: FBC, U&Es, LFTs, cardiac assessment,

ECG Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: 5HT3 antiemetics as per local protocol Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (NWLCN red book) BACUP information sheet(s) 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 page 6


Table: FEC Side effect: FEC Dose Modification Haematology

See relevant haematological toxicity table page 3

Renal Function (NLCN) Crcl

≥50mls/min 30-50mls/min

<30mls/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 Do not give regimen

Hepatic Function

See Guidance page 5

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

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

Second Line 3a. Docetaxel 100 (CTIS: 649) Dexamethasone 8mg BD Oral Days 0 to 2 Docetaxel 100mg/m2 IV over 1 hour Day 1 Interval between cycles: Repeat every 21 days Number of cycles: 4 cycles after 4 cycles of FEC-75 if response is sub optimal or if

node positive 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: 5HT3 antiemetics as per local protocol,

dexamethasone as above Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (NWLCN red book) BACUP information sheet(s) 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 below 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

Hepatic Function See table page 5

Neurotoxicity ≤ Grade 2≥ Grade 3

Full dose Omit docetaxel

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.

4. Monoclonal Antibodies – see Adjuvant page 9


Adjuvant Breast Cancer Regimens Surgery followed by radiotherapy then chemotherapy then (in oestrogen receptor positive patients only) followed by endocrine therapy. 5. Adjuvant Chemotherapy Regimens Node Positive Patients First line choice for NODE positive patients is an anthracycline/taxane containing regimen. In the NWLCN this is FEC-100/Docetaxel-100 5a. 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 Interval between cycles: Repeat every 21 days Number of cycles: 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: 5HT3 antiemetics as per local protocol

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

BACUP information sheet(s) Additional information:

Administration notes: See FEC-75 page 5 Dose modifications: See FEC table page 6 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: 5HT3 antiemetics as per local protocol,


Your chemotherapy record (NWLCN red book) BACUP information sheet(s) Additional information: Administration notes: See notes for Docetaxel-100 page 6 Dose modifications: See Docetaxel table page 6


5b. 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 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: 5HT3 antiemetics as per local protocol,


Your chemotherapy record (NWLCN red book) BACUP information sheet(s) Additional information: Administration notes: See notes for Docetaxel-100 page 6

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. clinical Oncology 2009 S.Jones et al 5c. Docetaxel-75/Carboplatin 6AUC/Trastuzumab (CTIS: )

For ‘Additional Private Care’ unless local NDP approved/PCT agreement to fund and 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 onwards

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). 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 maintanence FBC every 3 months.

Cardiac assessment every 3 months. If LVEF drops by 10% (ejection) points or more from baseline and to below 50% then trastuzumab treatment should be suspended.

Supportive drugs with each cycle: 5HT3 antiemetics as per local protocol, dexamethasone as above


BACUP information sheet(s) Additional information: Administration notes: Docetaxel see page 6

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


6. Node Negative Patients Non-taxane regimens for Node negative patients off trial and node positive patients unable to receive taxanes. 6a. 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: 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: 5HT3 antiemetics as per local protocol Patient information: Chemotherapy treatment booklet (local information)


Administration notes: See notes for FEC-75 page 5 Dose modifications: See FEC table page 6 7. Regimen for the Elderly/Frail7a. 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: 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: 5HT3 antiemetics as per local protocol



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 page 12 Reference: J. Clin Oncol 1990;8(9):1483-96


Table: AC Side effect: AC Dose Modification Haematology

See relevant haematological toxicity table page 2/3

Hepatic Function

See table page 5

Renal Function ≥50mls/min

30-50mls/min

Doxorubicin Full dose Full dose

Cyclophosphamide Full dose 25% dose reduction

<30mls/min Do not give. Discuss with consultant Non Haematological Toxicity CTC Grade ≥ Grade 2

Delay chemo until resolved Restart with 25% dose reduction in all drugs

7b. 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: 5HT3 antiemetics as per local protocol


BACUP information sheet(s) Additional information: See FEC-75 page 5 Dose modifications: See FEC table page 6 Reference:

8. Non Anthracycline Regimen (To avoid alopecia or if unable to receive anthracyclines) 8a. 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: FBC, U&Es, LFTs Supportive drugs with each cycle: Low risk antiemetics



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 30 9. Monoclonal Antibodies (Adjuvant)Adjuvant Trastuzumab (Herceptin)Available according to NICE guidance No. 107 (August 2006) for early stage HER-2 positive breast cancer following surgery, chemotherapy (neo-adjuvant or adjuvant) and radiotherapy if applicable. 9a. 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 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). 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: FBC every 3 months. Cardiac assessment every 3 months.

If LVEF drops by 10% (ejection) points or more from baseline and to below 50% then trastuzumab treatment should be suspended.

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


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.

10. Locally Recurrent Breast Cancer Miltefosine 6% Topical Solution This product is NOT available in the UK. It can be imported via IDIS from Baxter, Germany. Product is supplied with information in German. No SPC is available so information has abeen based on RCT published in JCO 19 2001 pg 4150-9. 10a. Mitefosine 6% topical solution

IndicationSuperficial or flat (less than 1cm depth), non infected, inoperable progressive breast cancer skin lesions, not manageable by radiotherapy or systemic endocrine or chemotherapy treatment.

DOSE WEEK 12 drops Miltefosine 6% solution per 10cm2 of skin ONCE A DAY. Area should include the affected area plus a margin of 3cm around each lesion to ensure any invisible cutaneous infiltration is treated. If no intolerable skin reactions occur, dose may be increased as stated below.

DOSE WEEK 2: If no intolerable skin reactions dose may be increased to 2 drops Miltefosine 6% solution per 10cm2 of skin TWICE A DAY. Area includes affected area plus 3cm margin described above.

Interval between cycles: Week 1: apply once a day

Week 2: if no intolerable skin reactions apply twice a day from week 2 onwards

Number of cycles: Continuous treatment until progression or intolerable local skin reaction. If complete response occurs, continue treatment for at least a further 4 weeks then at clinical discretion.

Tests before starting cycle: Physical examination, adequate renal and hepatic function.

Test to confirm each cycle: Physical examination, adequate renal and hepatic function.

Supportive drugs: No routine supportive drugs Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (WLCN red book) BACUP information sheet(s)

Additional information: From JCO trial 2001 Presentation of Miltefosin 6% topical solution

Miltefosine 6% solution is a clear colourless and odourless, slightly viscous liquid. It is manufactured and supplied in a 10ml glass bottle with a dropper that allows the delivery of the solution in drops (approximately 38-40 drops/ml) and a box of disposable non sterile gloves.

Application of Miltefosine 6% topical solution


1. Was the affected area and put on one of the supplied gloves. 2. The calculated amount of solution should be carefully dropped on to the

affected area. 3. With the glove protected hand, gently massage the solution on to the affected

area and 3cms around the lesion. If the area is large, then the solution should be applied in several fractions.

4. Allow the skin to absorb the solution (approximately 1-2 minutes). 5. Cover the area, if necessary using gauze or a non occlusive medical dessing. 6. Discard the glove in a cytotoxic sharps bin.

Dose modifications: • Standard dose, duration and frequency may be modified if local skin reactions occur. • Before dose modification, apply an inert cream such as aqueous cream or petroleum

jelly for symptomatic treatment of cutaneous reactions such as dry skin, pruritis and desquamation, with a period of 2-3 hours between application of inert cream and miltefosine.

• If symptoms persist, modify schedule depending on type and severity of symptoms; either a reduction in number of drops or a delay of treatment.

• If dose reduction is necessary in the first week, then reduce standard dose by 50% (and apply twice a day) ie. same dose divided into 2 applications.

• If a dose is reduction is necessary after the first week then reduce dose at each application by 50% ie. total dose reduced by 50%.

• If necessary treatment may be stopped for up to a week to allow for improvement of symptoms. If the symptoms are still intolerable, then stop treatment.

Reference: JCO 19 2001 pg 4150-4159. Leonard R et al 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 paclitaxel 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. Start endocrine therapy once chemotherapy is complete. d) Bisphosphonates - Determined by the presence and burden of metastatic

bone disease 11. Anthracycline Regimens If no prior anthracycline or if >3-5 years since anthracycline chemotherapy given, consider re-challenge with anthracycline 11a. AC-60/600 1 day (CTIS: 496/1263) 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: 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: 5HT3 antiemetics as per local protocol



Administration notes: See notes for AC 60/600 1 day page 12 Dose modifications: See table AC/EC page 12 Reference: J. Clin Oncol 1990;8(9):1483-96 11b. 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: 5HT3 antiemetics as per local protocol



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 Epi table below Table: Epirubicin Side effect: Epirubicin Dose Modification Haematology


Liver function

See table page 5

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

11c. Myocet-Cyclo 60/600 (CTIS: 1361) Liposomal Doxorubicin (Myocet) Cyclophosphamide 600mg/m2 IV over 30 minutes Day 1 Liposomal Doxorubicin 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

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs


Supportive drugs with each cycle: 5HT3 antiemetics as per local protocol Patient information: Chemotherapy treatment booklet (local information)


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 T able: Myocet-Cyclophosphamide Side effect

Dose Modification (SPC)

Haematology


Renal function Doxorubicin is metabolised largely by the liver and excreted in the bile. Therefore dose modification is not required for patients with renal function impairment.

Hepatic functionBilirubin 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 1Grade 2Grade 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.

12. Taxanes If relapse after anthracycline or if relapse within 1 year of anthracycline: 12a. 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



BACUP information sheet(s) Additional information: Administration notes: See notes for Docetaxel-100 page 6

Dose modifications: See Docetaxel table page 7 12b. Docetaxel-75 plus Capecitabine (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 1250mg*/m2 Oral twice a day Day 1 to 14 Ie 2500mg/m2/day (*some clinicians may start capecitabine at 1000mg/m2) 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: 5HT3 antiemetics as per local protocol, loperamide and chlorhexidine mouthwash Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (NWLCN red book) BACUP information sheet(s) Additional information: Administration notes:

Docetaxel Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before, the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity reactions, therefore, the patient must be discharged with enough dexamethasone to take before their next cycle. Ensure patient understands how to take their steroids at home. Diabetic patients will need to monitor blood sugar levels more regularly and inform their doctor if they are having problems with the control of their blood sugar levels. IV dexamethasone should not be given to replace oral doses. Acute hypersensitivity reactions can occur, observe closely especially during the first two cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair loss and liaise with wig fitter. Scalp cooling should be offered. Capecitabine Patients must attend a nurse capecitabine clinic prior to cycles 1 and 2. Capecitabine tablets should be taken with water 30 minutes after food and approximately 12 hours apart. Patients must be given written and verbal information on capecitabine including how to take the tablets, when to stop (ie. In the event of toxicity and after 14 days), and whom to contact when side effects occur. Written information should be sent to the patient’s GP. Capecitabine interacts with warfarin 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.


12c. 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 Interval between cycles: Repeat every 7 days Number of cycles: 18 cycles Tests before starting course of chemo: FBC, U&Es, LFTs




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 ≥ 75 <1.0 <75

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

Thrombocytopenia <25 x 109/L

Febrile neutropeniaN <0.5 and fever >38oC

OrSepsis with grade 3/4

neutropenia

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 Delay until recovered then give Paclitaxel 20% dose reduction

Non Haematological Toxicities (excluding alopecia)

≤Grade 1Grade 2Grade 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 1Grade 2≥Grade 3

Full dose Next cycle give paclitaxel 20% dose reduction Stop paclitaxel. Discuss with consultant

12d. 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: FBC, U&Es, LFTs




Administration notes: Paclitaxel: See Paclitaxel page 19 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 Capecitabine/Paclitaxel table below Table: Gemcitabine/Paclitaxel Side effect: Gemcitabine/Paclitaxel Dose Modification Haematology


Renal Function Crcl ≥40mls/min

<40mls/min

Full dose Do not give

Hepatic Function

See table page 5

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


Bevacizumab (Avastin)Funding for Bevacizumab is not currently (June 2010) available on the NHS.

12e. Bevacizumab-Docetaxel For ‘Additional Private Care’ unless NDP approved/PCT agreement to fund

Bevacizumab 15mg/kg IV over 90 mins* Day 1 Dexamethasone 8mg Oral Twice a day For three days starting

the day before docetaxel Docetaxel 75-100mg/m2 IV over 1 hour Day 1

*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: Metastatic breast cancer;

Docetaxel up to 9 cycles Bevacizumab continue until disease progression

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 22 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: 5HT3 antiemetics as local protocol Chlorhexidine mouthwash 10mls QDS

Loperamide 2-4mg QDS PRN (Max 16mg/day) Patient information: Chemotherapy treatment booklet (local information) Your chemotherapy record book (NWLCN Red Book) BACUP sheets 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. Docetaxel see breast page:


Dose modifications/cautions: 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. Docetaxel see breast page

Reference: BO17708 Trial (AVADO) Avastin SPC September 2009 12f. Bevacizumab-10/ Paclitaxel-90 weekly

For ‘Additional Private Care’ unless NDP approved/PCT agreement to fund 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 90mg/m2 IV over 1 hour Day 1, 8 and 15 *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: Metastatic breast cancer; continue until disease progression 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 22 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: 5HT3 antiemetics as local protocol Chlorhexidine mouthwash 10mls QDS

Loperamide 2-4mg QDS PRN (Max 16mg/day) Patient information: Chemotherapy treatment booklet (local information) Your chemotherapy record book (NWLCN Red Book) BACUP sheets General advice on EGFR related skin reactions Additional information: Administration notes: Bevacizumab: See breast page: 21

Paclitaxel See breast page: 20 Dose modifications/cautions:

Bevacizumab See breast page: 23 Paclitaxel See breast page: 19

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

Second and subsequent occurrence of

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) ≥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 perforationGastro-intestinal perforation or dehiscence

Discontinue bevacizumab permanently and institute appropriate treatment

Wound healing complicationsPrevention 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 abscessFistula 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 HypertensionAsymptomatic, 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 HypertensionRequiring more than one anti-hypertensive or more intensive therapy than previously. Grade 4 HypertensionLife 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)

Reference:

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 13. 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. 13a. Vinorelbine-25 IV (SPC regimen) (CTIS: ) Vinorelbine 25mg/m2 (max 60mg) IV minibag over 10mins Day 1 Interval between cycles: Repeat every 7 days Number of cycles: 12cycles Tests before starting course of chemo: FBC, U&Es, LFTs



BACUP information sheet(s) Additional information: See page 28

Dose modifications: See page 28 13b. 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



BACUP information sheet(s) Additional information: See page 28

Dose modifications: See page 28


13c. 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




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/L36-50micromol/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

13d. Vinorelbine ORAL Single Agent (SPC regimen) Subject to local approval of oral formulation 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

Tests to OK/Confirm each cycle of chemo: FBC, U&Es, LFTs Supportive drugs with each cycle: Low risk antiemetics, consider prophylactic laxatives



Capsules should be swallowed whole with water, do not suck or chew as the 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 or oral vinorelbine is approximately 40% Dose modifications: See table below Vinorelbine dose table from SPC

Body Surface Area

m2Dose 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

T able: 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

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


Side effect: Vinorelbine Oral

Dose Modification

≥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 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 60mg/m2 Repeat every 7 days Vinorelbine 60mg/m2 Repeat every 7 days 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/L36-50micromol/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

14. Capecitabine14a. 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

>65 years consider 1000mg/m2 twice a day for 14 days 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, Loperamide,

Chlorhexidine mouth wash Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (NWLCN red book)


BACUP information sheet(s) Capecitabine patient diary Additional information:

Administration notes: CapecitabinePatients 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 T able: Breast/Capecitabine S ide Effects

Dose Modification

Haematology

See relevant haematological toxicity table page 2/3

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

Full dose 25% dose reduction Increased incidence of grade 3 and 4 adverse reactions with Crcl 30-50mls/min. Interrupt treatment promptly if grade 2,3 or 4 toxicity develops. 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 CYCLEContinue 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 CYCLEFull dose Full dose 25% dose reduction 50% dose reduction 25% dose reduction 50% dose reduction 50% dose reduction


15. Carboplatin15a. MV-Carbo (CTIS 1164)

Mitomycin C 6mg/m2 (max 14mg) 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 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: Low risk antiemetics Patient information: Chemotherapy treatment booklet (local information)


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

Dose modifications: See table below T able: MV-Carbo Side effect

Dose Modification (Adapted from Focus Trial)

Haematology


Renal function Crcl

≥60 mls/mim

50-59 mls/min

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

Hepatic functionBilirubin >30micromol/L

Do not give mitomycin and discuss with consultant


16. CMF If no prior alkylating agent 16a. 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 Interval between cycles: Repeat every 21 days Number of cycles: 6 cycles Tests before starting course of chemo: FBC, U&Es, LFTs




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 34 Table: CMF Side effect: CMF Dose Modification Haematology

See relevant haematological toxicity table page 4 Cyclophosphamide Full dose 25% dose reduction

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 (Drugs in Renal Failure 1999/WLCN) Crcl ≥60mls/min

30-59mls/min

<30mls/min Discuss with consultant Hepatic Function

See table page 4

Non Haematological Toxicity eg. mucositis CTC ≥ Grade 2

Delay until recovery then 25% dose reduction all drugs


17. Gemcitabine 17a. Gemcitabine – Carboplatin (CTIS: )

For ‘Additional Private Care’ unless local NDP approved/PCT agreement to fund Gemcitabine 800mg/m2 IV over 30 mins Days 1 and 8 Carboplatin 4x (GFR+25)mg IV over 1 hour 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: 5HT3 antiemetics as per local protocol Patient information: Chemotherapy treatment booklet (local information)

Your chemotherapy record (NWLCN red book) BACUP information sheet(s)

Additional information: Administration notesCarboplatin may cause allergic reactions and can occur within minutes of Administration. Gemcitabine should be administered over 30 minutes.

Dose modifications: See table Gem/Carbo page 27 Reference: Laessiq et al. BJCancer 1994 Nov; 70 (5):990-3 Dose reduced in line with recommendation for pre-treated patients


Table Gemcitabine-Carboplatin Side effect: Gem/Carbo Dose Modification (Adapted from OII trial) Haematology Neutrophils Plateletsx109/L x109/L Day 1 ≥1.5 and ≥100 <1.5 or <100

If ≤1 week delay:

If delay >1week but ≤2 weeksOr Neutropenic fever

Or Platelets <25 x109/L

If further recurrence despite 1st dose reduction

If further 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: 3AUC Once recovered give Gemcitabine: Day 1: 20% dose reduction Day 8: omit dose Carboplatin 3AUC 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

18. Lapatinib 18a. Lapatinib plus Capecitabine 2500 (CTIS: )

For ‘Additional Private Care’ unless local NDP approved/PCT agreement to fund 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 ie 28 doses in Food total

Tablets only available as 500mg and 150mg. Interval between cycles: Repeat every 21 days Number of cycles: Subject to local approval HER2 positive 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

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

Chlorhexidine mouth wash Patient information: Chemotherapy treatment booklet (local information)


Administration notes: CapecitabinePatients 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: Capecitabine; see capecitabine table page Lapatinib; see table below


T able: Lapatinib S ide Effects

Dose Modification

Haematology (lapatinib EAP) Neutrophils Platelets Hbx109/L x109/L x109/L ≥1.5 and ≥100 and ≥100 <1.5 or <100 or <100

1st appearance

2nd appearance

3rd appearance

4th appearance

Lapatinib

Full dose lapatinib Interrupt lapatinib until resolved to above these levels. Once recovered: Resume at 100% dose Resume at 100% dose or dose reduce to 1000mg/day Resume at 100% dose or dose reduce to 1000mg/day or 750mg/day -

Capecitabine

Full dose capecitabine

Interrupt capecitabine until resolved to above these levels. Once recovered; Resume at 100% or 75% dose Resume at 75% dose Resume at 50% dose

Discontinue permanently

Renal Function (lapatinib EAP)Crcl

≥51mls/min 30-50mls/min

<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 100% dose Resume at 100% dose or dose reduce to 1000mg/day Resume at 100% dose or dose reduce to 1000mg/day or 750mg/day

Full dose capecitabine 25% dose reduction Omit capecitabine

Hepatic Function (lapatinib EAP) Bilirubin

≤ 3xULN

> 3xULN

1st appearance

2nd appearance

3rd appearance

4th appearance

Full dose lapatinib Interrupt lapatinib until recovered to above this level. Once recovered: Resume at 100% dose Resume at 100% dose or dose reduce to 1000mg/day Resume at 100% dose or dose reduce to 1000mg/day or 750mg/day

Full dose capecitabine Interrupt capecitabine until resolved to above these levels. Once recovered; Resume at 100% or 75% dose Resume at 75% dose Resume at 50% dose

Discontinue permanently


Side Effects

Dose Modification

Hepatic Function (lapatinib EAP) Amino transferases (treatment related elevation) >2.5 x ULN

Discuss with consultant

Stop capecitabine until elevation resolved and discuss with consultant

Asymptomatic Cardiac Events Decreased left ventricular ejection fraction

Stop lapatinib, consult lapatinib SPC and discuss with consultant


Symptomatic Cardiac Events Interstitial Lung disease or Pneumonitits

Stop lapatinib, consult lapatinib SPC and discuss with consultant


Hand Foot Syndrome

See capecitabine table page 28

Diarrhoea

See capecitabine table page 28

Other Toxicities (SPC) NCICTC Any toxicity ≥ grade 2

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 lapatinib cn be restarted at lower dose (1000mg/day).


19. Monoclonal Antibodies 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) 19a. 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 19b. 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


19c. 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, repeat every

3 months – see SPC for action if cardiac function deteriorates. FBC

Tests to OK/confirm chemo: FBC and cardiac assessment every 3 months, Supportive drugs with each cycle: None Patient information: Chemotherapy treatment booklet (local 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 regimens v5.2 nwlcn 22jul10

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